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https://f1000research.com/articles/11-917/v1
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09 Aug 22
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{
"type": "Research Article",
"title": "Unmasking the cloak of comorbidities in OSA-association and their severity – a prospective observational study",
"authors": [
"Sindhu Kamath",
"B Venkat Naidu",
"Vishak Acharya K",
"Unnikrishnan B",
"B Venkat Naidu",
"Vishak Acharya K",
"Unnikrishnan B"
],
"abstract": "Background: Obstructive sleep apnoea (OSA) is a common sleep disorder with high prevalence in the community but highly underreported. It is also seen that a significant number of cases with OSA are associated with various comorbidities. The study objective was to estimate and assess the specific type and proportion of various comorbidities seen in association with OSA and association of severity of OSA with comorbidities. Methods: The study was a hospital-based descriptive study of 85 patients with OSA. Descriptive statistics were used to analyse the data and Chi-square test was done to find out the association. Results: The most common comorbidity associated with OSA was obesity (60%). Around half of the patients (49.4%) had severe OSA based on Apnea Hypopnea Index (AHI) scores. Statistically significant association was seen between presence of comorbidities, like diabetes and hypertension, and risk of OSA based on the snoring, tiredness, observed apnea, blood pressure (S.T.O.P) questionnaire. Conclusions: In our study, a significant proportion (73%) of patients with OSA had associated\n\ncomorbidities at the time of initial diagnosis. This indicates a delayed diagnosis as OSA is diagnosed only after multiple and irreversible comorbidities have developed. A majority (49%) had a severe OSA on initial presentation. This combination of multiple comorbidities and severe OSA at the time on diagnosis is reflective of a huge problem that is peculiar to OSA at large at a community level.",
"keywords": [
"OSA",
"Comorbidities",
"Polysomnography",
"STOP questionnaire"
],
"content": "Introduction\n\nObstructive sleep apnea (OSA) is defined as “repetitive episodes of complete (apnea) or partial (hypopnea) upper airway obstruction occurring during sleep. These events often result in reductions in blood oxygen saturation and are usually terminated by brief arousals from sleep.1” In 2007, the World Health Organization (WHO) conducted a study to find the prevalence of OSA in the world. The numbers came close to 100 million.2 However, a recent study in 2018 suggested that the numbers are almost ten times the previous findings.3\n\nThe prevalence is increasing with the increase of non-communicable diseases and the aging population.4 According to a study published in 2006, the prevalence of OSA in India was 13.7%.5 In contrast, recent literature quotes the prevalence of 34% in males and 17% in females in the United States of America.6 OSA is associated with many comorbidities such as diabetes mellitus, hypertension, thyroid disease, and gastroesophageal reflux disease (GERD).7\n\nOSA is a disease of growing concern because of its association with comorbidities, mortality, and morbidity, which can be prevented by early diagnosis and treatment of OSA. Early detection and effective therapy can reduce the subsequent complications and possibly avoid the progression to irreversible comorbidities.8 Presently, the majority of the OSA cases are diagnosed only after single or multiple comorbidities have been established. Clinically, when such patients with comorbidities are screened, OSA is suspected and eventually diagnosed. Some critical factors in this nexus between the OSA and comorbidities beg to be studied in greater detail. First is the onset of comorbidity to the initial diagnosis of OSA. Second is the severity of OSA and its association with comorbidities. There is little data in the scientific domain on the association between the severity of OSA with specific comorbidities and temporal association between OSA and development of comorbidities.\n\nThis study aims at determining the\n\n1. Prevalence of various comorbidities with OSA\n\n2. Stratification of OSA severity at the time of initial presentation and diagnosis\n\n3. To assess the severity of OSA to the presence of specific comorbidities.\n\n\nMethods\n\nEthical approval was received for this study on 10 April 2019 by the Institutional Ethics Committee Kasturba Medical College, Mangaluru (no. ECR/54/Inst/KA/2014/RR-17). Written informed consent was taken from participants prior to recruitment.\n\nThe study was conducted in a tertiary care teaching hospital in Mangalore, India. The study was conducted after obtaining approval from the institutional ethics committee (IEC).\n\nAssuming 39% prevalence of hypertension in patients with obstructive sleep apnea (OSA) to attain the significant results with 95% confidence interval at 80% power, a modified sample size of 80 was calculated.9\n\nInclusion criteria were: 1. Subjects screened by pulmonologists and diagnosed to have likely OSA based on clinical grounds and sleep questionnaire. 2. Subjects willing to undergo overnight polysomnography in sleep lab. 3. Subjects in the age group of 18-80 years.\n\nExclusion criteria were: 1. Those with hemodynamic instability (checked by the research team). 2. Subjects with acute disease states which are a contraindication for overnight polysomnography (e.g., patients with acute myocardial infarction, acute mental illness, acute exacerbation of chronic obstructive pulmonary disease and critically ill patients). 3. Patients with respiratory failure on room air with PaO2 of < 60 mm of Hg. 4. Poor quality report polysomnography due to low sleep efficiency. 5. Patient on sedatives and not on steady long-term dosing.\n\nThe study was a hospital-based descriptive study that included all the patients who visited the hospital with OSA symptoms. The software used was ALICE 5 sleep study machine by Philips. After proper patient preparation (abstain from sedatives, caffeine, and alcohol prior to the study) patients were taken up for sleep study and recording was done from 10:30pm - 6am and the parameters viz. EEG (electroencephalography), EOG (electrooculography) right and left, ECG (electrocardiography), chin and leg EMG (electromyography), nasal pressure, abdominal and thoracic movement, snoring (with snoring microphone) and saturation monitoring were conducted. A total of 120 patients who underwent screening polysomnography were included in the study and analysis was done on patients who met the inclusion and exclusion criteria after taking written informed consent from them. The study was carried out from April 2019 to September 2019. Clinical details of the patients’ demographic profile, sleep-related complaints past and current, and `medical history were collected.\n\nThe S.T.O.P questionnaire was administered to all patients before polysomnography. Patients were classified for OSA risk based on their scores obtained from the S.T.O.P questionnaire. Patients with a score of 0-2 categorized as low risk of OSA and those with a score >2 were categorized as high risk of OSA.8 Apnea-Hypopnea index (AHI) from the Polysomnography report were collected. OSA Patients were categorized based on Apnea-Hypopnea index (AHI) as follows: no OSA (<5), mild OSA (≥ 5 to < 15 events/hour), moderate OSA (≥ 15 to < 30 events/hour), and severe OSA (≥ 30 events/hour).\n\nNon-probability sampling (Convenient sampling) was used in this study. Data analysis was done using SPSS ver. 20.0. Data were summarized using mean and standard deviation (SD), and percentages. A Chi-square test was used to find the association. P<0.05 was considered as statistically significant.\n\n\nResults\n\nIn our study,120 patients were screened during a period April 2019-September 2019 out of which 5 patients refused consent, and 30 patients were excluded later in view of poor sleep efficiency. The majority of the study group were male (67%). The median age of the study group is 50 (range 39.5, 57). The majority of the patients had a higher body mass index (BMI), in the range of 30-34.99 (29.4%). Only 27.1% of the study group did not have any comorbidities. Among those with comorbidities, the most common observed include obesity (60%), hypertension (42%), and diabetes (32%). The most common symptoms of OSA observed are snoring (84%), excessive fatigue (77%), and excessive weight gain (52%) (Table 1).\n\nBased on AHI scores, 49.4% of participants were suggested to have severe OSA (≥ 5 to < 15 events/hour), followed by 24% of the group having mild OSA (≥ 5 to < 15 events/hour). 18.8% of the group had moderate OSA (≥ 15 to < 30 events/hour) while 8% had scores not indicating OSA (<5) (Table 2).\n\nAs per the S.T.O.P questionnaire, 51% of the study group had a higher risk of OSA while 49% had a low risk of OSA.\n\nOn analysis by Chi-square test, the association between the comorbidities and the severity of OSA by AHI scores was made. Association with diabetes was not statistically significant (p value-0.059). No comorbidity showed any association with the severity of OSA as per the AHI scores (Table 3).\n\nOn analysis by Chi-square test, the association between the comorbidities and the risk of OSA by S.T.O.P questionnaire was studied. Association with diabetes and hypertension with the severity of OSA with the S.T.O.P questionnaire was found to be significant (hypertension p value-0, diabetes p value-0.003) (Table 4).\n\nOn analysis by Chi-square test, the association between the BMI and severity of OSA by AHI index did not show any statistical significance.\n\n\nDiscussion\n\nOSA is a common sleep disorder with a worldwide prevalence that is on the rise.2 The prevalence of OSA in the general population has not been accurately documented and is a tip of the iceberg phenomenon due to the subtle nature of its symptoms, poor self-reporting, and lack of robust diagnostics in healthcare. OSA is also associated with certain crucial risk factors which play a vital role in its natural history of evolution. Studies have revealed that OSA contributes to several non-communicable diseases such as hypertension, cardiovascular diseases, and impaired glucose metabolism.10 The association of OSA with comorbidities is quite complex and confounding. Obesity and certain comorbidities like hypothyroidism are known to be definite risk factors for the subsequent development of OSA.11 However, metabolic comorbidities have a more complex causality. It is explained physiologically that diabetes mellitus and hypertension can develop as a complication of OSA and in turn may accentuate the OSA severity and progression.\n\nOSA is a disease that is often diagnosed late and rarely diagnosed before the onset of metabolic complications and comorbidities. It is a common observation among clinicians that OSA is diagnosed after end-organ damage has resulted in cardiovascular and neurological events. On presentation and initial diagnosis, it is often severe OSA that is diagnosed and often with the development of multiple and irreversible comorbidities. This study probes in greater detail the spectrum comorbidities suffered by OSA patient, their prevalence, and the association of comorbidities to the severity state of OSA if any.\n\nRisk factors for OSA include age, gender, race, BMI, and lifestyle habits associated comorbidities. In our study, the median age of the patients is 50.0(39.5, 57), with a majority of them being male, similar to other studies.11\n\nIn our study, we used the AHI score from polysomnography reports and the S.T.O.P questionnaire to assess the severity of OSA. As per AHI scores, 42(49%) of patients had severe OSA with AHI scores of more than 30/hr, followed by 20 patients (23.5%) who had mild OSA with scores of 5-14/hr. These are in line with a study done in Brazil where the majority of the population had severe OSA.11 A severe form of OSA as confirmed by AHI during the initial diagnosis is an important outcome of our study. This finding suggests that OSA is often diagnosed late and only after comorbidities and metabolic complications set in. The reasons for late presentation and subsequent diagnosis could be multifactorial like lack of awareness of the disease amongst the general population and even among the treating physicians. The subtle nature of symptoms in OSA and lack of high quality, easily available diagnostics may also be other compounding reasons. This finding in our study is critical as there is a huge scope for an early diagnosis that might modify and prevent progression to comorbidities.\n\nAs per the S.T.O.P questionnaire, 43(50%) of the sample had a high risk of OSA. This finding is significant as it reinforces the belief that a simple questionnaire in the form of S.T.O.P questionnaire has good sensitivity in an accurate early screening and diagnosis of OSA thereby preventing complications and onset of metabolic comorbidities. In settings where diagnostic polysomnography is a luxury, the S.T.O.P questionnaire is a good alternative at least as a screening tool.\n\nIn our study, a total of 62 OSA patients (73%) had any one of the comorbidities. The most common comorbidity observed in our study was obesity (51(60%)), while hypertension (39%) followed by obesity (34%) were the most common comorbidities observed by Jose Antonio Pinto et al.12 The Indian study done by Surendra K. Sharma et al. showed that patients with obesity also had four times more risk of having OSA, an observation similar to our study.13\n\nIn our study diabetes is seen in 31.8% of the patients suffering from OSA. On assessing the severity of OSA symptoms in patients who had diabetes using the S.T.O.P questionnaire, it was found that among the people with diabetes, the majority of them (74%) had a high risk of OSA, and the data was found to be statistically significant. On using AHI scores, it was observed that among diabetics, the majority of them had moderate to severe OSA (72%). However, this was not of statistical significance. One possible reason is that OSA leads to obesity which further increases the risk of diabetes. Whether the patients with OSA become more obese than those who do not is uncertain.14–16 Another theory is decreased sleep may increase appetite.17 In one of the studies, it has been discussed that patients with OSA had high levels of leptin, which suggested the association between OSA and leptin resistance.18 Diabetes may be the cause of OSA and studies have found that diabetic patients had more propensities to OSA than those without diabetes.19 Autonomic dysfunction in diabetic patients also may lead to OSA due to leptin resistance/deficiency causing depressed respiratory control.20–25 However, we could not deduce if diabetes was the cause or effect of OSA as the sample size was not large enough. These results might imply that early screening, diagnosis and treatment of OSA may prevent the subsequent development or modify the progression of diabetes.\n\nThe next commonly associated comorbidity with OSA is hypertension (42%). On assessing the severity association between the patients having hypertension and OSA using AHI, it was seen that around 72% of the hypertensive patients had moderate to severe OSA. As per the S.T.O.P questionnaire, 75% of the hypertensives had moderate to severe risk of OSA. 55% of non-hypertensive patients had no to mild risk of OSA. This data was statistically significant. Many hypotheses for the causal association between them have been stated, but the exact underlying mechanisms have not been clearly understood.26 Many theories such as recurrent and temporary negative intrathoracic pressure during apnoeic spells, recurrent hypoxemia, or hypercapnia, which cause sympathetic system stimulation, may lead to hypertension.27–29 A study showed that use of continuous positive airway pressure (CPAP) has helped to better control blood pressure in hypertensive patients.30–32\n\nThe link between the severe form of OSA and comorbidities was explored. Occurrence of diabetes and hypertension with the severe form of OSA by S.T.O.P questionnaire reached statistical significance while only hypertension showed a significant correlation with severe OSA as graded by AHI score.\n\nThere was no association among other comorbidities with the severity of OSA. These findings emphasize the fact that diabetes and hypertension are perhaps the two most significant comorbidities that need to be addressed in OSA patients. These comorbidities are often encountered with a severe form of OSA. This suggests that these two comorbidities may accentuate the progression of OSA into more severe and refractory diseases. Alternatively, the presence of diabetes and hypertension in OSA patients may be a harbinger of a severe disease state and suggests the need for active intervention to prevent end-organ complications, often seen with these two serious comorbidities.\n\nOverweight or obese people are strongly linked with OSA.11,33 It is often difficult to establish which is the cause or effect among them, hence the disease progression is difficult to establish. In our study, at least 80% of the study population were overweight or obese. The most common comorbidity with OSA was obesity which was seen in 60% of the patients. On assessing the association between these two, it was seen that among the obese, 60% of them had moderate to severe OSA compared to other groups. Obesity manifests as a change in certain anatomical features such as the increase in neck circumference that might narrow the airway.34,35 Obesity is known to cause reduced lung volume36 which may lead to an increased risk of oropharyngeal collapse during sleep (due to decreased strength of airways),37,38 increase CPAP requirements,39 and greater severity of OSA.40 Secondly, the risk of collapse of the upper airway is higher in obese individuals.41 Other theories include the imbalance of carbohydrate and lipid metabolism.42–44 Reduction in body weight is an effective strategy for treating sleep apnea.41,45,46\n\nOur study had a few limitations. Probing in detail the duration of onset of each specific comorbidity to the onset of OSA would have given vital data on the predilection and causality of the comorbidities with OSA. This complex exercise was not captured in our study data due to technical shortcomings. The findings of our study should be substantiated with a study involving a larger population and probably a multicentric study for more representative data.\n\n\nConclusion\n\nIn our study, a significant proportion (73%) of patients with OSA at the time of diagnosis had comorbidities. This is indicative of a delayed presentation in OSA patients and that OSA is often diagnosed only after multiple and irreversible comorbidities have set in.\n\nAmong the spectrum of comorbidities encountered in our study, the most common were obesity, hypertension, and diabetes, among many others (dyslipidemia, GERD, asthma, COPD). It was seen that there was an association between the comorbidities and the severity of OSA as graded by the S.T.O.P questionnaire for both diabetes and hypertension and hypertension alone when graded by AHI scores. There was no association among other comorbidities with the severity of OSA. This crucial data implies that among the basket of comorbidities often seen with OSA, diabetes and hypertension are probably the most significant of the comorbidities. Both these may have a disease-modifying role in OSA and lead to a severe form of OSA and vice-versa. This finding needs to be validated with larger studies and the pathophysiological link needs a more comprehensive exploration too.\n\nAnother disconcerting finding from our study was the skewed presentation of OSA at the time of initial diagnosis. A majority (49%) had a severe form of OSA at the time of diagnosis. This, combined with multiple comorbidities at diagnosis, is reflective of a huge problem that is peculiar to OSA at large on a community level. OSA as a disease entity has poor awareness in the community and is seldom screened early in primary health care, thereby leading to suboptimal early intervention and care. There is strong evidence that early detection of OSA can benefit the patient by preventing the development of irreversible comorbidities. The inverse is also true. More importantly, due to late diagnosis and delayed intervention of OSA more often, these subjects present with multiple comorbidities that result in end-organ damage due to progression of these comorbidities (e.g., uncontrolled hypertension or diabetes leading to ischaemic heart disease or stroke). Early identification of OSA has a critical role in preventing the development of comorbidities in some patients, progression of comorbidities in majority and preventing complications arising out of the comorbidities in many.\n\n\nData availability\n\nfigshare: Unmasking the cloak of comorbidities in OSA-association and their severity – A Prospective observational study. https://doi.org/10.6084/m9.figshare.19571365\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
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PubMed Abstract | Publisher Full Text\n\nRees PJ, Prior JG, Cochrane GM, et al.: Sleep apnoea in diabetic patients with autonomic neuropathy. J. R. Soc. Med. 1981; 74: 192–195. Publisher Full Text\n\nO'Donnell CP, Tankersley CG, Polotsky VP, et al.: Leptin, obesity, and respiratory function. Respir. Physiol. 2000; 119: 163–170. Publisher Full Text\n\nNieto FJ, Young TB, Lind BK, et al.: Association of Sleep-Disordered Breathing, Sleep Apnea, and Hypertension in a Large Community-Based Study. JAMA. 2000; 283(14): 1829–1836. PubMed Abstract | Publisher Full Text\n\nLevinson PD, Millman RP: Causes and consequences of blood pressure alterations in obstructive sleep apnea. Arch. Intern. Med. 1991; 151: 455–462. PubMed Abstract | Publisher Full Text\n\nSilverberg DS, Oksenberg A, Radwan H, et al.: Is obstructive sleep apnea a common cause of essential hypertension?. Isr. J. Med. Sci. 1995; 31: 527–535. PubMed Abstract\n\nBonsignore MR, Marrone O, Insalaco G, et al.: The cardiovascular effects of obstructive sleep apnoeas: analysis of pathogenetic mechanisms. Eur. Respir. J. 1994; 7: 786–805. Publisher Full Text\n\nWilcox I, Grunstein RR, Hedner JA, et al.: Effect of nasal continuous positive airway pressure during sleep on 24-hour blood pressure in obstructive sleep apnea. Sleep. 1993; 16: 539–544. Publisher Full Text\n\nSuzuki M, Otsuka K, Guilleminault C: Long-term continuous positive airway pressure administration can normalize hypertension in obstructive sleep apnea patients. Sleep. 1993; 16: 545–549. Publisher Full Text\n\nSilverberg DS, Oksenberg A, Radwan H, et al.: Is obstructive sleep apnea a common cause of essential hypertension?. Isr. J. Med. Sci. 1995; 31: 235–527.\n\nWittels EH, Thompson S: Obstructive sleep apnea and obesity. Otolaryngol. Clin. N. Am. 1990; 23(4): 751–760. Publisher Full Text\n\nDavies RJ, Stradling JR: The relationship between neck circumference, radiographic pharyngeal anatomy, and obstructive sleep apnoea syndrome. Eur. Respir. J. 1990; 3: 509–514.\n\nSchwab RJ, Gupta KB, Gefter WB, et al.: Upper airway and soft tissue anatomy in normal subjects and patients with sleep-disordered breathing: significance of the lateral pharyngeal walls. Am. J. Respir. Crit. Care Med. 1995; 152: 1673–1689. PubMed Abstract | Publisher Full Text\n\nSharp JT, Henry JP, Sweany SK, et al.: Effects of mass loading the respiratory system in man. J. Appl. Physiol. 1964; 19: 959–966. PubMed Abstract | Publisher Full Text\n\nSeries F, Marc I: Influence of lung volume dependence of upper airway resistance during continuous negative airway pressure. J. Appl. Physiol. 1994; 77: 840–844. Publisher Full Text\n\nSeries F, Cormier Y, Desmeules M: Influence of passive changes of lung volume on upper airways. J. Appl. Physiol. 1990; 68: 2159–2164. Publisher Full Text\n\nHeinzer RC, Stanchina ML, Malhotra A, et al.: Lung volume and continuous positive airway pressure requirements in obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 2005; 172: 114–117. PubMed Abstract | Publisher Full Text\n\nBrown IG, Bradley TD, Phillipson EA, et al.: Pharyngeal compliance in snoring subjects with and without obstructive sleep apnea. Am. Rev. Respir. Dis. 1985; 132: 211–215. PubMed Abstract\n\nSchwartz AR, Gold AR, Schubert N, et al.: Effect of weight loss on upper airway collapsibility in obstructive sleep apnea. Am. Rev. Respir. Dis. 1991; 144: 494–498. PubMed Abstract | Publisher Full Text\n\nBasta M, Vgontzas AN: Metabolic abnormalities in obesity and sleep apnea are in a continuum. Sleep Med. 2007; 8: 5–7. PubMed Abstract | Publisher Full Text\n\nGruber A, Horwood F, Sithole J, et al.: Obstructive sleep apnoea is independently associated with the metabolic syndrome but not insulin resistance state. Cardiovasc. Diabetol. 2006; 5: 22. Publisher Full Text\n\nLam JC, Lam B, Lam CL, et al.: Obstructive sleep apnea and the metabolic syndrome in community-based Chinese adults in Hong Kong. Respir. Med. 2006; 100: 980–987. PubMed Abstract | Publisher Full Text\n\nSmith PL, Gold AR, Meyers DA, et al.: Weight loss in mildly to moderately obese patients with obstructive sleep apnea. Ann. Intern. Med. 1985; 103: 850–855. Publisher Full Text"
}
|
[
{
"id": "159163",
"date": "23 Jan 2023",
"name": "Maria R Bonsignore",
"expertise": [
"Reviewer Expertise Respiratory sleep 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 confirms that patients with suspected OSA often show comorbidities, the most common being obesity, hypertension and diabetes. The sample size is rather small, likely explaining the lack of a significant association between diabetes and polysomnographic OSA diagnosis. Use of the STOP questionnaire confirms its validity as a screening tool.\nThe author should consider some additional aspects:\nThe panel of comorbidities found associated with OSA confirms the association of OSA with the metabolic syndrome. It would be interesting to know the prevalence of the metabolic syndrome in the OSA and non-OSA group. This may add to the STOP questionnaire as a clinically useful screening tool.\n\nThere is no mention about the symptoms referred by the patients. Were those with OSA more symptomatic than the patients without OSA? An analysis of symptoms may also be useful to raise the suspicion of OSA together with the STOP questionnaire, especially in settings without adequate resources. There is no mention of excessive daytime sleepiness in the paper.\n\nThe diagnosis of OSA is based only on AHI. There is a lot of literature now indicating that AHI alone is probably inadequate to classify patients (Pevernagie et al., 20201; Malhotra et al., 20212). A good proxy for severity of nocturnal hypoxemia could be the % of time spent at SpO2<90% during the nocturnal study. Intermittent hypoxemia could be a risk factor for both the development of hypertension and worsening of glycemic control. Since the PSG data are available, the Authors may wish to further dig into the data in this regard.\n\nI am not sure it could be possible to assess the sequence of events, namely if hypertension and/or diabetes precede or follow occurrence of OSA. The obesity factor is a very strong one for the pathogenesis of all three diseases, OSA, hypertension and diabetes, and tackling obesity would be a simple and very important action from a Public Health point of view to identify or prevent them.\n\nThe paper examined only patients with a suspicion of OSA raised by a physician, and represent a highly selected population. The data are not applicable to the general population, and this should be stated as a limitation of the 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? 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? Partly",
"responses": [
{
"c_id": "9297",
"date": "23 Feb 2023",
"name": "sindhu kamath",
"role": "Author Response",
"response": "Query no.1 Reviewers query It would be interesting to know the prevalence of metabolic syndrome in OSA & non-OSA group. This may add to the usefulness of STOP questionnaire as a clinically useful screening tool. Authors response We appreciate the novelty of the suggestion by the reviewer. However, our study by design was a descriptive study without a control group. So, we screened all the patients who visited the hospital with OSA symptoms. The S.T.O.P questionnaire was administered to all patients before polysomnography. The patients were not grouped into a separate non-OSA control group. Hence, unfortunately our study was not designed to provide the data as suggested by the esteemed reviewer. However, we were able to elicit this useful data correlating STOP questionnaire with co-morbidities. As per the S.T.O.P questionnaire, 75% of the hypertensive had moderate to severe risk of OSA. 55% of non-hypertensive patients had no to mild risk of OSA. It was found that among the people with diabetes, the majority of them (74%) had a high risk of OSA as per STOP questionnaire, and the data was found to be statistically significant . Location of the correction/ edits In discussion section 8th paragraph. In discussion section 7th paragraph. Query no 2. Reviewers query There is no mention of the symptoms referred by the patients. Was the OSAS group more symptomatic than the Non-OSAS group.There is no mention of excessive daytime sleepiness in the paper. Authors response: Our study by design was a descriptive study without control group. So we were not in a position to compare the symptomatology between the groups as suggested by reviewer. We have assessed only the three most common symptoms of OSA observed snoring (84%), excessive fatigue (77%), and excessive weight gain (52%). Unfortunately we have not assessed the symptoms of excessive daytime somnolence separately and it was clubbed with joint questionnaire of Tired, fatigued or sleepy frequently during daytime which is admittedly a lapse overlooked. The details of this expanded questionnaire is already provided in the raw data sheet submitted by us and can be cross- verified. Query no 3. Reviewers query The diagnosis of OSAS was based only on AHI. There is now a lot of data indicating AHI alone is inadequate to classify patients. A good proxy of severity of nocturnal hypoxemia could be % of time spent under spo2< 90 during the nocturnal study. Authors response: We are fully in agreement with the insightful observation of the reviewer. We have the data of oxygen desaturation index (ODI) recorded in the study. We had not extracted the data initially. After the suggestion from the reviewer we have extricated the data of ODI in all the patients and the severity of AHI was correlated with average ODI. The same has been incorporated as a table. A Table (no.5) has been added at the last paragraph of the result section of the manuscript."
}
]
}
] | 1
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https://f1000research.com/articles/11-917
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https://f1000research.com/articles/11-732/v1
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01 Jul 22
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{
"type": "Method Article",
"title": "Diagnostic accuracy for a plasma SARS-CoV-2 Nucleocapsid Protein method",
"authors": [
"Søren Kristiansen",
"Laura Emilie Schmidt",
"Ann-Britt Nygaard Hillig",
"Thyge Lynghøj Nielsen",
"Thomas Ingemann Pedersen",
"Nikolai Søren Kirkby",
"Thomas Schiøler",
"Thore Hillig",
"Laura Emilie Schmidt",
"Ann-Britt Nygaard Hillig",
"Thyge Lynghøj Nielsen",
"Thomas Ingemann Pedersen",
"Nikolai Søren Kirkby",
"Thomas Schiøler",
"Thore Hillig"
],
"abstract": "Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) releases nucleocapsid proteins (NP) into the blood circulation in infected patients. We investigated whether plasma NP analysis could be used for diagnosing an infection and used for nosocomial screening. Methods: We collected blood samples from patients admitted to the hospital during a period with reverse transcription polymerase chain reaction (RT-PCR) based-screening of patients for SARS-CoV-2. Retrospectively the SARS-CoV-2 NP plasma concentrations were measured with an enzyme-linked immunosorbent assay (ELISA) method and used for an initial time course study to find the optimal time-point for sampling blood. Next, we estimated the diagnostic accuracy i.e. the clinical sensitivity and specificity at different plasma NP cut-off concentrations. Results: The time course study revealed profiles with rapid or more slow declines in NP titers after the RT-PCR result. Nevertheless, in the time interval 0 – 7 days after the RT-PCR result, the NP concentration was always above the level of detection at 1.66 pg/ml suggesting that the diagnosis could be established in the time interval of 0 - 7 days. The median time gap between the plasma NP and RT-PCR results was 0.0 days (n = 1957, interval: -26 to + 21 days). Reducing the time gap to seven days, the clinical sensitivity was 90.0% (n= 60, 95% CI, 82.4% to 97.6%) at a specificity of 95.9% (n=1876, 95% CI, 95.0% to 96.8%). Curve analysis by receiver operation characteristics identified a cut-off concentration of 1.87 pg/mL NP as optimal resulting in a positive predictive value of 41.2%, a negative predictive value of 99.7% and a prevalence of 3.1%. Conclusions: In conclusion, the NP method is acceptable for making the laboratory diagnosis of SARS-CoV-2, and an intended use of plasma NP as a prospective nosocomial screening method is considered feasible.",
"keywords": [
"Plasma SARS-CoV-2 Nucleocapsid protein",
"SARS-CoV-2",
"diagnostic accuracy",
"clinical specificity",
"clinical sensitivity"
],
"content": "Introduction\n\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus which first appeared in Wuhan, China, in 2019.1–3 SARS-CoV-2 is an enveloped RNA virus that is distributed broadly among humans, other mammals and birds and that causes respiratory, enteric, hepatic and neurologic diseases and has presented an acute global challenge for both the public health, economy, and social life.4\n\nHopefully, the SARS-CoV-2 prevalence in the general population will decrease over the coming years. Nevertheless, it is envisioned that diagnosis of SARS-CoV-2 by systematic screening will still be required by the health authorities for several reasons. First of all, screening is the systematic application of a test or enquiry to identify individuals at sufficient risk of a specific disorder to warrant further investigation or direct preventive action amongst persons who have not sought medical attention on account of symptoms of that disorder.5 By analyzing over 350 studies, Sah et al.6 estimated that the percentage of SARS-CoV-2 infections that never developed clinical symptoms, and thus were truly asymptomatic, was 35.1% (95% confidence interval [CI]: 30.7 to 39.9%). At the time of testing, 42.8% (95% prediction interval: 5.2 to 91.1%) of cases exhibited no symptoms, a group comprising both asymptomatic and presymptomatic infections. Thus, a systematic screening may identify SARS-CoV-2 in asymptomatic subjects that otherwise would not have been tested. Thus, systematic screening opens for due diligence to introduce precautions that may reduce the spreading of SARS-CoV-2 in the general population.\n\nMolecular and immunochemical-based methods can in principle analyze a plethora of bodily fluids e.g. the upper respiratory tract can be investigated with nasopharyngeal and oropharyngeal swab techniques, and the lower tract by collection of tracheal secretions. However, variations in sampling technique and the heterogeneity in the obtained material may compromise the quality of the analysis. In general, the clinical sensitivity and specificity of the rapid flow immunoassays are considered inferior to the more sensitive reverse transcription polymerase chain reaction (RT-PCR) based-methods.7–12\n\nInterestingly, early studies of coronavirus replicating via infection of human cells revealed large amounts of NP antigen in the blood circulation.13–15 In contrast to swab material, plasma samples are a homogenous well-defined material and the most predominant type of sample in hospital laboratories, which may enable plasma SARS-CoV-2 diagnosis without extra cost or trauma to the patients.16–19 Furthermore, analysis of blood samples allows for a meaningful determination of a concentration by a quantitative method, and thereby also for definition of the appropriate specific diagnostic cut-off value of said method.\n\nWe hypothesized that screening of blood samples could be used to detect SARS-CoV-2 infections among patients being admitted to the hospital. In the present retrospective method comparison study, we estimated the diagnostic accuracy i.e. the clinical sensitivity and specificity of an ELISA-based plasma NP method as a potential prospective tool for nosocomial screening.\n\n\nMethods\n\nThis retrospective study was checked for essential items as described in the guideline “standard for reporting of studies of diagnostic accuracy” (STARD criteria).20\n\nIn the period from 1st - 30th November 2021 oro- and nasopharyngeal swab samples were obtained from patients admitted to the North Zealand Hospital, Hillerød, Denmark. To diagnose SARS-CoV-2 the samples were analyzed for the presence or absence of viral RNA with a RT-PCR method. As part of the standard procedure venous blood was also collected as requested by the clinicians for routine biochemical analysis. All plasma samples where P-Amylase were requested by the clinicians were collected and analyzed by an ELISA-based plasma NP method. P-Amylase is requested for all admitted patients at the emergency department and is a rare request from other departments. No other criteria were used to select or exclude samples for NP analysis. Several serial samples were obtained from the same patients and time course studies of changes in NP concentrations were then carried out. Paired NP and RT-PCR results were obtained, either with an either positive or negative time gap between the time of collection of blood samples for NP ELISA and pharyngeal swab for RT-PCR, respectively. The time course study was used to identify valid paired data within an optimal time gap. These paired data were used for calculating the final diagnostic accuracy i.e. the clinical sensitivity and specificity of the NP assay using the RT-PCR as the reference method. The paired data analysis was carried out by a person without prior influence or knowledge of the results from the RT-PCR and NP analysis.\n\nWithin 2-3 hours oro- and nasopharyngeal swab samples were subjected to RNA isolation and RT-PCR amplification. In brief, viral RNA and human RNA/DNA were isolated from 0.2 mL inactivating NEST buffer (Wuxi NEST Biotechnology Co, Ltd., Jiangsu, China) using a CE-marked method (MagMAXTM viral/pathogen nucleic acid kit). The isolation was performed on an automated flow Robot system (Flow Robotics A/S, Copenhagen, Denmark) and the KingFisherTM Flex purification system (Thermo Fisher Scientific, Darmstadt, Germany).\n\nFive μL RNA elution buffer was transferred to 15 μl TaqMan Fast Virus 1-step master mix (Thermo Fisher Scientific, Darmstadt, Germany) containing 200 nmol/L and 400 nmol/L Envelope (E) gene and Ribonuclease protein (RNAse P) hydrolysis probes and primers, final concentrations respectively.4,21 The probes were dual labelled with 6-carboxyfluoresecein and black hole quencher (E gene) and 6-carboxy-rhodamine and black hole quencher (RNAse P) (Merck KGaA, Darmstadt, Germany). RT-PCR was performed at 55°C for 10 min, 95°C for 1 min, and 38 cycles at 95°C for 10 sec and 60°C for 30 sec (AriaDX instruments, Agilent Technologies, USA).\n\nAn arbitrary threshold in signals was set to remove background amplification noise. Exponential curve signals above the background noise with Ct values < 32 were considered positive. Samples with Ct values of 32 – 38 were re-analyzed. The PCR amplification efficiency was > 96% with a level of detection of 13 ± 25 (mean ± standard deviation [SD]) DNA copies per reaction. Internal negative and positive E gene synthetic RNA controls (Twist Bioscience, South San Francisco, CA, USA) were included in every run. The intra-analytical precision for the E gene and RNAse P methods were 6.3% at Ct values of 13.8 ± 0.86 and 21.3 ± 1.35 (mean ± SD, n =14), respectively. Analytical precision of the entire laboratory set up was estimated by adding MS-2 phages (American Type Culture Collection) to NEST buffer followed by RNA isolation and RT-qPCR. The intra-analytical precision for the Ct value was 2.2% (Ct mean 22.37 ± 0.50, n = 16).\n\nThe diagnostic performance of the RT-PCR reference method was validated by analyzing a blinded batch of swab samples collected by the Department of Clinical Microbiology (Herlev Hospital, Denmark). In brief, the blinded result of 21 positive and 73 negative SARS-CoV-2 were 100% in concordance with the result initially found by the external laboratory. SARS-CoV-2 positive samples were sent daily to an independent laboratory for mutation analysis (Department of Clinical Microbiology, Herlev Hospital, Denmark).\n\nRoutine blood samples were sent to the local Department of Clinical Biochemistry by a Tempus 600 pneumatic tube system (Timedico A/S, Bording, Denmark). After all the requested biochemical analyses were carried out, the centrifuged plasma samples were kept for one day at 4°C. The plasma samples were frozen at -20°C and later thawed batch-wise for NP analysis.16 The NP analysis was carried out by a person without knowledge of the RT-PCR results.\n\nFor the plasma NP analysis, a BEP 2000 Advance System (Siemens Healthineers Inc) was programmed according to the instructions given by the local distributor (Solsten Diagnostics International, Aarhus, Denmark).22 Up to 12 strips of each 8 wells precoated with antibody to SARS-CoV-2 NP were mounted in each 96-well frame. First, 50 μL of biotin-conjugated antibody was added to each well and then directly supplemented with 50 μL of either internal NP calibrator or plasma. The wells were incubated for 1 h at 37°C, washed five times, incubated with 100 mL/well peroxidase-conjugated streptavidin for 30 min at 37°C, washed five times and then incubated with the provided substrate for 15 min at 37°C. The chromogenic enzyme reaction was stopped before photometrical measurements of the absorbance. Standard curves of five internal calibrators (0 and 160 pg/mL) were used as defined by the manufacturer.22 The cut off value is prespecified by the manufacturer.22 However, in the present study optimal cut-off values for the NP ELISA results were determined in an exploratory fashion by receiver operating characteristic (ROC) curve analysis.\n\nThe present quality control study of the NP test method did not imply extra blood sampling from the patients. The obtained results had no impact on clinical care decisions, and no clinical information (except age and sex) was collected. Accordingly, the present quality control study of two methods required no written or oral permission from the patients.23\n\nCsv-files were downloaded from the Oracle database PKLABKA (LABKA, HealthCare Denmark – CSC A/S, Odense, Denmark) using the SQL Developer software version 11.0.4.1774 (Allround Automations V.O.F, Enschede, Netherlands). Only plasma samples where P-amylase was requested by the clinicians was selected for later NP analysis (please see prior section). The SQL algorithm used the plasma sample number from the P-amylase and NP analysis to find the date for the collection of the blood sample, the age of the patient and sex. The RT-qPCR results was extracted from the Clinical Microbiology Laboratory database system. To ensure full data security each patient was equipped with one unique random number. Pairing of NP and RT-qPCR results originating from the two databases was carried out with standard EXCEL 2016 software by the use of the unique random number. Patients without a paired NP and RT-qPCR result was discarded. Please see Table 1 for description and number of individuals. The author S. K was responsible for accessing the PKLABKA database, and Tina Profft Larsen (acknowledgement) for providing the RT-qPCR results.\n\nIn the period from 1st - 30th November 2021 oro- and nasopharyngeal swab and blood samples were obtained from patients admitted to the North Zealand Hospital, Hillerød, Denmark. To diagnose severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) the swab samples were analyzed for the presence or absence of viral RNA with a reverse transcriptase-polymerase chain reaction (RT-PCR) method and the plasma was analyzed for nucleocapsid protein (NP) content with an enzyme-linked immunoassay (ELISA) method.\n\n* Data excluded due to time-lag between test-results.\n\nThe statistical uncertainty of the estimates is reported as mean ± SD, number of measurement (n). A p < 0.05 was considered statistically significant. The 95% confidence intervals of percentages (p̂) were calculated as p̂±1.96·√(p̂·(1- p̂)/n.\n\nThe power and intended sample size were calculated a priori as requested by the STARD criteria by following the Clinical and Laboratory Standards Institute (CLSI) guideline EP-24.20,24 The manufacturer claimed a clinical sensitivity of 30/32 subjects, or 93.75% (95CI: 79.19% - 99.23%) for results analyzed ≤ 3 days from start of symptoms, and a specificity of 649/649 subjects giving 100% (95CI: 99.43-100.00%) when using a cut-off of 2.97 pg/ml.22 The intended minimum subjects with an error < 5% was estimated to 90 subjects. The screen positive rate of approximately 4.8% in November 202125,26 consequently required at least 1875 (90 x 100/4,8) samples. The study was carried out with collection of the required number of samples before the blinded analysis was carried out.\n\n\nResults\n\nAs shown in Figure 1, the time course study of plasma NP concentrations showed considerable individual variations among the SARS-CoV-2 positive patients. Overall, there was a decline in NP concentrations and a time gap of 0-7 days was identified as a window for collecting samples for NP analysis.\n\nThe graph shows individual relative change (%) in plasma NP concentrations (y-axis) 0-17 days after first positive SARS-CoV-2 diagnosis (x-axis).\n\nA total of 3334 plasma samples were analyzed with the NP test method. Among the 3334 plasma samples 2653 unique patients were identified; this cohort consisted of 1415 women and 1238 male subjects with 13 subjects excluded due to lack of identification, as shown in Table 1.36\n\nA total of 1957 unique patients with a paired NP and PCR results were identified. This cohort included 63 and 1894 patients with a positive or negative RT-PCR result, respectively. Hence, an initial screen positive rate of 3.2% (63/1957) could be calculated.\n\nThe median time lag between the RT-PCR and NP analysis date were 0.0 days (n = 1957, lag interval: - 26 to + 21 days). Since 83% and 98% of the present paired data were collected within 0-3 and 0-7 days apart, respectively, we performed an initial ROC curve analysis without exclusion of any paired data set.\n\nAs shown in Figure 2, nine different NP cut-off values ranging from 0.83 pg/mL to 116.6 pg/mL were plotted. The sensitivity and specificity changed from 59–95% and 21–100%, respectively, with the nine different cut-off values. After comparing the distance from the nine data points to the X-Y line, the cut-off value of 1.87 pg/mL was selected. This cut-off gave an initial maximal sensitivity and specificity of 86% (54/63) and 95% (1808/1894), respectively. Selection of paired data with a maximal time gap between PCR and NP measurement of seven days finally adjusted the sensitivity and specificity to 90.0% (n = 60, 95% CI, 82.4% to 97.6%) and 95.9% (n = 1876, 95% CI, 95.0% to 96.8%), respectively. Using the RT-PCR results as a reference this resulted in a positive predictive value of 41.2%, a negative predictive value of 99.7% and a prevalence of 3.1%.\n\nPlasma samples were also analyzed for SARS-CoV-2 nucleocapsid protein (NP) concentration by an enzyme-linked immunoassay (ELISA) method. The NP concentrations from the ELISA method were tested against the RT-PCR results considered as the reference method. Different cut-off values of NP concentrations and the corresponding sensitivities and specificities were plotted in a receiver operation characteristic (ROC) curve. The nine different NP cut-off concentrations (0.83 pg/mL to 116 pg/mL) produced sensitivities and specificities in the interval from 59–95% and 21–100%, respectively.\n\n\nDiscussion\n\nIn the present study we first estimated an acceptable time gap for including plasma samples for NP analysis. The typical course of the NP concentrations was an initial high titer followed by a gradual decrease with only a few patients showing deviations from this pattern. We identified 0-7 days as an optimal time gap. This finding is in accordance with the study by Thudium et al,16 where the diagnostic accuracy of the NP method was shown to be strongly dependent on the time gap from the timepoint for the first PCR positive swap. The higher sensitivity after 4-7 days may reflect the prior time needed for invasion, synthesis, and release of N-antigens into the bloodstream upon lysis of the human epithelial cells.16 Furthermore, it could be speculated that the decrease or delta-value of NP could predict patient outcome. Moreover, the plasma NP may indicate that epithelial cells infected with SARS-CoV-2 are actively making virus proteins. Thus, a patient without NP - or with rapidly decreasing NP - could be viewed as non- or minimally contagious and could be withdrawn from an isolation protocol.\n\nUsing ROC curve analysis for setting the cut-off value with a time gap of seven days, the clinical sensitivity was 90.0% (n= 60, 95% CI, 82.4 % to 97.6%) with a clinical specificity of 95.9% (n=1876, 95% CI, 95.0% to 96.8%). The study found a positive and negative predictive value of 41.2% and 99.7%, respectively, and a prevalence of 3.1%. The present screen-positive rate was obtained in November 2021 at the Hospital of North Zealand. In the same period the PCR screen-positive rate in the capital area of North Zealand was initially 3.4 % in week 44 and increased to 4.8% by the end of week 48. This period was covered 98.9-100.0% (binomial 95% confidence interval) by the Delta variant B.1.617.2 containing the L452R mutation in the Spike protein.25,26 The high negative predictive value (99.7%) for the NP method could be used to rule out SARS-CoV-2 and thereby lead to reduction in the need for swab sampling including PCR analyses and/or suspension of quarantine of suspected SARS-CoV-2 patients.\n\nThe a priori specified intended sample size for the claimed clinical sensitivity was 90 positive SARS-CoV-2 subjects. However retrospectively 60 positive subjects were included after the study period. Recalculating with the present sample size of 60 subjects increases the p value to avoid a type II error from 0.05 to 0.07. Thus, in 7% of the cases the hypothesis will be untrue in the full study population. The 7% chance of a type II error is considered acceptable for an initial pilot study. In comparison, the CE-labelled NP assay claimed a clinical sensitivity of 93.75% (30 subjects out of 32) and 100.00% (38/38) when the NP test was carried out ≤ 3 days and 4-7 days from start of symptoms, respectively, with a cut-off value of 2.97 pg/mL.22\n\nIn the study by Thudium et al.16 a group of 99 inpatients and 505 outpatients was evaluated using a cut-off value of 10 pg/mL. When blood was collected between 0-6 days a specificity of 99.8% was found in the group of out-patients, and the sensitivity was 81.4% and 92.9% for the group of out – and inpatients, respectively. Taken together, the present study and the study by Thudium et al.16 shows that the clinical accuracy depends on the time gap and can be adjusted by an optional cut-off value.\n\nThe present study used the E gene as the target for detecting SARS-CoV-2 RNA.21 Studies of the analytical27,28 and clinical performance27,29–34 of RT-PCR methods based on E gene supports the notion that RT-PCR of the E gene is an acceptable refence method. However, a systematic review of 34 studies enrolling 12.057 SARS-CoV-2-19 confirmed cases reinforces the need for repeated testing in patients with suspicion of SARS-CoV-2 infection given that up to 54% of SARS-CoV-2 patients may have an initial false-negative RT-PCR.35 Taken together,35 the relatively high false negative rates of SARS-CoV-2 RT-PCR testing need to be accounted for in clinical decision making, epidemiological interpretations, and when using RT-PCR as a reference for other tests.\n\nThe NP ELISA method could contribute to reduce the risk of nosocomial SARS-CoV-2 infection. A suitable laboratory diagnostic method for NP in blood samples must provide an analytic limit of detection close to 1 pg/mL corresponding to 20 fM. Also, it must be sufficiently robust and specific to avoid false positives even when used for analysis of undiluted blood samples. However, many hospital laboratories must handle many samples with a minimum of manual resources and short turn-around times. These requirements are often solved by an automated continuous single-cell reaction of beads coated with specific antibodies. The present NP ELISA format requires manual handling and collection of a batch of plasma samples before a run can be initiated. Thus, the overall economy and turn-around times of implementing nosocomial screening with the NP method should be considered.\n\nIn conclusion, the retrospective comparison of the plasma NP test against the RT-PCR reference method shows that the NP method has an acceptable diagnostic accuracy. Thus, the NP method is suitable for diagnosis of SARS-CoV-2. Finally, the NP method could be used for prospective nosocomial screening for SARS-CoV-2.\n\n\nData availability\n\nDryad. Repository NP and RT-qPCR results. https://doi/10.5061/dryad.2v6wwpzr3.36\n\nThis project contains the following underlying data:\n\n- Data file 1. SARS-CoV-2 Nuclecapsid and RT-PCR results.csv\n\n- Data file 1. READMe.file.txt\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\nThe laboratory technician Maria Jennifer Borg Eiding, Department of Clinical Biochemistry, North Zealand Hospital is acknowledged for the helping with the NP analysis.\n\nTina Profft Larsen, Department of Clinical Microbiology, Herlev Hospital is acknowledged for database searching.\n\nNiels T. Foged, Solsten Diagnostics Intl. ApS, Langdyssen 5, DK-8200 Aarhus, Denmark is acknowledged for providing the SARS-CoV-2 NP ELISA kits.\n\n\nReferences\n\nZhou P, Yang XL, Wang XG, et al.: A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579: 270–273. PubMed Abstract | Publisher Full Text\n\nZhu N, Zhang D, Wang W, et al.: A novel coronavirus from patients with pneumonia in china, 2019. N. Engl. J. Med. 2020; 382: 727–733. Publisher Full Text\n\nWu F, Zhao S, Yu B, et al.: A new coronavirus associated with human respiratory disease in china. Nature. 2020; 579: 265–269. 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Clinical and Laboratory Standards Institute;2012; EP24-A2.\n\nStatus for udvikling af SARS-CoV-2 varianter der overvåges i Danmark.Reference Source\n\nUgentlige tendenser: Covid-19 og andre luftvejsinfektioner.Reference Source\n\nMostafa HH, Hardick J, Morehead E, et al.: Comparison of the analytical sensitivity of seven commonly used commercial SARS-CoV-2 automated molecular assays. J. Clin. Virol. 2020; 130: 104578. Publisher Full Text\n\nYip CC, Sridhar S, Cheng AK, et al.: Evaluation of the commercially available LightMix® modular E-gene kit using clinical and proficiency testing specimens for SARS-CoV-2 detection. J. Clin. Virol. 2020; 129: 104476. PubMed Abstract | Publisher Full Text\n\nMoran A, Beavis KG, Matushek SM, et al.: Detection of SARS-CoV-2 by use of the cepheid xpert xpress SARS-CoV-2 and Roche Cobas SARS-CoV-2 assays. J. Clin. Microbiol. 2020; 58: 772.\n\nOpota O, Brouillet R, Greub G, et al.: Comparison of SARS-CoV-2 RT-PCR on a high-throughput molecular diagnostic platform and the cobas SARS-CoV-2 test for the diagnostic of COVID-19 on various clinical samples. Pathog. Dis. 2020; 78: 61. Publisher Full Text\n\nLieberman JA, Pepper G, Naccache SN, et al.: Comparison of commercially available and laboratory-developed assays for in vitro detection of SARS-CoV-2 in clinical laboratories. J. Clin. Microbiol. 2020; 58: 821.\n\nSmithgall MC, Scherberkova I, Whittier S, et al.: Comparison of Cepheid Xpert Xpress and Abbott ID now to Roche Cobas for the rapid detection of SARS-CoV-2. J. Clin. Virol. 2020; 128: 104428. PubMed Abstract | Publisher Full Text\n\nCraney AR, Velu PD, Satlin MJ, et al.: Comparison of two high-throughput reverse transcription-PCR systems for the detection of severe acute respiratory syndrome coronavirus 2. J. Clin. Microbiol. 2020; 58: 890.\n\nPoljak M, Korva M, Knap Gašper N, et al.: Clinical evaluation of the Cobas SARS-CoV-2 test and a diagnostic platform switch during 48 hours in the midst of the COVID-19 pandemic. J. Clin. Microbiol. 2020; 58: 599.\n\nArevalo-Rodriguez I, Buitrago-Garcia D, Simancas-Racines D, et al.: False-negative results of initial RT-PCR assays for COVID-19: A systematic review. PLoS One. 2020; 15: 242958. Publisher Full Text\n\nKristiansen S, Schmidt LE, Hillig ABN: Repository NP and RT-qPCR results. [Dataset] Dryad.2022. Publisher Full Text"
}
|
[
{
"id": "155025",
"date": "05 Dec 2022",
"name": "Mohammad M. Sajadi",
"expertise": [
"Reviewer Expertise Humoral immunity."
],
"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 this manuscript, Kristiansen et al. evaluated the potential of quantitative ELISA for diagnosing and screening SARS-CoV-2 infections based on the viral nucleocapsid released into plasma. Appropriate cut-off value and time gap were identified for the optimum sensitivity and specificity of detection. As a result of this study, it was concluded that the NP method is suitable for diagnosis of infection.\nMajor comments:\nIn the 'RT-PCR reference method', paragraph 3, the authors claim that \"[t]he PCR amplification efficiency was > 96% with a level of detection of 13 ± 25 (mean ± standard deviation [SD]) DNA copies per reaction.\" Please provide the results of this evaluation if it has been done in this study. If not, please add the reference, and also consider changing “level” to “limit”.\n\nIn the serial samples post-infection, the decrease in NP antigen signal has been shown over time (Figure 1). Since this ELISA is a one-step heterogeneous immunoassay, you should demonstrate that this is due to a decrease in NP concentration, and not hook effect or immune complex formation. These can definitely affect the sensitivity/specificity of the assay.\n\nThe 5th paragraph in the Discussion section (\"The present study used the E gene as the target for….\"), this conclusion is not supported by the data in this study.\n\nMinor comments:\nPlease rewrite this sentence in the method in a clearer way: \"Paired NP and RT-PCR results were obtained, either with an either positive or negative time gap...\"\n\n“In general, the clinical sensitivity and specificity of the rapid flow immunoassays are considered inferior to the more sensitive reverse transcription polymerase chain reaction (RT-PCR) based-methods.” These are not considered to have lower sensitivity/specificity, they have less.\n\nThere is no information on replications in the ELISA test. Please add this information in the manuscript.\n\nIn Figure 2, please indicate the concentration of NP at each point, e.g. by adding a legend.\n\nThe first sentence of the second paragraph of the Introduction (\"Hopefully, the SARS-CoV-2 prevalence in the general population…\") is not supported scientifically.\n\nThe instruction for the NP-ELISA method is not available in the provided link in reference 22.\n\nIn Method > Analysis of Data > line 3: Please remove the word “please” from the sentence.\n\nIn Discussion > first paragraph > line 5: It should be \"swab\" instead of \"swap\".\n\nIn Discussion > sixth paragraph: Please add a reference for the second sentence (NP ELISA must provide a limit of detection close to 20 fM).\n\n“P-Amylase is requested for all admitted patients at the emergency department\" - Is this a true statement, or all those who have P-Amylase requested are at the emergency department?\n\n“Thus, a patient without NP - or with rapidly decreasing NP - could be viewed as non- or minimally contagious and could be withdrawn from an isolation protocol.” This doesn’t match with what is known about maximal time of infectivity which is during the first few days (please provide reference if otherwise).\n\nLimitations should be included in the discussion (lack of info on samples, and especially lack of known time since infection started). Time to testing has changed throughout the pandemic so hard to generalize results.\n\nThe page in reference 4 is not given.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "9193",
"date": "22 Feb 2023",
"name": "Søren Kristiansen",
"role": "Author Response",
"response": "Response to Major comments. The evaluation was done prior to clinical use of the PCR reference method which was followed up by the present study. The result of the evaluation of the PCR method has now been added to a new version of the manuscript: E gene plasmid cDNA (Integrated DNA Technologies, Leuven, Belgium) was serial diluted ten-fold in 6 different concentrations and each concentration was PCR amplificated in triplicates. The Ct value from the most diluted sample was < 32. The six average Ct values was linear plotted (Y-axis) against the logarithmic input of E plasmid cDNA (X-axis). By standard linear regression of the line Y = αX + b and the efficiency E = -1+10(-1/slope) the PCR efficiency was estimated to 96 %. E gene synthetic RNA (Twist Bioscience, South San Francisco, CA, USA) was serial diluted five-fold in 6 different concentrations in the interval from 0.5 to 1625 input of RNA copies per RT-PCR reaction. Exponential curve signals above the background signal from multiple blind samples was used to estimate the analytical sensitivity to 13 copies of RNA per reaction at an average Ct value of 38. “Level” has been changed to “limit”. It is correct that the test principle behind the N-antigen immunoassay is based on incubation of serum/plasma together with biotin-labelled N-antigen antibody in wells coated with N-antigen antibodies. This is followed by washing and addition of streptavidin HRP-labelled antibody. Thus, large excess of N-antigen could potentially result in a HOOK effect i.e., which may underestimate the true concentration of N-antigen. However, the SOLSTEN supplier of the CE-IVD assay has evaluated the potential HOOK effect by adding 200 ng/ml (0.2 mg/L) recombinant N-antigen without any observation of any HOOK effect. The study by Thudium et al. (reference 16) used the same assay and determined the N-antigen concentrations in two independent runs with a 24x dilution. The highest N-antigen was 3840 pg/ml (3,830 ng/ml) which is below the test concentration of 200 ng/ml where no HOOK effect was observed. This information has been added to a new version of the manuscript. Thudium et al.16 used the same immunoassay assay as in the present study and determined the N-antigen concentrations in two independent runs with dilution of the sample. The maximal observed N-antigen concentration was 3.840 ng/ml. In comparison when 200 ng/ml recombinant N-antigen was added to control serum no HOOK effect was observed (Solsten Diagnostics International, Aarhus, Denmark). It is correct that the present study has not investigated the overall clinical performance of RT-PCR, but carried out a method comparison of a relatively novel method against the standard method. However, in the discussion section, it is considered mandatory to discuss the strength and the weakness of the study. We have indeed used E gene-based RT-PCR as the reference method. The purpose of the 5th paragraph is to admit the fact that also the standard method (RT-PCR) may cause false results. Especially, when considering the speed in which PCR-based Covid-19 diagnostics was established in independent laboratories without international harmonization, standardization etc. Minor comments Please rewrite this sentence in the method in a clearer way: \"Paired NP and RT-PCR results were obtained, either with an either positive or negative time gap...\" The sentence has been deleted since it may confuse the reader and we believe that the reader will be able to better understand the design and results without this sentence. “In general, the clinical sensitivity and specificity of the rapid flow immunoassays are considered inferior to the more sensitive reverse transcription polymerase chain reaction (RT-PCR) based-methods.” These are not considered to have lower sensitivity/specificity, they have less. Thanks, the error has been corrected. There is no information on replications in the ELISA test. Please add this information in the manuscript. The information has been added in a new version. In Figure 2, please indicate the concentration of NP at each point, e.g. by adding a legend. We have now revised Figure 2 and added specific concentrations to each data point. The first sentence of the second paragraph of the Introduction (\"Hopefully, the SARS-CoV-2 prevalence in the general population…\") is not supported scientifically. Thanks, the sentence has been changed to: If the SARS-CoV-2 prevalence in the general population decrease over the coming years, it is envisioned that diagnosis of SARS-CoV-2 by systematic screening will still be required… The instruction for the NP-ELISA method is not available in the provided link in reference 22. Unfortunately, the method (IFU) is only provided together with the product and not available on the SOLSTEN homepage. We have now changed change reference 22. In Method > Analysis of Data > line 3: Please remove the word “please” from the sentence. “Please” has been deleted. In Discussion > first paragraph > line 5: It should be \"swab\" instead of \"swap\". Thanks, we have replaced replace \"swap\". In Discussion > sixth paragraph: Please add a reference for the second sentence (NP ELISA must provide a limit of detection close to 20 fM). The sentence is deleted. “P-Amylase is requested for all admitted patients at the emergency department\" - Is this a true statement, or all those who have P-Amylase requested are at the emergency department? The sentence is deleted since P-amylase will not be requested for all admitted patients at the emergency department for P-amylase, but we collected samples where P-amylase was requested. “Thus, a patient without NP - or with rapidly decreasing NP - could be viewed as non- or minimally contagious and could be withdrawn from an isolation protocol.” This doesn’t match with what is known about maximal time of infectivity which is during the first few days (please provide reference if otherwise). We have used the phrase “could” with the intention to give the reader this option e.g., the clinical consequence “could” be withdrawn from isolation protocol when no blood NP or decreasing NP concentration was observed. This was one potential aim provided by the clinic before we initiated this study due to the high cost of resources required to isolate patients. The handling of the patient by the medical staff is based on integration of all available information and this could also potentially include monitoring of N-antigen titer. We do not disagree with the reviewer’s notion that isolation should match the time course for maximal infectivity. The sentence is now deleted. Limitations should be included in the discussion (lack of info on samples, and especially lack of known time since infection started). Time to testing has changed throughout the pandemic so hard to generalize results. We agree, and the following paragraph has been added: There are several limitations related to the present study. First, the real time points for the start as well as the end of the infection is unknown. The time point in the present study is the blood and the swab sampling time points, respectively. In fact, it is very likely that the SARS-CoV-2 infection could present in patients several days prior to the sampling time point. However, in the present design aiming at nosocomial screening sampling of blood and swab material is only possible when patients are visiting the hospital. Secondly, the present quality control study of the NP method does not give access to the patient record and other types of sample information. Thirdly, the need to test and time to testing has changed throughout the pandemic due to variations in prevalence of infection and modalities in vaccination strategies. The page in reference 4 is not given. The year and page 1-4 have been added."
}
]
}
] | 1
|
https://f1000research.com/articles/11-732
|
https://f1000research.com/articles/12-203/v1
|
21 Feb 23
|
{
"type": "Opinion Article",
"title": "Interoperability for EU DSM: Implementation of CEF building blocks in the Smart4Health project - success stories and lessons learned",
"authors": [
"Kerstin Neininger",
"Tamara Slosarek",
"Claudia Marx",
"Attila Wohlbrandt",
"Murali Sukumaran",
"Wei Gu",
"Gabriel Sieglerschmid",
"Erwin Böttinger",
"Andreas Kremer",
"Tamara Slosarek",
"Claudia Marx",
"Attila Wohlbrandt",
"Murali Sukumaran",
"Wei Gu",
"Gabriel Sieglerschmid",
"Erwin Böttinger",
"Andreas Kremer"
],
"abstract": "The Smart4Health (S4H) software application will enable European Union (EU) citizens to manage, analyse, and exchange their aggregated electronic health data. This citizen-centred EU electronic health record (EHR) exchange approach for personalised health services will be the first step for the provision of citizen-centred solutions and services in a digital single market for wellbeing and healthcare. Establishing interoperability between the diverse EU EHR data and citizen-generated health data is mandatory to guarantee adequate usability, reliability, and trust of the service. The Connecting Europe Facility (CEF) building blocks address/fulfil such aspects while complying with EU regulations. Here we demonstrate the current status and applicability of the CEF building blocks in the digital health environment for the envisioned S4H software application. The major findings and success stories resulted from the S4H Project are as follows: (1) a secure and user-friendly eID service for the EU-wide Smart4Health community was successfully integrated into the Smart4Health platform, whereby 7 out of the 13 supported EU Member States are already connected, (2) the eTranslation service was compared to other popular alternatives on the market with the result that eTranslation is a secure and valid tool to address multi-language challenges and (3) we identified several use cases for which Smart4Health can benefit from the usage of CEF building blocks, including the improvement of data quality and increase of trust in data sharing.",
"keywords": [
"Electronic health record (EHR)",
"Connecting Europe Facility (CEF) building blocks",
"Digital Single Market (DSM)",
"Digital Service Infrastructure (DSI)",
"data quality and trust",
"Citizen-centred",
"Interoperability",
"Digital Health"
],
"content": "Introduction\n\nSmart4Health (S4H) aims at enabling citizens to manage their own health data throughout the EU and beyond, advancing own and societal health and well-being. To guarantee this sustainability across different data ecosystems, a strong emphasis needs to be placed on ensuring interoperability between different health systems within the European Union. The cross-border usage of digital services and infrastructures by European citizens and businesses can be limited by country-specific regulations, implementations or infrastructures. Consequently, the benefit of using digital services and tools is restricted and the full potential of the digital transformation cannot be realised. To overcome these digital limitations, the Digital Single Market (DSM) will be crucial to provide simplified access for all EU citizens and businesses to available digital tools and services and will also pave the way for new opportunities in the cross-border digital transformation.\n\nThe European Union is funding a pan-European infrastructure, which covers the areas transport, energy as well as digital projects and which is known as the Connecting Europe Facility (CEF) (European Commission, 2020). Thereby, the implementation of the so-called CEF building blocks aims at the digital connection and interoperability between member states of the European Union (2014–2020). The CEF building blocks, provided by the CEF programme, cover several digital services in the field of electronic user identification, document archiving and secure digital communication. The building blocks are in accordance with European regulations and are based on European standards. They can be used by every European citizen or organisation and aim to ensure cross-border interoperability by using a fast, easy and profitable approach for the digital transformation. CEF building blocks are used by European projects and public administration to deliver cross border digital services.\n\nIntegrating the CEF building blocks eID, eDelivery, eSignature, eTranslation, and eHealth enables the DSI to provide a maximum of interoperability with existing services. Very recently, the coronavirus disease 2019 (COVID-19) pandemic has demonstrated the importance of secure digital tools in this critical situation to provide (EU-wide) interoperability. In this regard, the initiative “Building Blocks against COVID-19” was launched by the European Commission (CEF Digital, 2021). The initiative highlights and supports different approaches to improve secure digital solutions in a pandemic setting, which prevent face-to-face appointments and impact different areas of society. The building blocks can be used by European citizens and support, besides governments and businesses, other projects in the fight against the COVID-19 pandemic. The eDelivery, eTranslation, and eSignature building blocks were reported to improve secure digital communication (CEF Digital, 2021; CEF Digital on eTranslation, 2021). Moreover, three big data test infrastructure (BDTI) pilot projects, that defined different use cases and were initiated in different cities and were highlighted by the European Commission to support the fight against COVID-19 (CEF Digital, 2021; CEF Digital on eTranslation, 2021). The three pilot projects based on BDTI were initiated in Florence (CEF Digital on COVID-19, 2021), Milan (CEF Digital on Lockdown Prediction, 2021) and Valencia (CEF Digital on Clinical Evidence, 2021).\n\nTherefore, the Smart4Health platform integrates CEF building blocks as bridging tools and actively engages with the European Commission services and CEF programme. The Smart4Health (S4H) software application will empower EU citizens to manage, analyze, and exchange their aggregated electronic health data. The Smart4Health project objective and platform architecture is described below. The CEF Digital programme has concluded that its platform is no longer being updated after 2020 (CEF Digital on the CEF Digital programme, 2021). The discussions on ‘How CEF digital would continue’ are ongoing, and we are actively monitoring the developments.\n\nHere we present our development efforts in the establishment of synergies and ensuring interoperability with existing services by using the EU Digital Single Market (DSM) CEF building blocks in healthcare. We focus on the implementation and usage of the CEF building blocks in the H2020 project Smart4Health, especially highlighting the integration and usage of eID, eTranslation, and Patient Summary as part of the eHealth DSI. In addition, an overview of all CEF building blocks together with an analysis of how different CEF building blocks can be integrated in Smart4Health is given.\n\n\nCEF DSIs and Smart4Health: basic infrastructure, governance, and interoperability framework for citizen-centred EU-EHR exchange\n\nThe Smart4Health project (S4H, started 2019) aims to create a citizen-centered platform for the management and exchange of health records across Europe. For the development of a usable service dealing with confidential information in the form of medical data, specific functionalities, such as identification & authentication, translation, and a secure data transfer, are needed, especially in the pan-European setup. Therefore, Connecting Europe Facility (CEF) programme (Connecting Europe Facility, 2022) funds different projects that implement Digital Service Infrastructures (DSIs). As more general DSIs, CEF building blocks, such as eID and eTranslation, can be reused by other projects and larger DSIs, for example, eHealth. CEF building blocks that implement trust services comply to European law as laid down in the eIDAS Regulation (Regulation (EU) No 910/2014).\n\nThe following sections highlight which DSIs were implemented in the S4H software application, the lessons learned and the usability of DSIs to support interoperability between different health systems within the European Union.\n\nThe Smart4Health project, which was funded by the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 826117), follows a truly multidisciplinary approach with a project team constituted by 18 beneficiaries from eight different European Union member states and the United States of America, including ICT developers, hospitals, social sciences researchers, physiotherapists, nurses, informal caregivers, regional government, research centres, universities and SMEs. The consortium (funded in period 2019-2023) aims at empowering EU Citizens with an interoperable European Electronic Health Record (EHR) exchange that supports EU citizens to manage and bridge their own health data throughout the EU and beyond, thereby advancing their own and societal health and wellbeing.\n\nThe key objective of Smart4Health is to place the citizen at the centre of decisions with regard to their own healthcare by enabling the possibility of sharing health data with different clinicians, healthcare facilities, local and international societies, for research activities as well as to engage directly with healthcare providers.\n\nThe S4H platform allows citizens to collect, store, manage, access and share their own health and healthcare data, through an easy-to-use, secure, constantly accessible and portable prototype; within the EU and beyond. Citizens are able to upload and share data with health care professionals in situations when reliable health information is essential to ensure efficient health care as well as with other persons of trust such as family members. Finally, citizens willing to support science can provide their data to the scientific community. Smart4Health will contribute to a positive impact on EU citizens’ health and wellbeing, for building today a healthier tomorrow.\n\nThis section explains relevant aspects of the S4H software application that are needed to assess the feasibility of the integration of CEF DSIs. Figure 1 shows the system architecture. The S4H platform is divided into the Citizen Health Data Platform (CHDP) and the Research Platform (RP). The CHDP holds all citizen data in encrypted form. Only the citizen can access their own data, the platform provider only receives it in the backend in encrypted form, according to the privacy-by-design principle, which ensures data confidentiality and security. Together, the Citizen Health Data Platform and the Research Platform combine into the so-called 4HealthPlatform (backend). The 4HealthNavigator functions as user interface (frontend) to access the 4HealthPlatform. Details are available in D2.1 4HealthPlatform detailed prototype plan and specifications requirements report (Smart4Health Deliverables, 2019-2022). As a result, all operations on the citizen data happen on the client-side, e.g., in third-party apps. When citizens provide their health data for research purposes, it is de-identified via the MyScience app and stored in the RP, from which approved researchers can then access it. The CHDP includes a web application called User Portal, where the citizens can access basic functionality such as viewing, managing, sharing, and providing their health data to research. The connection between the User Portal and the CHDP is enabled by a software development kit (SDK) that takes care of the authorization and en-/decryption processes for external applications. The health data stored and transferred into CHDP follows the Fast Healthcare Interoperability Resources (FHIR) standard. Moreover, third-party apps can also connect to CHDP using the SDK, if they are registered by the platform provider and granted access by the user.\n\nTogether, the two components Citizen Health Data Platform and the Research Platform combine into the so-called 4HealthPlatform, which is accessible to the user via the 4HealthNavigator (user-facing frontend).\n\nDifferent healthcare and consumer health data sources can be connected to the CHDP, either through an ingestion pipeline, or through applications connected via the SDK. The data stored in the platform uses the FHIR standard, which requires preparatory steps such as data harmonization and quality validation.\n\nIn the process of providing data for research, the data is de-identified and converted to follow the OMOP Common Data Model specification. Subsequently, researchers can access the data using the Researcher Portal, which is also part of the RP. This enables them to conduct analytical queries as well as work on machine-learning algorithms. From there, data can be exported to external, 3rd. party research infrastructures, as conducted in the project with ELIXIR.\n\nThis section describes the basic infrastructure of the CEF DSIs and the current implementation in the Smart4Health project. We highlight the CEF DSIs that qualify for the inclusion into the S4H software application: eID, eSignature, eTranslation, eDelivery, and the patient Summary as part of the eHealth DSI. Each DSI section is separated into several subsections describing the CEF usage, implementation in its current status and an outlook. Another article, which covers parts of the preparatory work of this article, can be found on arxiv.org (doi: arXiv.2001.01477).\n\nAs Smart4Health is managing confidential information (medical and health-related data), secure data transfer as well as robust identification and authorisation functionalities are of utmost importance. This feature is especially relevant in a cross-border or pan-European setup. The Connecting Europe Facility programme funds different projects that implement Digital Service Infrastructures. More general DSIs, called CEF building blocks, such as eID and eTranslation, can be reused by other projects and larger DSIs, including eHealth. An overview of the possible CEF building block integration and their Smart4Health implementation is described in the following chapters and is shown in Figure 2.\n\nThe current implementations of eID and eTranslation are described in the following sections. Note that the 4HealthPlatform consists of the Citizen Health Data Platform and the Research Platform, whereas the 4HealthNavigator describes the user-interface of the S4H platform.\n\nCEF building block eID\n\nThe CEF eID building block enables cross-border identification for EU citizens when accessing online services by using their national electronic identification (eID) schemes, such as smartcards (CEF Digital, 2020). EU citizens will be able to use their eID credentials to access digital public services in EU Member States that are different to their eID issuing country. The mutual recognition of national eID schemes across the EU is laid down in the eIDAS regulation. It defines aspects such as notifications, assurance levels, and a minimum data set, which are explained as follows.\n\nThe notification process monitors that national electronic identification schemes comply with certain criteria to ensure interoperability (Art. 9 eIDAS). The process roughly consists of pre-notification, peer-review, and notification. The notification of a national eID scheme is voluntary, however, only notified schemes need to be recognized by other Member States. Assurance levels refer to the “degree of confidence in the claimed or asserted identity of a person” (Art. 8(2) eIDAS). To be recognized by other Member States in cross-border identification, the assurance level needs to be substantial or high.\n\nThe Commission Implementing Regulation (EU) 2015/-1501 lays down technical and operational requirements of the interoperability framework. This ensures that the interoperability of the electronic identification schemes which Member States notify to the Commission are compliant with the eIDAS regulation. It defines a “minimum data set of person identification data, uniquely representing a natural or legal person, pursuant to Article 12(8) of the eIDAS Regulation”. For example, for a natural person, the mandatory attributes are current family name(s), current first name(s), date of birth and a unique identifier. Note that every citizen who is applying for an eID will have an own eID card and therefore a distinct unique identifier. The unique identifier is determined as “constructed by the sending Member State in accordance with the technical specifications [as set out in article 12 of regulation 2015/-1501] for the purposes of cross-border identification and which is as persistent as possible in time”. This is implemented differently by Member States, Germany for example creates a pseudonym that depends on the smartcard and the requesting Member State (for public-sector bodies) or the relying party (for non-public-sector bodies); other countries use tax codes or national personal identification codes.\n\nThe mutual recognition between member states is implemented by the decentralized eIDAS network that consists of eIDAS nodes. Every Member State needs to implement and maintain its own node. A node can receive and send eIDAS requests in a common format and translate between the national eID scheme and the eIDAS request.\n\nUsage in Smart4Health\n\nWithin the Smart4Health project, the eID is integrated as an alternative authentication method to using email and password. In order to use this authentication method, an account must be created first, to which the eID may then be added.\n\nAdministrative prerequisites\n\nFrom the administrative side, before starting the technical implementation, a certificate of authorisation was needed to be obtained by the responsible authorities. It was necessary to communicate internally applied measures and compliance for data protection matters, the intended eID information request (family name, name at birth, first name, date of birth, unique identifier), as well as a description of the intended use within the service planned.\n\nThe certificate in the context of the Smart4Health project was issued by the German Federal Office of Administration (Bundesverwaltungsamt). Subsequently, an eID service provider was contracted to establish the necessary technical eIDAS connection to the respective country nodes. As a part of the signed agreement, the service provider will not only provide the technical information needed to implement the infrastructure but also assists further with the handling of technical difficulties or occurring error messages.\n\nTechnical integration\n\nFor enabling the eID login, a split of the user authentication from the cryptographic operations needed for the en-/decryption of the users data, was necessary.\n\nUser interface\n\nUsers can connect their eID to their account via the account settings. The user chooses the issuing country of their e-ID and is subsequently directed to the correct national eID service provider portal, see Figure 3. After going through the steps to connect their eID with the external eID service provider, the user gets redirected to the S4H account settings. The eID status window now shows the successful eID connection to the account. Users can remove their eID, for instance to protect their account in case they lose their eID, or to replace it with a new eID in the future.\n\nFor the user authentication flow, the design was optimized by adding an eID sign-in option using a new button on the sign-in page. Anticipating that some people might not be familiar with the concept of eID, it was suggested to add a modal to offer some guidance. The modal appears after clicking “What’s e-ID?” and briefly explains what eID is, how eID could improve the experience for the user, and how the user could connect an eID to their account, see Figure 4. Once the user clicks “Sign in with e-ID”, they are led to an overview of supported countries (Figure 3). The procedure is then identical to the establishment of the eID account connection. After successful authentication via the external eID service provider portal, the user is redirected to the S4H overview screen, and has access to the usual functionalities.\n\nTechnical background\n\nThe technical integration is centred around the concept of eIDAS tokens. An eIDAS token is a document implementing the TR-03110 specification (BSI TR-03110 specification, 2021). Examples of such tokens are federal ID cards or electronic residence documents. The notion of eIDAS token and eID card will be used synonymously in this document. eIDAS tokens contain an RFID chip that stores encrypted data fields with holder’s data such as names, address, etc. It also offers to execute functions and return their results as if they were normal data fields. The German ID card, as an example, offers age verification, where during card initialization, a probe age (e.g., 18 years) is sent to the chip which will reply with either true or false, thus not revealing the actual birth date. Another function of the German ID card is the restricted ID. Given an application ID (called sector-specific ID in eID parlance), it uses hard-coded card data (like a serial number) to deterministically derive an application-specific pseudonym. The returned value will be the same whenever “reading” that pseudonym from the same card using the same sector-specific ID. This restricted ID is used in eIDAS as the unique identifier.\n\nSpecific design goals and decisions were applied to implement eID in Smart4Health. Firstly, the unique identifier is used as an alternative user ID. To re-recognize a user during login, only the eIDAS token needs to be re-recognized. Hence, the unique identifier from the eIDAS token needs to be read and associated with a user account as an alternative user ID. Second, the unique identifier is kept in the backend only. The decryption of the unique identifier its storing and checking are activities carried out by services in the backend of Citizen Health Data Platform (CHDP). Hence, there is no reason to transfer the unique identifier to the browser. Last, to encapsulate the integration component in an internal layer, the integration component, known as the eService, implements the eID/eIDAS protocol and is hosted in the backend.\n\nInteraction flow\n\nOnce the user is in the web application, they have two options (use cases): (1) Signing in - while being in the WebAuthApp, or (2) Connecting an eID to the user account - while being in the account settings page. The user will be presented with a country list (country codes) from which they select the issuing country of their eID. Next, the Smart4Health platform generates a random value called a verifier and stores it in the app's secure storage.\n\nThe browser will then follow a sequence of HTTP redirects, during which the user will be asked to interact with a connected card reader device, a mobile phone app, or any other option, depending on the protocol of the respective country. In detail, this URL contains a challenge query parameter which is the SHA256 hash of the aforementioned verifier. The navigation to the liftoff URL leads to a sequence of HTTP GET redirects or HTTP POST bounces and eventually to either an “AusweisApp” popup or eIDAS interaction. If successful, the eID data (here: the encrypted unique identifier) will be sent to the eService as a SAML response from these HTTP GET or HTTP POST requests where the eService then decrypts and keeps the unique identifier for a predefined amount of time (currently two minutes).\n\nFinally, the browser will re-enter the S4H app from where the user started and command the CHDP to retrieve the unique identifier from the eService to execute what the selected use case requires. For instance, issuing an access token for signing in or amending the user account for connecting an eID. The app sends the verifier to the CHDP which uses it to retrieve the corresponding unique identifier.\n\nCurrent status and outlook\n\nThe technical integration has been successfully completed and rolled out to the productive system. Currently, 7 out of the 13 EU Member States supported by our service provider are successfully connected and available to S4H users (cf. Table 1). The service provider currently engages with the pending Member States in order to bring the pending Member States into our integration. As Austria is listed as a pre-notified member state since 27/09/2021, it is expected to be added soon.\n\nThe setup of this monitoring capability is currently still in progress as the events must be defined in detail and need to be technically implemented subsequently.\n\nCEF building block eSignature\n\nThe eSignature CEF building block provides a sample implementation to create and validate electronic signatures. In the eIDAS regulation, three types of electronic signatures are defined. In this section, the differences between available electronic signatures are highlighted. Moreover, certificates, electronic signature creation devices and electronic seals are described.\n\nFirst, a basic electronic signature is “data in electronic form which is attached to or logically associated with other data in electronic form, and which is used by the signatory to sign” (Article 3(10) eIDAS), while the signatory is a natural person (Article 3(9) eIDAS). This means, an electronic signature can simply be a name typed under an email or a checkbox clicked by a user. An advanced electronic signature “is uniquely linked to the signatory, capable of identifying the signatory created, using electronic signature creation data that the signatory can, with a high level of confidence, use under his sole control, and linked to the data signed therewith in such a way that any subsequent change in the data is detectable” (Article 26 eIDAS). This, for example, can be accomplished using a digital signature based on a certificate (see Figure 5 for details).\n\nAlice wants to sign a document and send it to Bob. The data is signed by creating a hash, encrypting it with Alice’s private key, and attaching it to the document When Bob receives the signed data, he creates the hash himself and decrypts the signature using Alice’s public key, which usually is stored in a certificate. If both hashes match, the signature is valid; it means that Alice is the signer and the document was not changed (adapted from Digital Signature Generation, 2019).\n\nThe most powerful type of electronic signature is the qualified electronic signature that has “the equivalent legal effect of a handwritten signature” (Article 25(2) eIDAS). It is “an advanced electronic signature that is created by a qualified electronic signature creation device, and which is based on a qualified certificate for electronic signatures” (Article3(12) eIDAS). A certificate for electronic signatures is “an electronic attestation which links electronic signature validation data to a natural person and confirms at least the name or the pseudonym of that person” (Article 3(14) eIDAS). A qualified certificate for electronic signatures is “a certificate for electronic signatures, that is issued by a qualified trust service provider” (Article 3(15) eIDAS) and moreover, meets certain criteria laid down in the eIDAS regulation, such as that it contains “details of the beginning and end of the certificate’s period of validity” (Annex I eIDAS).\n\nAn electronic signature creation device is “configured software or hardware used to create an electronic signature”. To become a qualified electronic signature creation device, it must meet further requirements, such as to ensure that “the confidentiality of the electronic signature creation data used for electronic signature creation is reasonably assured” (Annex II eIDAS). The German eID smartcard, for example, is an electronic signature creation device that holds a qualified certificate for electronic signatures and is capable to create qualified signatures. Electronic seals follow similar regulations as electronic signatures but are applicable to legal persons instead of natural persons (available via the eSeal building block). Primarily, the type of certificate needed for a qualified electronic seal differs.\n\nUsage in Smart4Health\n\nWithin the Smart4Health project, use cases such as signing informed consent forms or as proof of origin are conceivable. These use cases comprise data flow through the ingestion pipeline and are also applicable for data exchanges between health care professionals beyond Smart4Health.\n\nFirst, eSignature can support the validation of signatures needed for the informed consent forms. To be able to use the different services within the Smart4Health program, the user or citizen needs to agree on different types of informed consent forms. Examples for these services are the platform usage consent or data donation consent in case health-related data is transferred from the citizen health data platform to the research platform.\n\nMoreover, the use of eSignature as proof of origin for third parties in ingestion is possible. Assume, for example, that a health care provider (e.g., a hospital) shares a medical document. The provider can sign it digitally using eSeal to make sure that (1) the medical document was not changed after signing and (2) it was issued by this specific health care provider. Electronic seals follow similar regulations as electronic signatures but are applicable to legal persons instead of natural persons. Primarily, the type of certificate needed for a qualified electronic seal differs. This could be especially reasonable if the citizen that receives the document shares it with another health care provider, for example their general practitioner, that also might want to ensure the integrity and origin of the document. Currently, the Smart4Health architecture uses a registered SDK for data ingestion and encryption, with which the integrity and origin are always ensured.\n\nFurthermore, eSignature could be used as proof of origin for professional user. In general, health care providers who are not part of Smart4Health, which means they are not connected through the ingestion pipeline, shall also be able to upload content for the user. To ensure data integrity and proof the origin of uploaded content, a digital signature could be used. Currently, this use case implementation is under consideration. We are aware that using eSignature can increase trust and facilitate the delivery of digital public services across borders. Therefore, this will be further investigated.\n\nImplementation plan and status\n\nAs a first step, the consortium has asked for a legal opinion by Dierks&Co, which concludes:\n\n“The service provider is not obliged by law or contractual agreements to verify the identity of citizens who wish to use the 4HP and to use an eID procedure or eSignature procedure for this purpose. Identity verification may be required in the future when doctors use 4HP as documentation for their patient files or provide remote treatment via 4HP.” (Dierks&Company, Memo on eID and eSignature, June 5th, 2020).\n\nConsidering the eSignature pan-European context, discussions were carried out with the eID and eSignature development teams. Following this, it was communicated that the eSignature sample implementation Digital Signature Service (DSS) would need to be adapted to fit into the pan-European context. The consortium is closely monitoring the ongoing developments and pro-actively follow-up with the CEF development teams. As eSignature is building on eID and is currently not blocking the developments, we have focused on the realisation of eID as described before.\n\nConsidering that a basic electronic signature is sufficient for all Smart4Health-related use cases, we see the efforts and risks to implement eSignature will be too high, and currently resort to other methods such as ticking a checkbox, e.g., within the Authentication Service, D3.2 4HealthNavigator portal user sign-up, login, and record deletion, or signing with a handwritten, yet digital signature, e.g, within the Dynamic Consent Service, D3.3 4HealthNavigator: Dynamic Consent, and Sharing (Smart4Health Deliverables, 2019-2022). For the consent forms signed for the participation in the use cases, paper-based signatures are used.\n\nCEF building block eTranslation\n\nProviding a service to support translations in a multi-language user community is also the aim of the cross-border platform Smart4Health. The CEF eTranslation building block is a translation service based on neural machine translation. It was trained on the Euramis translation memories that include over one billion sentences in the 24 official EU languages, most originating from legislative documents. Therefore, eTranslation can translate between all these languages and is particularly suited for the needs of EU policy documents (Euramis eTranslation Documentation, 2022). An ongoing discussion with the responsible teams at the commission indicated a strong interest to broaden the text-corpus and to include medical terminology.\n\nAs an input, either plain text or formatted files in various formats (e.g., docx, pdf, html) can be provided. The service is accessible in two ways, either via a web-interface for human-to-machine use, or through an API for machine-to-machine use.\n\nUsage in Smart4Health\n\nIn Smart4Health, eTranslation shall be used to translate medical content that is either not in the citizen’s preferred language or that should be shared with parties speaking other languages. In this way, the Smart4Health infrastructure supports and provides interoperability with cross-border health systems interactions. Additional to the translation of medical documents, the meaning of medical codes in structured data could be translated by eTranslation but generally they are already available in multiple languages.\n\nThe eTranslation component could be included in Smart4Health as a translation service, so that data sets can be translated into the needed language on demand. An example could be when a citizen gets injured in their vacation outside their country of origin. The citizen can provide the pre-existing health documents to the local health care professional in a foreign language. After the treatment, the citizen receives medical documents in a foreign language. Therefore, eTranslation could help to directly translate these documents from and into the mother language of the citizen.\n\nMoreover, another use case is in the context of communication, training, and education to reach citizens, medical, research and ICT communities. A goal could be to translate direct communication, education and training materials that are developed in the Smart4Health context within WP6 Dissemination, Exploitation, Sustainability and Communication for tasks T6.1 Helpdesk and assistance hubs, T6.2 Massive Open Online Courses, T6.3 Training and education: User-targeted education, and T6.5 Communication and Visibility Plan (Smart4Health Deliverables, 2019-2022).\n\nTechnical integration and evaluation\n\nThis section describes the usage of CEF eTranslation as part of the project internal communication, the evaluation of it, and the envisioned architecture to include it in Smart4Health.\n\nProject communication\n\nThe language is a big challenge when one wants to support and reach people in Europe. Therefore, Smart4Health is successfully using the eTranslation language tool (2021) provided by the Connecting Europe Facility (CEF). For instance, concerning the Helpdesk, eTranslation is used to enable a quick support of non-English speaking citizens during the project phase: it has been used successfully to translate enquiries from German and Portuguese into English. For now, Smart4Health curate the answers to citizens and the automatically generated template answers available in the internal knowledge base, provided by native speakers that are part of project consortium. The public knowledge base provides information in all supported languages (English, German, Portuguese, French, Italia, Dutch, Spanish) utilizing the eTranslation language tools to provide the information with an appropriate disclaimer. News posts on the website also make use of eTranslation for all supported languages using a disclaimer. The actual website content is currently curated with the consortium before taking it live due to the very specific domain language. For further information also see D6.14 2nd Training and education modules and events: education campaign (Smart4Health Deliverables, 2019-2022).\n\nCEF eTranslation evaluation\n\nTo evaluate and compare CEF eTranslation to three other commonly used machine translation services in the biomedical context, a master’s thesis work was conducted at HPI. The other machine translation services are DeepL, Google Translate, and IBM Watson Language Translator. A publication of the results is planned but a short overview is given below.\n\nDifferent biomedical corpora were identified that include the same text in different language pairs. According to a power analysis, a final corpus was assembled from the identified corpora. Sentence pairs presented in English-French, English-German, and English-Spanish were included, based on their availability in the identified corpora. Then, machine translation services were used to translate sentences from French, German, and Spanish to English. Based on their similarity to the expected English sentence, the translations were evaluated using established measures in Natural Language Processing. Finally, the similarity scores were statistically evaluated, accompanied by a human validation of the results. The evaluation pipeline is depicted in Figure 6.\n\nConcerning the quality of translation, all the translation services performed well. Two translation services, DeepL and Google Translate, significantly outperformed the CEF eTranslation, but with small effect size. With respect to translation speed, CEF performed worst. This is probably due to its asynchronous implementation. However, when it is used as a service in Smart4Health, we assume that slightly higher response times are acceptable.\n\nRegarding data protection and privacy, we consider CEF eTranslation the best of the four options, since it is being developed, deployed, and used in the environment of the European Commission. As of now, the identifiable health data needs to be sent to that environment, so S4H highly encourage CEF to provide on-premise solutions to minimize security and privacy concerns. CEF eTranslation supports PDF document translation, which is a valuable feature in the Smart4Health context. Therefore, CEF eTranslation appears as a reasonable choice to be used in Smart4Health project. Additionally, according to its documentation, eTranslation supports language detection of the source language, which would be another useful feature; however, it currently only available via the web service.\n\nEmbedding in Smart4Health architecture\n\nUsers can trigger translations directly from their smartphones using the Translation App. The decrypted health data is then sent to a separate backend service, the Translation Connector, which forwards it to the Translation Service, i.e., CEF eTranslation, receives the translation, and sends the translated data back (see Figure 7). A separate backend was implemented to (1) send the request and (2) abstract the translation service and make the asynchronous CEF eTranslation service flow usable for smartphones. However, it shall be noted that sending data to an external service violates the privacy-by-design principle and requires informed user consent. It is currently deployed in a secure on-premises environment at the HPI.\n\neTranslation App\n\nThe eTranslation App has the responsibility of moving health data between the CHDP and the Translation Connector. The translation workflow of the Translation App is shown in Figure 8. Users see a list of resources that are available for translation, select which ones should be translated and what the target language should be, and the app handles uploading, checking for results, and storing results in the CHDP automatically.\n\nCEF eTranslation does not have language detection capabilities, nor could any automatic language detection be considered perfect, so another important function of the eTranslation App is to manage the original language of resources. New resources without existing language information are assumed to be in the language of the user's device, or, if that language is unsupported, English. Users may override this assumption for all resources or on a case-by-case basis.\n\nAfter a resource is translated, the original language, whether it was inferred or set by the user, is embedded as FHIR extension data within the newly translated resource, along with other metadata. Downstream consumers, including the eTranslation App itself, can then understand that a resource was automatically translated between a pair of languages, and process it accordingly. In the case that a translation was done with an incorrect original language, or in the case that a resource was translated again with the same language pair, previous translated resources are updated with additional FHIR extension data marking them as “deprecated”.\n\nCEF building block eDelivery\n\nThe CEF eDelivery building block works independently of a specific technical environment and defines the technical requirements for secure and reliable data exchange between different parties (eDelivery Documentation, 2022). It is based on encryption and digital signatures, and provides legal assurance that data is delivered once (and only once), even when the receiving party is temporarily unavailable.\n\nThe building block is structured in a so-called 4-corner model, where the communicating systems do not interact with each other directly but via Access Points that exchange data based on specific standardized protocols (eDelivery Access Points, 2019).\n\nFor all components, sample implementations exist. The software components are intended to be deployed as part of a backend setup on an application server with a dedicated database. Additionally, the CEF eDelivery Public Key Infrastructure service can be used to issue and manage digital certificates for signing and encrypting messages.\n\nUsage in Smart4Health\n\nWithin the Smart4Health project, eDelivery can be used to perform data transfer from the Research Platform to ELIXIR-LU, from the Research Platform to researchers, and communication with eHealth National Contact Points. These uses cases will be described as follows: First, considering data transfer to ELIXIR-LU, the initial process for transferring data from the Research Platform will be manually transfers of dedicated data dumps. For an automation, eDelivery can be considered whereby the Smart4Health infrastructure would be connected to one access point and ELIXIR-LU to the other access point. However, after evaluating the use case of data provisioning from 4HP-RP to ELIXIR-LU’s platform, which is between two trusted services, we concluded that the eDelivery is not necessary for this process and would likely become an overhead.\n\nCurrently, researchers access data directly, which could be supported by the eDelivery CEF building block to directly transfer data from the Research Platform to researchers. Smart4Health have further examined that data should not be transferable to the researchers (e.g., via a download). Thus, further elaborations on secure measures concerning the data transfer are not necessary.\n\nFor the data transfer with eHealth National Contact Points, eDelivery could be of interest. Smart4Health assessed how data is transferred and how security of the data transfer is ensured. Moreover, whether eDelivery is a reasonable solution also depends on the architecture of national contact points (NCPs).\n\nImplementation plan and status\n\nCurrently, Smart4Health project partners do not see useful scenarios to incorporate eDelivery in the S4H system. But a close monitoring of the ongoing developments will be made, plus pro-actively keep following-up with the CEF development teams, and further inspecting other use cases and scenarios.\n\nPatient Summary as part of the eHealth DSI\n\nThe eHealth DSI (eHDSI) is being developed in an ongoing EU project and aims to provide services and infrastructures that enable cross-border healthcare facilities (CEF Digital, 2017). It is defined by two main use cases that are particularly of importance abroad: The Patient Summary that holds key health data of a patient, which supports health professionals in unplanned care encounters, and ePrescription that describes a process to enable digital prescription and dispensation from a health care provider to a patient. To ensure interoperability between countries, the eHDSI architecture consists of only few central services, including facilities for configuration and terminology. The focus lies on distributed services per Member State, in form of national contact points for eHealth (NCPeHs, in the following called NCPs). NCPs of different countries can exchange health data, such as Patient Summaries and ePrescriptions, on top of national data formats and schemes in a standardized way.\n\nDue to the eHealth Digital Service Infrastructure both ePrescriptions and Patient Summaries can be exchanged between EU countries. Looking at the official website (European Union, 2021), the currently operational exchanges are visualised in Figure 9. It was found that\n\nBackground map from (Nations Online Project, 2021), own visualisation.\n\n“By 2025, both services will be gradually implemented in 25 EU countries: Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Luxembourg, Malta, the Netherlands, Poland, Portugal, Slovenia, Spain, Sweden, Slovakia, Latvia, and Bulgaria.” (European Union, 2021).\n\nUsage in Smart4Health\n\nIn the context of Smart4Health, being a citizen-centred solution, the project is not addressing the actual ePrescription process but enables the inclusion of the incorporated data of this process to be available to citizens. Smart4Health incorporates the international patient summary, which contains medications, allergies and intolerances etc. This is well aligned with the efforts of the policy owner of the eHDSI, the eHealth Network (eHN). As reported in their 16th annual meeting planned actions:\n\n“regarding the alignment of the guidelines, the associated eHDSI services and the International Patient Summary (IPS) standard. Contributions have been provided by the CEN IPS team. […] It is proposed that […] a paper be written for the eHN which provides:\n\nConfirmation that the IPS will form the basis of the technical specification for the guidelines\n\nA statement of intended convergence between IPS and eHDSI;\n\nAn outline roadmap and schedule that are realistic for eHDSI;\n\nProposals for the governance of the IPS and eHDSI specifications.”\n\n(eHealth Network, 2019)\n\nTo clarify the difference between the process (ePrescription/Dispensation) and the incorporated data (medication plan) a renaming is documented in D7.5 1st Risk management, quality assurance and contingency strategy report (Smart4Health Deliverables, 2019-2022). More information regarding the international patient summary formats and their usage in Smart4Health is described in D3.4 4HealthNavigator User Portal (Smart4Health Deliverables, 2019-2022).\n\nImplementation plan and status\n\nThe cross-border exchange of the international patient summary is central in the Smart4Health project and is directly addressed in the so-called Citizen Use Case 2. For this, Smart4Health is connecting the healthcare providers directly. How a connection to the eHDSI via the National Contact points could be established needs to be further discussed. The Smart4Health consortium partners have established the connection to the gematik GmbH on April 27th, 2020, to establish a close collaboration and follow up on the developments of a German NCP. Also, UNINOVA has established links with SPMS for the Portuguese NCP. Smart4Health is also following closely the developments of the eHDSI, and the eHealth Network. An investigation on interoperability and status of the NCPs is provided in D6.20 (M36).\n\n\nSmart4Health outcomes and lessons learned\n\nThis section examines, which DSIs are implemented in the S4H software application, the lessons learned and their usability to support interoperability between different health systems within the European Union. Box 1 summarises the success stories and lessons learned by evaluation and integration of CEF Digital Service Infrastructures in the Smart4Health project.\n\nConnecting Europe Facility (CEF): fund from the European Union to support interoperability throughout all member states by, for instance, providing digital services and infrastructures; Electronic identification (eID): CEF Building block that enables user authentication and authorization services; eHealth Digital Service Infrastructures (eHDSI): health-related services and infrastructure with the goal to support European citizens and enable cross-border interoperability in the healthcare sector.\n\nSuccess stories: “Implementation of Connecting Europe Facility (CEF) building blocks in the Smart4Health project”\n\nThe integration of electronic identification (eID), which works as an alternative authentication scheme, was built into Smart4Health application. It is used by the citizens in a user-friendly and straightforward process.\n\nAlso, eTranslation is being used for the translation of information material in the Smart4Health consortium. The integration as a translation service in the Smart4Health software application is being continued by conducting an evaluation of the service and its translation quality. An in-depth evaluation and comparison with other state-of-the-art translation services showed that CEF eTranslation appears as a reasonable choice to be used in the Smart4Health project. The developed eTranslation App implements CEF eTranslation service, extends this by language detection capabilities and is tailored to the citizen needs in Smart4Health.\n\nGenerally, the Coronavirus disease (COVID-19) pandemic shows the importance of secure digital solutions that support interoperability across European Union (EU) member states and further emphasizes the importance for Smart4Health to continue developing and integrating these solutions in the form of CEF building blocks.\n\nLessons learned: “Using CEF Digital Service Infrastructures in the Smart4Health Project for the Exchange of Electronic Health Records”\n\nBased on the experience gained within the Smart4Health project, and several success stories as outlined, the authors suggest that their lessons learned should be considered when using the CEF Digital Service infrastructures:\n\n\n\n1. The definition of use cases is of utmost importance. We identified several use cases for which Smart4Health can benefit from usage of CEF building blocks. Among them are improvement of data quality, verification of identification data during registration and increase of trust in data sharing.\n\n2. By using eID, we successfully demonstrate the integration of an alternative authentication method in addition to the commonly existing ones, for example, using email and password.\n\n3. Besides technical prerequisites, also administrative prerequisites must be considered and evaluated prior to the implementation. External partners such as the (national) eID service provider are necessary.\n\n4. Being secure and user-friendly at the same time is often challenging when integrating digital services such as eID. An approach to manage this balancing act was demonstrated here.\n\n5. Regarding data protection and privacy, we consider CEF eTranslation service as the best of the four options presented in this report (options: CEF, Google, IBM, and DeepL).\n\n6. CEF eTranslation offers several useful translation services and, for instance, supports PDF document translation. These are all valuable features in the Smart4Health context.\n\n7. Evaluation of secure electronic signature in the context of eSignature showed that the basic electronic signature is sufficient for all Smart4Health-related use cases.\n\n8. Cross-border exchange of the international patient summary is central to the Smart4Health project. Due to the eHealth Digital Service Infrastructure, both ePrescriptions and Patient Summaries can be exchanged between EU countries. In order to do so, a connection to the eHealth Digital Service Infrastructures (eHDSI) can be established via the National Contact points.\n\n\nConclusion\n\nWe believe that this technical report demonstrates, on the one hand, the importance of secure digital tools to provide (EU-wide) interoperability, and on the other hand outlines the challenges, lessons learned and finally success stories by using the CEF Digital Service Infrastructures to exchange of electronic health records. After evaluation of several use cases, the Smart4Health consortium integrated eID and eTranslation building blocks.\n\nThe integration of the eID CEF building block in Smart4Health supports cross-border identification, verification of personal attributes at Smart4Health registration and was integrated to increase trust between the citizen and other parties. In Smart4Health, the technical integration of eID has been successfully completed and rolled out to the productive system. Thereby, 7 out of the 13 supported EU Member States are successfully connected and available to the EU-wide Smart4Health user community.\n\nThe evaluation study showed that eTranslation offers the best service regarding data protection and privacy compared to other popular translation services on the market. Nevertheless, Smart4Health highly encourages CEF to provide on-premise solutions for the eTranslation tool, considering security and privacy.\n\nConsidering building blocks such as eSignature, eDelivery and eHealthDSI, the consortium is closely following the ongoing developments and evaluating a potential implementation in Smart4Health, thereby also evaluating efforts and risks of an integration (see e.g., eSignature). Regarding the eHealthDSI, we reported that Smart4Health now incorporates the international patient summary, which contains both medication plan and patient summary.\n\n\nAuthor contributions\n\nK.N., T.S., C.M., and A.W. have been the main contributors to the paper. M.S., G.S., W.G., E.B., and A.K. co-wrote the manuscript.",
"appendix": "Data availability\n\nNo data is associated with this article.\n\n\nAcknowledgements\n\nWe thank all members of the Smart4Health consortium for their contribution and support. We thank Renza Roncarati and Caroline Schulte from ITTM S.A., Pablo Guerrero from D4L data4life gGmbH, Thomas Harris from Hasso Plattner Institute, Christophe Normand and Guy Doumeingts from INTEROP-Vlab, Ruben Duarte Dias da Costa as well as Pedro Oliveira from Knowledgebiz, and finally Maria Marques from Uninova for all their valuable comments and the fruitful discussions of the paper's content."
}
|
[
{
"id": "178563",
"date": "22 Jun 2023",
"name": "Snezana Savoska",
"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 presents just results from the current Smart4Health project and do not considered similar research in the area. There are many EU project, which tackle this research, but they are not mentioned at all. In my opinion, some related work have to be taken into consideration in order to highlighted what is new in this research. In my opinion, the paper is more as the Project summary and do not satisfied standards for scientific or research paper. The paper does not consider any other research than the current one.\n\nSome statements are supported by citations, but these used for the project. There is not research about the pros and cons for these statements. They are like to confirm the project objectives without critical review and analysis of these statements.\n\nI cannot see that the arguments are supported by the relevant literature. All citations are the project’s part that are used for this research, but without explanation why these are used, why they do not chose the different solution.\n\nThe paper has to clarify the aims and explain how they are achieved. Also the results have to be verified, maybe explain which part is implemented, how much data are in the system now, did they used by group of citizens etc. Many research questions are not highlighted.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? No\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": []
},
{
"id": "210219",
"date": "09 Oct 2023",
"name": "Mario Ciampi",
"expertise": [
"Reviewer Expertise eHealth interoperability"
],
"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 illustrates the experiences gained within the European project Smart4Health, which aims to allow citizens of the European Union to manage and analyse their digital health data through specific personalised services, as well as to encourage their exchange through the adoption of standard protocols and software components. In particular, some building blocks implemented under the EU CEF funding program are reused, such as eID, eSignature, eTranslation, eDelivery.\nSharing the methodologies adopted and the results obtained in field experiences is of undoubted value in a context in which the European Union is making numerous efforts to support Member States in creating IT infrastructures that are interoperable with each other to facilitate the exchange of data healthcare, also through the development of the eHealth Digital Service Infrastructure (eHDSI), the adoption of technical standards based on HL7 and IHE, the proposed of the European Health Data Space regulation.\nTherefore, the indexing of the article would provide useful feedback to researchers and technologists interested in working on related topics.\nHowever, the article would benefit from some revisions before its indexing, as described below.\nAs an opinion article, the paper correctly does not present new research activities, but should better describe the results of academic discussions based on scientific literature. Therefore, the article should add a section describing scientific-related work, where it should also include results obtained in other European projects (e.g. InteropEHRate), as well as provide more references to scientific contributions, such as 1, 2, 3.\n\nThe article often uses the terms building block and DSI loosely. More precisely, CEF Digital is composed of two types of DSIs: \"Sector-specific DSIs\", which support the development of pan-European services such as eHealth, and \"Generic Enablers\", such as DSIs known as building blocks. In order to be in line with the terminology used at the European level, it would be appropriate to update some terms used in the article.\nMinor comments:\nIn the introduction, the acronym DSI is used without being described.\n\n3rd. party --> 3rd party.\n\nFor now, Smart4Health curate the answers... -> For now, Smart4Health curates the answers...\n\nIt currently only available via the web service --> It is currently only available via the web service.\n\nIn the \"CEF building block eDelivery\" section, the term \"eHealth National Contact Points\" is used without being described.\n\nIn the \"Patient Summary as part of the eHealth DSI\" section, describe what the international patient summary is and its purpose.\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? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/12-203
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https://f1000research.com/articles/12-202/v1
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21 Feb 23
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{
"type": "Research Article",
"title": "Determinants of pre-lacteal feeding practice in Ethiopia: Evidence from the 2019 Mini Demographic and Health Survey (MDHS), a community-based cross-sectional study",
"authors": [
"Gebeyaw Molla",
"Fikreselassie Getachew",
"Ashenif Tadele",
"Girum Taye",
"Tefera Taddele",
"Geremew Gonfa",
"Misrak Getnet",
"Tigist Shumet",
"Atkure Defar",
"Habtamu Teklie",
"Hiwot Achamyeleh",
"Hanim Tesfaye",
"Theodros Getachew",
"Fikreselassie Getachew",
"Ashenif Tadele",
"Girum Taye",
"Tefera Taddele",
"Geremew Gonfa",
"Misrak Getnet",
"Tigist Shumet",
"Atkure Defar",
"Habtamu Teklie",
"Hiwot Achamyeleh",
"Hanim Tesfaye",
"Theodros Getachew"
],
"abstract": "Background: Every year, 10.9 million people die around the world. More than two-thirds of deaths were associated with inappropriate feeding practices. Within the first three days after birth, nearly two out of every five newborns are given fluids other than breast milk. The aim of this study was to assess the determinants of pre-lacteal feeding practice in Ethiopia among mothers who had a live birth child under the age of 24 months. Methods: Secondary data from Ethiopia's 2019 Mini Demographic and Health Survey (MDHS) were used. A stratified, two-stage cluster sampling method was employed in the MDHS. A total of 8,885 reproductive-age women were interviewed in the survey, but only 2,061 women with a live birth child under the age of two years were included. Our study focused on the details obtained for these 2,061 women. Logistic regression analysis was used to identify factors associated with pre-lacteal feeding practices among them. A Hosmer-Lemeshow goodness of fit test was used to check the model fitness and a multicollinearity test was used to diagnosis collinearity between independent variables. Results: The results revealed that 12.1% (95%CI; 10.30%, 13.9%) of the women practiced pre-lacteal feeding. Mothers who lived in pastoralist regions (AOR:3.2; 95%CI: 1.5-6.84), who hadn’t attended antenatal care (ANC) visits (AOR:3.83; 95%CI: 1.55-6.27), who had attended 1-3 visits (AOR:1.65; 95%CI: 1.15-3.94), who delivered at home (AOR:1.72, 95%CI: 1.20-2.43), those who delivered by Caesarean section (AOR:3.72; 95%CI: 2.32-5.96), mothers who started breastfeeding after one hour (AOR:4.41; 95%CI: 3.23-6.02) were identified as the groups most associated with pre-lacteal feeding. Conclusions: Pre-lacteal feeding was practiced by a significant number of women in this study. Living in a pastoralist region, attending 1-3 ANC visits, home delivery, caesarean section delivery, and late initiation of breastfeeding were the determinant factors of prelacteal feeding among the women.",
"keywords": [
"Live birth",
"Alive",
"Pre-lacteal feeding"
],
"content": "Background\n\nBreastfeeding at birth plays an important role in determining the health of a child, and it is a means of contributing to the UN’s Sustainable Development Goals (SDGs). These include a focus on ending all forms of malnutrition globally by 2030,1,2 particularly for those less than six months of age, and on achieving 2025 internationally agreed targets on stunting and wasting in children less than five years old.3 In recognition of the benefits of human breast milk, particularly when infants are exclusively breastfed, the World Health Organization (WHO) and United Nations Children’s Fund (UNICEF) advise against pre-lacteal feeding for infants within the first six months of life, unless medically indicated.1,4\n\nGlobally, children under the age of five years account for 60% of the 10.9 million deaths that occurred annually. More than two-thirds of deaths are linked to poor feeding practices during the first year of life.5 Breastfeeding has the potential to save the lives of neonates, infants, and young children, as well as to reduce morbidity. Every day, 3,000 to 4,000 infant deaths occur in developing countries, most of them as a result of problems arising from breastfeeding issues, such as diarrhea and acute respiratory infections.6,7\n\nPre-lacteal feeding is the practice of giving an infant foods or liquids other than breast milk during the first three days after birth.8,9 It is the most significant impediment to exclusive breastfeeding and the significant predictor of infant mortality and morbidity.10,11 Globally, almost two out of every five breastfed newborns received pre-lacteal foods and liquids.12 Honey, butter, goat’s milk, cow’s milk, boiled water, and clean water are the most common pre-lacteal foods and liquids that are usually given to newborns.13–16 Pre-lacteal feeding deprives an infant of essential nutrients during the first six months of life.16 Every year, inadequate breastfeeding practices, including pre-lacteal feeding, harm 823,000 children under the age of five years.17,18\n\nThe evidence has suggested that improving breastfeeding practices, such as avoiding pre-lacteal feeding, starting breastfeeding within the first hour of life, and breastfeeding on demand could save the lives of over 820,000 children each year.4,18 However, many infants did not receive such optimal feeding practices, and died from various easily preventable diseases. It has previously been established that pre-lacteal feeding is harmful and can expose infants to the risk of infection.19 Furthermore, it has been found that pre-lacteal feeding is responsible for 45% of neonatal infectious deaths, 30% of diarrheal deaths, and 18% of acute respiratory deaths in children.4,20 Additionally, newborns that were exposed to pre-lacteal feeding were more likely to be stunted or wasted than those who were exclusively breastfed.19,21\n\nAccording to various local and national studies, pre-lacteal feeding is a common and widespread practice in Ethiopia.6,14,22–27 However, these works indicate that there is a paucity of information about the causes of pre-lacteal feeding. Thus, one of the most accurate pictures of the prevalence of pre-lacteal feeding is found in the national data source, the Ethiopian Mini Demographic Health Survey (MDHS), which was conducted in 2019. The purpose of our study was to examine the determinants of pre-lacteal feeding practice among mothers who had a live birth child under the age of 24 months, in Ethiopia, 2019.\n\n\nMethods\n\nThis study analyzes secondary data from the 2019 Ethiopia Mini Demographic and Health Survey (EMDHS), conducted by the Ethiopian Public Health Institute and the DHS Program, ICF Macro.28 The survey was carried out between March 21 and June 28, 2019. Its participants were chosen using a stratified, two-stage cluster probability sample method to represent the entire population. The sample for the 2019 EMDHS was generated using the frame of the 2019 Ethiopian Population and Housing Census (EPHC). In the first stage, 305 census enumeration areas (EAs) – 93 from urban areas and 212 from rural areas – were chosen from the 149,093 EAs created for the 2019 EPHC, with the aim of enabling a representative sampling of households in the Ethiopian population. The methodology for this involved using the probability of proportional allocation to size, and other measures like calculating the cumulative size, finding the selection interval, generating a random number and calculating the sampling numbers to select the 305 EAs. As part of this first stage, a new household list was created for each of the 305 selected EAs, and the resulting household list was used as a sampling frame to select households from those EAs. Then, in the second stage, a fixed number of 30 households were chosen from the newly created fresh household list from each EA, with an equal probability of systematic selection. Finally, all women aged 15-49 years who were either permanent residents, or visitors who slept in the selected households the night before the survey, were eligible to be interviewed for the EMDHS. The 2019 Mini DHS study design and details of its methods are available in the full report of the 2019 Ethiopia Mini Demographic and Health Survey,28 as well as on the ICF Macro website.\n\nFor our study, only mothers who gave birth in the two years preceding the survey (2,226) were included out of the total 8,885 reproductive women interviewed in the 2019 EMDHS. However, mothers who did not have a live child under the age of two years old were excluded from the study (n=165). As a result, the final sample size was 2,061 women.\n\nPre-lacteal feeding practice is defined as those mothers who had started pre-lacteal food within three days of delivery, excluding breast milk.28,29\n\nThe dependent variable of our study is pre-lacteal feeding practice. The independent variables were socio-demographic variables (like maternal age, educational status, religion, place of residence, region, marital status, child’s sex, socio-economic position (wealth quintile), and family size); maternal health service utilization factors (like antenatal care, iron taken during pregnancy, place of delivery, mode of delivery, breastfeeding initiation time, health checked after delivery at home, health checked before discharge from hospital, and child health checked within two months); and maternal and birth-related factors such as age at first birth, parity, number of under-five children, and number of ever-born children. Information about all these independent variables was collected and included systematically in the 2019 EDMHS.\n\nFigure 1 shows a schematic presentation of the sampling procedure for those mothers who had a live birth child under the age of 24 months in Ethiopia, 2019, based on data sourced from the 2019 EMHDS.\n\nData for the EMDHS were collected by 25 field teams, and each team was composed of five individuals (one supervisor, one CAPI supervisor, two female interviewers and one female anthropometrist – to measure the child weight and height). All data collectors who were directly contact with the participants were female. Data was collected through an electronic data collection system using a computer-assisted personal interview technique (CAPI), and CSPro software, version 3.1 was used. Each day the collected data was sent to the Ethiopian Public Health Institute data server through the internet file streaming system (IFSS) and the data were stored on a password-protected computer. Secondary editing, which required the resolution of computer-identified inconsistencies and coding of open-ended questions, was part of the data processing operation. The collected data were exported to SPSS version 28 for further analysis. Descriptive statistics like frequency and percentage were used to describe the socio-demographic and obstetrics characteristics of participants.\n\nFor the purposes of our study, a correlation test was performed to examine the relationship between independent variables. Thus, the highest correlation was found between ANC visit and frequency of ANC visit, with a value of 0.85, and between ANC visit and iron taken during pregnancy, with a value of 0.56. ANC visit was measured by those who attended or did not attend ANC during their previous pregnancy, and the frequency of ANC visit was measured by those who attended one, two, three, or four or more visits during their previous pregnancy. Furthermore, iron intake was measured by categorizing participants depending on whether they took iron tablets for more than one month during their previous pregnancy. Furthermore, the variance inflation factor (VIF) was used to perform a multicollinearity test, and all variables with a VIF greater than 4.5 were excluded from the analysis. However, multicollinearity between independent variables was not observed. Furthermore, the Hosmer-Lemeshow test was used to evaluate the goodness of fit model, yielding a value of 0.3, which is a good-fit model. Bivariate logistic regression was used to examine the relationship between dependent and independent variables, followed by multiple logistic regressions to identify factors associated with women's pre-lacteal feeding practice. Finally, an AOR with a 95% confidence interval (95%CI) was reported, and those independent variables with a p-value of 0.05 in the multiple logistic regression models were identified as a significant predictor of pre-lacteal feeding practice.\n\n\nResults\n\nThe analysis included 2,061 mothers who had a live child under the age of 24 months. In our study, the mean age of the respondents was 27.68 (SD 6.43), with a range of 15 to 49 years. The majority (30.6%) of the mothers were in the age category of 25-29 years old. Around three quarters (73.2%) of the respondents were from rural residences, and 45.7% (942) of them had no formal education. Regarding religion, Orthodox and Muslim were the dominant religions, which accounted for 35.6% (734) and 36.3% (749) of the mothers respectively, 94% were married and 50.3% (1,038) of the respondents had a male child (Table 1).\n\n* Traditional and other religions.\n\n** Divorced, Widowed, Separated.\n\nThe majority of the respondents (62.8%) were over the age of 18 years, 98.4% (2,028) had less than or equal to two under-five children in the household, 66.5% (1,371) of mothers had more than four household members (Table 2).\n\nOur study showed that only 24.8% (511) mothers who had a live birth with a child under the age of two years did not attend an ANC visit in their previous pregnancy, while 44.6% (920) of the mothers attended more than three ANC visits. More than half (55.5%) of mothers had delivered a child in a health facility, and 6.3% (131) of them were delivered via caesarian section. Only 60% (1,239) of mothers in our study took iron during their pregnancy, and 85.5% (1,763) of women started breastfeeding within one hour. According to the finding from our analysis, 12.1% (95%CI; 10.30%, 13.9%) of participants started pre-lacteal feeding within three days of birth, while only 13% (267) of mothers checked their child's health in health institution within two months (Table 3).\n\n* NGO health facility, Health post, Other NGO facility and others.\n\nRegion, wealth quintile, religion, ANC visit, frequency of ANC visit, iron taken during pregnancy, place of delivery, mode of delivery, initiation of breastfeeding time, mother's health checked after delivery, and child health checked within 2 months were factors significantly associated with pre-lacteal feeding practice in our bivariate logistic regression analysis. The ANC visit was excluded from the final model of multiple regressions due to its strong correlation with the participant's iron intake during their previous pregnancy. As a result, the region, wealth quintile, religion, frequency of ANC visit, iron taken during pregnancy, place of delivery, mode of delivery, time of breastfeeding initiation, mother's health checked after delivery, and child health checked within 2 months fitted the model of logistic regression. Therefore, these variables were used in multiple logistic regressions. In the final model of multivariable logistic regression analysis, region, frequency of ANC visit, place of delivery, mode of delivery, and breastfeeding initiation time were the predictors of mothers’ pre-lacteal feeding practice.\n\nThe results from our study revealed that, mothers living in the pastoralist region were 3.2 times more likely to practice pre-lacteal feeding than those living in urban regions (AOR: 3.2; 95%CI 1.5-6.84). Mothers who had not attended ANC visits and those who attended 1-3 ANC visits were 3.8 and 1.65 times more likely to practice pre-lacteal feeding than those who attended 4 or more ANC visits (AOR: 3.83; 95%CI: 1.55-6.27 and AOR: 1.65; 95%CI: 1.15-3.94) respectively. In regards to breastfeeding initiation, mothers who started breastfeeding after one hour of birth were 4.4 times more likely to practice pre-lacteal feeding (AOR: 4.41; 95%CI: 3.23-6.02) (Table 4).\n\n* P-value < 0.25.\n\n** P-value < 0.05.\n\n*** P-value ≤ 0.01.\n\n**** P-value ≤ 0.001.\n\n\nDiscussion\n\nBreast milk contains all of the nutrients required for children in their first six months of life, and the World Health Organization recommends starting breastfeeding within one hour of birth and exclusively breastfeeding for the first months. Pre-lacteal feeding, on the other hand is widely practiced in Ethiopia,9,14,30,31 Thus, in the current study pre-lacteal feeding was practiced by 12.1% (95%CI: 10.30%-13.9%). However, this was lower than that found in other studies conducted in Vietnam (73.3%32), Nigeria (26.5%33), Pakistan (64.7%34), the Himachal Pradesh district of India (49.5%35), Egypt (58%36) and in other local studies conducted in some districts of Ethiopia (Dire Dawa, 15.7%,9 Raya Kobo district, 38.8%,14 Harari region, 45.4%,30 and Kersa district, 46.6%31). This variation in pre-lacteal feeding could be attributed to socio-cultural differences between countries and districts. Furthermore, the current study concentrated on the national demographic health survey, which covered a wide proportion of the population. However, the figure is higher than that found in the 2016 Ethiopia Democratic and Health Survey (EDHS) which was 8%.23 This disparity could be attributed to an increase in caesarian section delivery, during which mothers were started on pre-lacteal feeding other than breast milk until they recovered from the anesthesia injection. Our study is also in line with other studies conducted in Ethiopian districts including Axum town (10.1%), Bure district (11.6%), Jinka town (12.6%) and Mettu district (14.2%).27,37–39\n\nIn our study, we identified that region, ANC visit, place of delivery, mode of delivery, and breastfeeding initiation time were significantly associated with pre-lacteal feeding practice in Ethiopia. Thus, we found that mothers who did not attend an ANC visit were 3.8 times more likely to practice pre-lacteal feeding than those who attended four or more ANC visits. This is consistent with other studies conducted in India33 and in the Harari and Mettu districts of Ethiopia.30,37 In addition to this, the odds of pre-lacteal feeding has increased by 65% in mothers who attended 1-3 ANC visits as compared with those who attended four or more visits. A possible explanation is that ANC use increases women’s awareness of the benefit of optimal breastfeeding and the danger of using pre-lacteal foods or liquids for the newborn.\n\nAccording to our results, mothers who gave birth at home were 1.7 times more likely to practice pre-lacteal feeding than those who gave birth in a health facility. This is consistent with the finding of a study conducted in the Kersa district of Ethiopia31 and EDHS 2016.29 However, it is lower than the findings of other studies conducted in Raya Kobo district, Mettu district, Bure district, Jinka town, and India.14,30,37–39 The possible explanation is that institutional delivery is a point of contact for labour mothers, where there is the initiation of a postnatal care (PNC) service for the mother and newborn care, and where healthcare professionals counsel the mother to refrain from exclusive breastfeeding practice for the first six months. Furthermore, giving birth at home creates a favorable environment for local community members, who may advise the use of pre-lacteal feed, thereby influencing newborn feeding practice.\n\nRegional variation was found to be a predictor of pre-lacteal feeding practice in our study, with mothers living in pastoralist regions being 3.2 times more likely to practice pre-lacteal feeding than those living in urban regions. This was due to the fact that most pastoralist communities did not have a permanent residence. Thus, an equitable distribution of basic health services, particularly maternal and child health services and adequate access to information and resources, are hard to achieve for these groups, lessening a mother’s awareness of the dangers of pre-lacteal feeding for the newborn child. Aside from these possible explanations, the pastoralist community has a variety of traditional and cultural breastfeeding practices that may encourage/enable the mother to practice pre-lacteal feeding.\n\nOur study also showed/emphasized the link between mode of delivery and mothers’ pre-lacteal feeding practice. Thus, our findings revealed that women who had caesarian section delivery were 3.7 times more likely to engage in pre-lacteal feeding practices. This result is consistent with studies conducted in Pakistan,32 India,35 and different studies in the Ethiopian districts of Dire Dawa, Aksum, and Metu.9,27,37 However, it is lower than in Nigeria’s study (1.5 times).33 The possible explanation is that the caesarian section post-anesthesia/post-operative effect may interfere with immediate colostrum feeding and delay breastfeeding initiation. As a result of this interference and delay, the mother may be compelled to initiate feedings other than with breast milk.\n\nThe proper implementation of Baby-Friendly Hospital Initiatives is a key solution for improving the mother's early initiation of breastfeeding within one hour of delivery.40 According to the current study, mothers who started breastfeeding after one hour of birth were 4.4 times more likely to practice pre-lacteal feeding than those mothers who initiated breastfeeding within one hour. This finding is consistent with studies conducted in Nigeria, Pakistan, India,33–35 and other different studies in Ethiopia.9,14,29,31,38 Furthermore, a study conducted in Ethiopia’s Kersa district31 found that starting breastfeeding early reduces pre-lacteal feeding by nearly 11 times. Thus, this indicates to us that there is a close relationship between early initiation of breastfeeding and avoiding pre-lacteal feeding.\n\nThe fact that our study relied on nationally representative secondary data is one of its strengths. The study also includes an in-depth look into pre-lacteal feeding practices, with a large number of participants from Ethiopia's diverse population. As a result, the findings have far-reaching implications for future breastfeeding promotion programs throughout the country, particularly in pastoralist areas. The EMDHS was designed to be a cross-sectional survey which measures the cause and the effect at the same time; hence our study has faced this limitation. As a result of the survey's methodological limitations, the causality effect is not avoided in our study. Furthermore, the data was gathered by asking the mother to recall their practice of prelacteal feeding in the previous two years, and the mothers' newborn feeding habits were inquired about for the first three days after delivery. As a result, the participants may be subject to recall bias. Another limitation of the study is that no data on the type of pre-lacteal food given to the newborn by the mothers in the first three days after delivery were gathered.\n\n\nConclusions and recommendations\n\nAccording to our study, 12.1% of women practiced pre-lacteal feeding within three days of delivery, which is higher than in the previous 2016 EDHS. Living in a pastoralist region, experiencing no ANC visit, attending 1-3 ANC visits, home delivery, delivery through C-section, and late initiation of breastfeeding were the determinant factors of pre-lacteal feeding practice among women. The first few days of a newborn’s life are the critical period to their survival. Thus, the government and stakeholders should enhance the continuum of care for pregnant women and continue the 1,000-Day initiative that helps the mother adhere to the optimal breastfeeding practice. The Baby-Friendly Hospital Initiative encourages health facilities to better support breastfeeding, with the goal of providing the best start in life for every baby by creating a healthcare environment that promotes breastfeeding as the norm. As a result, the initiative enables mothers to exclusively breastfeed their children for the first six months. Furthermore, the Initiative provides appropriate counseling services to the mother and her accompanying relative/s regarding the dangers of pre-lacteal feeding and the importance of optimal breastfeeding for the newborn, particularly for women who have had a C-section. Improving the use of institutional delivery would help to reduce pre-lacteal feeding practice. Additionally, strategies to reduce or eliminate pre-lacteal feeding practices will need to take into account Ethiopia’s disadvantaged population and pastoralist regions.\n\n\nEthical approval and participants’ consent\n\nThe study relied on secondary data, which did not require ethical clearance. The Ethiopian Public Health Institute (EPHI) Institutional Review Board and ICF International’s institutional review board provided ethical approval for the 2019 EMDHS. Respondents were informed about the survey and their random selection for inclusion, and verbal informed consent was obtained from each participant for their participation. Each participant was required to participate in and withdraw from the study voluntarily. During interview and data analysis, participants’ confidentiality was maintained.\n\n\nAuthors’ contributions\n\nGM designed the study, conducted data analysis, and wrote the original paper. The data analysis and write-up sections of the manuscript were primarily supported by FG, AT, and GT. Some of the manuscript section was written by FG. The manuscript was critically reviewed and approved by TG, FG, GT, AT, TT, MG, TS, GG, AD, HT, and HT. All authors contributed to the drafting, the acquisition, analysis, and interpretation of the data, reviewed related articles, agreed on the journal to which the article would be submitted, gave final approval of the version to be published, and agreed to accept responsibility for all aspects of the work. The manuscript was submitted for publication by GM, the corresponding author.",
"appendix": "Data availability\n\nThe datasets used and/or analyzed during the current study were gathered for the 2019 EMDHS and are available in the data repository at the national data management center of the Ethiopian Public Health Institute (EPHI) and ICF Macro.\n\n\nAcknowledgments\n\nWe gratefully acknowledge the contributions of all study participants, enumerators, and officials who contributed to the 2019 EMDHS's successful completion. It is our pleasure to thank the authors, who contributed to the development of this manuscript for their willingness, tremendous support, and invaluable feedback. Finally, I'd like to thank the Ethiopian Public Health Institute's national data management center for providing access to datasets.\n\n\nReferences\n\nTiwari S, Bharadva K, Yadav B, et al.: Infant and Young Child Feeding Guidelines, 2016. Indian Pediatr. 2016; 53(2): 703–713. Publisher Full Text\n\nUnited Nations: The 2030 Agenda and the Sustainable Development Goals: An Opportunity for Latin America and the Caribbean (LC/G.2681-P/Rev.3). Santiago.2018; 1–94.Reference Source\n\nBuse K, Hawkes S: Health in the sustainable development goals: Ready for a paradigm shift? Global Health. 2015; 11(13): 1–8.\n\nWHO: Key facts sheet on infant and young child feeding.2021. Access date May 02/2022.Reference Source\n\nBhutta ZA, Ahmed T, Black RE, et al.: What works? Interventions for maternal and child undernutrition and survival. Lancet. 2008; 371: 417–440. Publisher Full Text\n\nYonas F, Asnakew M, Wondafrash M, et al.: Infant and Young Child Feeding Practice Status and Associated Factors among Mothers of Under-24-Month-Old Children in Shashemene Woreda, Oromia Region. Open Access Libr. J. Infant. 2015; 02: 1–15. Publisher Full Text\n\nBekele Y, Mengistie B, Mesfine F: Prelacteal Feeding Practice and Associated Factors among Mothers Attending Immunization Clinic in Harari Region Public Health Facilities, Eastern Ethiopia. Open J. Prev. Med. 2014; 04(July): 529–534. Publisher Full Text\n\nNguyen PH, Keithly SC, Nguyen NT, et al.: Prelacteal feeding practices in Vietnam: Challenges and associated factors. BMC Public Health. 2013; 13: 1–11. Publisher Full Text\n\nDechasa N, Feyisa W, Alemnew F, et al.: Factors Associated with Pre-lacteal Feeding in Eastern Ethiopia. Heal. Sci. J. 2021; 15(11): 1–9.\n\nNguyen P, Binns CW, Van HAV, et al.: Prelacteal and early formula feeding increase risk of infant hospitalisation: a prospective cohort study. Arch. Dis. Child. 2020; 105: 122–126. PubMed Abstract | Publisher Full Text\n\nKambale RM, Buliga JB, Isia NF, et al.: Delayed initiation of breastfeeding in Bukavu, South Kivu, eastern Democratic Republic of the Congo: a cross-sectional study. Int. Breastfeed. J. 2018; 13(6): 1–9.\n\nUNICEF: From the first: Making the case for improved infant and young child feeding everywhere.2016; 1–104.Reference Source\n\nKhanal V, Adhikari M, Sauer K, et al.: Factors associated with the introduction of prelacteal feeds in Nepal: Findings from the Nepal Demographic and Health Survey 2011. Int. Breastfeed. J. 2013; 8: 1–9.\n\nLegesse M, Demena M, Mesfin F, et al.: Prelacteal feeding practices and associated factors among mothers of children aged less than 24 months in Raya Kobo district, North Eastern Ethiopia: A cross-sectional study. Int. Breastfeed. J. 2014; 9: 1–8.\n\nWHO: Infant and young child feeding Model Chapter for textbooks for medical students and allied health professionals. Geneva, Switzerland:Mountain Research and Development;2009; 1–112.Reference Source\n\nMukuria AG, Kothari MT, Abderrahim N: Infant and Young Child Feeding Update. Calverton, Maryland, USA:ORC Macro;2006.Reference Source\n\nJones AD, Ickes SB, Smith LE, et al.: World Health Organization infant and young child feeding indicators and their associations with child anthropometry: a synthesis of recent findings. Matern. Child Nutr. 2014; 10: 1–17. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBahl R, Barros AJD, De PUF, et al.: Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet. 2016; 387: 475–490. Publisher Full Text\n\nAgho KE, Ogeleka P, Ogbo FA, et al.: Trends and Predictors of Prelacteal Feeding Practices in Nigeria (2003–2013). Nutrients. 2016; 8(462): 1–13. Publisher Full Text\n\nWorld Health Organization (WHO): Global health risks: Mortality and burden of disease attributable to selected major risks. Geneva, Switzerland:2009.Reference Source\n\nMeshram AL II, Laxmaiah A, Venkaiah K, et al.: Impact of feeding and breastfeeding practices on the nutritional status of infants in a district of Andhra Pradesh, India. Natl. Med. J. India. 2012; 25(4): 201–206. PubMed Abstract\n\nCentral Statistical Agency [Ethiopia] and ORC Macro: Ethiopia Demographic and Health Survey 2005. Addis Ababa, Ethiopia and Calverton, Maryland, USA:2006.\n\nCentral Statistical Agency (CSA) ICF International: Ethiopia Demographic and Health Survey. Addis Ababa, Ethiopia, and Rockville, Maryland, USA:CSA and ICF;2016.Reference Source\n\nCentral Statistical Agency (CSA) ICF international. Ethiopia Demographic and Health Survey. Addis Ababa, Ethiopia and Calverton, Maryland, USA:2011.Reference Source\n\nChea N, Asefa A: Prelacteal feeding and associated factors among newborns in rural Sidama, south Ethiopia: A community based cross-sectional survey. Int. Breastfeed. J. 2018; 13(1): 1–8.\n\nBlack RE, Morris SS, Bryce J: Where and why are 10 million children dying every year? Lancet. 2003; 361: 2226–2234. PubMed Abstract | Publisher Full Text\n\nTekaly G, Kassa M, Belete T, et al.: Pre-lacteal feeding practice and associated factors among mothers having children less than two years of age in Aksum town, Tigray, Ethiopia, 2017: A cross-sectional study. BMC Pediatr. 2018; 18: 1–10. Publisher Full Text\n\nEthiopian Public Health Institute, Federal Ministry of Health and the DHS Program, ICF. Ethiopian Mini Demographic and Health Survey 2019. Addis Ababa, Ethiopia:2019.Reference Source\n\nMerga BT, Balis B, Fekadu G, et al.: Determinants of pre-lacteal feeding practices among mothers having children aged less than 36 months in Ethiopia: Evidence from 2016 Ethiopian demographic and health survey. SAGE Open Med. 2021; 9: 205031212110192–205031212110198. Publisher Full Text\n\nBekele Y, Mengistie B, Mesfine F: Prelacteal Feeding Practice and Associated Factors among Mothers Attending Immunization Clinic in Harari Region Public Health Facilities, Eastern Ethiopia. Open J. Prev. Med. 2014; 04: 529–534. Publisher Full Text\n\nAdem A, Assefa N, Deresa M, et al.: Prelacteal Feeding Practices and Associated Factors among Mother of Children Less Than 2 Years of Age in Kersa District, Eastern Ethiopia. Glob Pediatr Heal. 2021; 8: 2333794X2110183–2333794X2110188. Publisher Full Text\n\nNguyen PH, Keithly SC, Nguyen NT, et al.: Prelacteal feeding practices in Vietnam: Challenges and associated factors. Ann. Nutr. Metab. 2013; 13: 1–11.\n\nOgundele T, Ogundele OA, Adegoke AI: Determinants of prelacteal feeding practices among mothers of children aged less than 24 months in Ile-Ife Southwest Nigeria: a community cross-sectional study. Pan. Afr. Med. J. 2019; 34: 1–11.\n\nAsim M, Ahmed ZH, Hayward MD, et al.: Prelacteal feeding practices in Pakistan: a mixed-methods study. Int. Breastfeed. J. 2020; 8: 1–11.\n\nParashar A, Sharma D, Gupta A, et al.: Pre-lacteal feeding practices and associated factors in Himachal Pradesh. Int. J. Heal. Allied Sci. 2017; 6(1): 30–34.\n\nEl-Gilany A-H, Abdel-Hady DM: Newborn First Feed and Prelacteal Feeds in Mansoura, Egypt. Biomed. Res. Int. 2014; 2014: 1–7. Publisher Full Text\n\nWolde TF, Ayele AD, Takele WW: Prelacteal feeding and associated factors among mothers having children less than 24 months of age, in Mettu district, Southwest Ethiopia: A community based cross-sectional study. BMC. Res. Notes. 2019; 12(1): 3–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMose A, Abebe H: Prelacteal feeding practice and its determinant factors among mothers having children less than 6 months of age in Bure district, Northwest Ethiopia: a community-based cross-sectional study. BMJ Open. 2021; 11: e046919–e046919. Publisher Full Text\n\nSorrie MB, Amaje E, Gebremeskel F: Pre-lacteal feeding practices and associated factors among mothers of children aged less than 12 months in Jinka Town, South Ethiopia, 2018/19. PLoS One. 2020; 15(10): e0240583–e0240513. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization and the United Nations Children’s Fund (UNICEF): Protecting, promoting and supporting breastfeeding in facilities providing maternity and newborn services: implementing the revised Baby-Friendly Hospital Initiative 2018. Geneva:World Health Organization and the United Nations Children’s Fund (UNICEF);2018; 64.Reference Source"
}
|
[
{
"id": "169627",
"date": "15 Jun 2023",
"name": "Faojia Sultana",
"expertise": [
"Reviewer Expertise Global Public Health",
"Health Systems and Policy 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\nThe manuscript titled \"Determinants of pre-lacteal feeding practice in Ethiopia: Evidence from the 2019 Mini Demographic and Health Survey (MDHS), a community-based cross-sectional study\" investigates the determinants of pre-lacteal feeding practice among mothers with live birth children under the age of 24 months in Ethiopia. The study utilized secondary data from the 2019 Ethiopia Mini Demographic and Health Survey and employed logistic regression analysis to identify factors associated with pre-lacteal feeding. The results indicated that region, antenatal care visit, place of delivery, mode of delivery, and breastfeeding initiation time were significantly associated with pre-lacteal feeding practice. Overall, the manuscript addresses an important topic and provides some valuable insights into the factors associated with pre-lacteal feeding in Ethiopia. However, there are some areas that can be revised and improved as mentioned below.\nIntroduction: The introduction provides a good overview of the importance of breastfeeding and the negative consequences of pre-lacteal feeding. However, it would benefit from a more focused and concise presentation of the specific research gap in Ethiopia that the study aims to address. Additionally, providing a brief review of existing literature on pre-lacteal feeding in Ethiopia would strengthen the rationale for the study since there has been some notable studies in this topic in Ethiopian context in the past.\n\nDiscussion: The discussion section should be expanded to include a more thorough interpretation of the study findings in light of the existing literature, especially those conducted in Ethiopian context, and provide possible explanations for the observed associations between the independent variables and pre-lacteal feeding practice in the country. Discuss the underlying mechanisms and contextual factors that might contribute to the identified determinants. The implications of the findings and their relevance to policy and interventions aimed at reducing pre-lacteal feeding can also be discussed in more depth.\n\nConclusion: The conclusion should provide a concise summary of the key findings and their implications. Avoid introducing new information or repeating what has been discussed in the results or discussion sections. Rather focus on providing recommendations and possible actions to reduce PLF and improve breastfeeding practices.\n\nLanguage and Writing Style: The manuscript needs significant improvement in terms of language and writing style. There are numerous grammatical errors, awkward phrasing, and inconsistencies in terminology and tense usage. I recommend thorough proofreading and editing for clarity and coherence. Also, the keywords are not inclusive of the topic of the study. Please check similar studies which have done before on PLF and change your keywords 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? 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": "240615",
"date": "06 Feb 2024",
"name": "Paula Ruffoni Moreira",
"expertise": [
"Reviewer Expertise Complementary feeding",
"Child nutrition."
],
"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 \"Determinants of pre-lacteal feeding practice in Ethiopia: Evidence from the 2019 Mini Demographic and Health Survey (MDHS), a community-based cross-sectional study\" aimed to analyze the determinants of pre-lacteal feeding in women with children under two years old residing in Ethiopia. The main findings of the study include the association of pre-lacteal feeding practice with region of residence, attended antenatal care visits, place of delivery, type of delivery, and breastfeeding. Introduction: The introduction provides a satisfactory review of the topic, but despite mentioning that pre-lacteal feeding has been investigated in the Ethiopian population, the results of these studies are not cited. The justification for conducting the study is indicated as the need to identify causes; however, since it is a cross-sectional study, it is not possible to assess causality but rather associated factors. Methodology: Mothers with deceased children under two years old were not included in the analyses. However, as pre-lacteal feeding is associated with the death of children under two years old, the presentation of these data may be relevant. The authors report that variables with a variance inflation factor (VIF) exceeding 4.5 were excluded from the analysis. Which variables were excluded? Some independent variables such as educational level, relationship status, and maternal age were not included in the logistic regression. Results: The results are presented satisfactorily. However, the table does not include the variables used in the adjusted model.\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?\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/12-202
|
https://f1000research.com/articles/11-443/v1
|
20 Apr 22
|
{
"type": "Research Article",
"title": "Genomic profiles of Indonesian colorectal cancer patients",
"authors": [
"Murdani Abdullah",
"Sofy Meilany",
"Hidayat Trimarsanto",
"Safarina G. Malik",
"Ninik Sukartini",
"Firhat Idrus",
"Saskia A. Nursyirwan",
"Virly N. Muzellina",
"Rabbinu R. Pribadi",
"Amanda P. Utari",
"Hasan Maulahela",
"Ari F. Syam",
"Murdani Abdullah",
"Sofy Meilany",
"Hidayat Trimarsanto",
"Safarina G. Malik",
"Ninik Sukartini",
"Firhat Idrus",
"Virly N. Muzellina",
"Rabbinu R. Pribadi",
"Amanda P. Utari",
"Hasan Maulahela",
"Ari F. Syam"
],
"abstract": "Background: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide and genetic mutation plays a vital role in CRC development. A previous study has suggested that genetic alterations among Indonesian patients with CRC might differ from those known in developed countries. This study aimed to describe the genomic profiles of Indonesian patients with CRC. Methods: A total of 13 patients were recruited for this study from May to July 2019. Tissue samples were collected, and genomic DNA was extracted from the samples. AmpliSeq for Illumina Cancer HotSpot Panel v2 Next-generation sequencing was used for DNA sequencing and a genome analysis toolkit was used for local realignment around the discovered variants. Results: A total of 45 genes comprising 391 single nucleotide variants (SNVs) with a depth >10 were observed. The genes with the most variants were STK11, SMAD4, EGFR, and ERBB4 and the genes with the most non-synonymous variants were SMAD4, TP53, FGFR3, CDKN2A, and STK11. Genes and SNVs in at least 90% of all samples consisted of 43 genes comprising 286 variants. Genes with the most non-synonymous SNVs were EGFR, SMO, FGFR3, TP53, STK11, CDKN2A. Genes related to the chromosomal instability pathway, such as TP53, SMAD4, KRAS, and APC, are also found in the analysis. Conclusions: Our findings showed that all patients with CRC in this study had genetic mutations in the chromosomal instability pathway. Analysis of genetic mutation of Indonesian patients with CRC might be crucial for advanced targeted therapy and for better clinical outcomes.",
"keywords": [
"genetics",
"mutation",
"colorectal cancer",
"Indonesia",
"sequencing"
],
"content": "Introduction\n\nColorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. CRC is the fourth most commonly diagnosed cancer and the third most deadly cancer in the world for both sexes.1 CRC has been responsible for 881,000 (9.2%) cases of cancer-related mortality worldwide. In Indonesia, the World Health Organization (WHO) placed CRC fourth in terms of the highest mortality burden caused by malignancies. The incidence and mortality rates of CRC have rapidly increased over the past decades due to environmental changes, such as sedentary lifestyles and increased lifespan. Several studies have shown that the 5-year survival rate of patients with CRC has remained at approximately 60% in the last decade.2,3\n\nThere are some reported differences in CRC characteristics between Western and other populations. The prevalence of CRC in the Western population under the age of 50 years is around 2–8%.4,5 Sehbai et al. reported that the incidence of CRC in Asian Indian and Pakistani populations under the age of 50 years was higher than that of white populations in the United States of America (USA).6 Epidemiological data in Indonesia also showed that the proportion of patients with CRC under 40 years old was more than 30%. Other studies in developed countries have found that young-onset CRC is often associated with family history. However, in a previous study among young Indonesian patients with CRC, there was no positive family history.7 Early onset CRC in developed countries showed several characteristics, such as localization in the ascending colon, low pathological stage, rare metastasis, and a better prognosis. By contrast, most young patients with CRC in the Indonesian population showed distal localization (rectum), a high clinical population, and poor prognosis.8\n\nGenomic instability, which allows the accumulation of numerous genetic mutations, is essential for CRC development. There are three pathways of genomic instability in CRC. The first pathway is the chromosomal instability (CIN) pathway, which consists of several gene mutations, including those in APC, KRAS, SMAD4, and TP53. The second pathway is the microsatellite instability (MSI) pathway, which is caused by defects in the nucleotide mismatch repair (MMR) mechanism and is represented by mutations in MSH2, MLH1, MSH3, PMS1, and PMS2. The third pathway is the inflammatory pathway, which involves the expression and activation of nuclear factor kappa-B (NF-κB) and COX-2.9 In developed countries, the CIN pathway is conventionally found among sporadic CRCs, whereas the MSI pathway is found among younger patients with CRC. A study in Indonesia indicated that young Indonesian patients with CRC have defects in the DNA MMR system, which may promote MSI. However, when tested using BAT26, a surrogate marker of MSI, the frequency of MSI was very low and consistent with sporadic cancer features. Further testing of the same specimens using SMAD4 protein expression confirmed that neither young nor older Indonesian patients with CRC exhibited the MSI pathway. Another study in Indonesia also supported the hypothesis that inflammation may play a role in Indonesian patients with CRC. These results indicate that the molecular characteristics of patients with CRC in Indonesia may differ, anchored by pathways different from those previously found in the developed countries.8,10\n\nThese highly heterogeneous results among populations require further investigation. The characterization of molecular subtypes, particularly among Indonesian patients with CRC, will lead to improved treatment selection and outcomes, such as molecularly targeted agents, often called precision medicine. In this study, we investigated the genomic profiles of patients with CRC in Indonesia using next-generation sequencing (NGS) analysis. NGS enables the identification of various genetic mutations that might be used further in the new era of targeted therapy among patients with CRC.\n\n\nMethods\n\nThis study was approved by the Research Ethics Committee of Universitas Indonesia, Jakarta (Ethical Approval Number KET-582/UN2.F1/ETIK/PPM.00.02/2019) and by the Research Division of Cipto Mangunkusumo National General Hospital, Jakarta (Research Permission Letter Number 1602/22/1670/2019). Written informed consent was obtained from all patients to participate in this study and publication of the patients’ details.\n\nA total of 13 patients with CRC undergoing surgical resection of primary tumors at Cipto Mangunkusumo National General Hospital, Indonesia, were consecutively recruited from May to July 2019. Clinical data, including gender, age, cancer location, metastasis, and staging, were recorded from a structural questionnaire and histopathological results. Tissues were collected and separated for the determination of the clinical stage of cancer by histopathologists and for specimen collection. The tissues were then stored with 10% fetal bovine serum in Dulbecco’s Modified Eagle’s Medium (DMEM) with 1% antibiotics containing penicillin and streptomycin in liquid nitrogen until the DNA extraction process was performed.\n\nDNA was extracted from the tissue using Quick-DNATM Mini prep plus kit (Zymo Research) following the manufacturer’s protocol. Nucleic acid quantity and purity were assessed using a Qubit fluorometer (Invitrogen, Carlsbad, CA, USA) and a Nanodrop spectrophotometer (Invitrogen), respectively. Only samples with a concentration of 1.04–5.5 ng/μL with purity range of 1.7–1.9 passed the assessment and were subjected to sequencing.\n\nSequencing libraries were generated using AmpliSeq for Illumina Cancer HotSpot Panel v2 following the manufacturer’s protocol, and 2 × 150 bp paired-end sequencing was performed on the Illumina MiSeq system. The variant discovery was performed following the GATK best practice. Briefly, the sequencing reads of each sample were aligned to the human reference genome GRCh38 (hg38) with Burrows–Wheeler Aligner version 1.61 (BWA, RRID:SCR_010910). As the AmpliSeq protocol was short amplicon sequencing, the PCR deduplication step was skipped. GATK v4 (GATK, RRID:SCR_001876) was used for local realignment around the variants. Variants calling of both single-nucleotide variants (SNVs) and indels were performed using the HaplotypeCaller tool from GATK, and the candidate variants were annotated using snpEff with the GRCh38.86 dataset. The following variants were defined as non-synonymous SNVs: stop-gain SNVs, stop-loss SNVs, and frameshift indels. Non-coding SNVs were defined as variants in the non-protein-coding regions of the genes, such as introns or untranslated regions.\n\n\nResults\n\nThirteen samples from colorectal patients were sequenced using AmpliSeq for Illumina Cancer HotSpot Panel v2. Table 1 shows the clinicopathological characteristics of the patients in this study. Among these patients, nine were male (69.2%) and four were female (30.8%), with the highest proportion of patients are aged 55–59 (23.1%). Regarding cancer location, nine patients (69.2%) were detected to have left-sided CRC, whereas the other four were on the right-sided colon. We used the terms left-sided and right-sided, based on the anatomical mark. Right-sided CRC is cancer of the caecum and the ascending colon up to the hepatic flexure, while left-sided CRC comprises cancer of the splenic flexure and the regions distal to the splenic flexure, including the rectum.11\n\nBased on the staging, we found that two patients, six patients, two patients, and three patients were on stage I, II, III, and IV, respectively. Among all the patients, three who were eventually on stage IV had liver metastasis. No metastasis was found in the other 10 patients (particularly for patients with stages I, II, and III).\n\nFigure 1 shows all the SNVs that occurred in every sample with a depth > 10. A total of 45 genes comprising 391 variants were observed. The genes with the most variants observed were ERBB4 (31 SNVs), EGFR (29 SNVs), SMAD4 (29 SNVs), and STK11 (26 SNVs). Genes with the most non-synonymous variants were STK11, CDKN2A, FGFR3, TP53, and SMAD4 with 21, 19, 15, 14, and 12 SNVs, respectively. Figure 2 shows the heatmap of non-synonymous variants observed in each gene for each sample in this study.\n\nNCSNV denotes non-coding SNVs, while NSSNV denotes non-synonymous SNVs, which include missense, stop-gain, stop-loss, and frameshift variants.\n\nTable 2 shows the gene details and SNVs that occurred in at least 90% of all samples, with a total of 43 genes comprising the 286 variants observed. Genes with the most non-synonymous SNVs were CDKN2A, STK11, TP53, FGFR3, SMO, and EGFR with 19, 16, 14, 12, 10, and 10 SNVs, respectively. It should be noted that genes related to the CIN pathway included APC, KRAS, SMAD4, and TP53, which had 5, 2, 4, and 14 non-synonymous SNVs, respectively (Table 2).\n\n\nDiscussion\n\nAmong the 13 patients recruited for this study, the highest proportion of patients are aged 55–59 (23.1%). Considering young or early-onset colorectal cancer (EOCRC) patients under 50 years old, we found that five out of 13 patients (38.5%) had EOCRC. In Indonesia, the prevalence of patients with CRC under 45 years of age was 47.85%.12 The percentage of patients under 30 years old also increased significantly from 4.4% (2002–2006) to 9% (2007–2011).13 These data are in concordance with those of a 25-year evaluation by Vuik et al., who showed that the incidence of CRC was increased by 7.9% per year among subjects aged 20–29 years, 4.9% per year among subjects 30–39 years, and 1.6% per year among subjects 40–49 years in Europe.14 The increasing dietary factors such as long-term consumption of alcohol and processed meat, lack of exercise, and obesity appear to be the possible causes for this increasing incidence.15 Furthermore, urbanization and pollution are also associated with the overall increase in cancer incidence.16\n\nRegarding cancer location, we observed that nine patients (69.2%) had left-sided CRC, while the other four patients had right-sided CRC. According to US data registries from 2009 to 2013, the lower gastrointestinal tract cancer distribution was more frequent in the proximal colon (proximal and including the splenic flexure, 41%), followed by the rectum (28%), distal colon (descending and sigmoid, 22%), and 8% in other sites.17 It seems that our patients with CRC have different common locations of cancer. Tumors and cancers in the proximal colon and distal colon have several morphological and genetic differences. Flat sessile serrated adenomas and cancers are more common in the proximal colon than polypoid adenomas and cancers, which are more common in the distal colon. Distal colon tumors also more commonly present with chromosomally unstable tumors,18,19 which is consistent with our finding that all subjects had genetic characteristics of mutation in the genes of the CIN pathway.\n\nThe next-generation sequencing (NGS) approach has been shown to be effective and accurate in determining the targeted therapy for cancer, including colorectal cancer.20 This study focused on genetic mutations in Indonesian patients with CRC. We used Illumina Cancer HotSpot Panel, which covered 50 genes attributable to cancer. The cancer stages of all patients included in this study ranged from stage I to IV, with two patients (15.4%), six patients (46.2%), two patients (15.4%), and three patients (23.1%) on stages I, II, III, and IV, respectively. Five patients who were categorized as early-onset CRCs were also staged as I–IV. Our findings differed slightly from the data provided by the American Cancer Society (ACS), in which the CRC stage distribution among Asian/Pacific Inlander population was 37% local, 37% regional, 20% distant, and 7% unstaged21 We found more local and distant stage CRC, and fewer regional stage CRC. Halpern et al., who investigated factors related to colon cancer stage at diagnosis, found that advanced-stage disease at diagnosis was common among uninsured patients, black patients, women, and patients from low socioeconomic status regions. Screening disparities may also lead to more advanced-stage colon cancer at diagnosis.22\n\nIn this study, we found that KIT, KDR, TP53, ERBB4, APC, RET, and FLT3KI, which correlated with CRC development, were among the genes with substantial mutations in all 13 patients. These mutations were predicted to be somatic due to the absence of a family history of CRC among our patients.\n\nKIT is a classic proto-oncogene and receptor tyrosine kinase that is activated through the PI3K, RAS, and JAK/STAT pathways.23 These pathways are involved in tumor cell proliferation. KIT signaling is activated by the binding of its ligand, the stem cell factor (SCF) protein, which is activated by a phosphorylation cascade, resulting in the regulation of cell growth.24\n\nKDR is a gene that plays a role in stimulating blood vessel permeability and dilatation. Several studies have shown that KDR is a therapeutic biomarker that can be targeted by tyrosine kinase inhibitors. KDR also plays an important role in VEGF signaling, stimulating proliferation, chemotaxis, survival, and differentiation of endothelial cells.25\n\nWe also observed a mutation in the TP53 gene. This gene is a tumor-suppressor gene and is associated with the progression of sporadic CRC. TP53 has many functions, such as DNA repair and cell cycle arrest, and it can trigger apoptosis when the damage is too severe. This gene mutation is associated with a poor prognosis due to the activation of the oncogenic and inflammatory pathways, which can accelerate CRC progression to later stages.26\n\nActivation of APC is a key process in β-catenin complex destruction. APC mutation leads to the accumulation of β-catenin protein in the cytoplasm and can promote the proliferation, migration, invasion, and metastasis of cancer cells. This gene mutation is found in 90% of patients with CRC.27\n\nERBB4 is a member of the tyrosine kinase and EGFR sub-family, which promotes colonocyte survival. Activation of this gene can promote cellular responses, including proliferation, differentiation, apoptosis, survival, and migration of tumor cells. ERBB4 alteration is an early step in tumorigenesis, although the mechanism remains incompletely understood.28\n\nRET is a proto-oncogene that encodes transmembrane receptors with the tyrosine-protein kinase domain. The main function of RET is to induce apoptosis in cells through the regulation of several signaling pathways.29 Mutation of RET results in kinase activation, which induces downstream signaling pathways such as PI3K, leading to tumor growth and cell survival.30\n\nFLT3KI is a gene that encodes a class III receptor tyrosine kinase that regulates hematopoiesis. This somatic mutation is most commonly observed in patients with acute myeloid leukemia. Mutation of this gene leads to the activation of the FLT3 receptor tyrosine kinase and the proliferation of cells in vitro.31\n\nUnfortunately, the amplicon panel used in this study only covered genes related to the microsatellite instability pathway, MLH1. Similarly, genes related to inflammatory pathways were absent from this panel. Nevertheless, our findings clearly showed that all the patients with CRC presented here had genetic characteristics of mutation in the genes of the CIN pathway. We found mutations in KIT, KDR, TP53, ERBB4, APC, RET, and FLT3KI. This finding is different from our previous results, which showed COX2 expression among 49% of patients with CRC, NF-kB expression in 73.5% of the patients, and KRAS gene expression in only 16.3% of them.9\n\nThe small sample size was a limitation of this study and could have affected the interpretation of the obtained results. However, this research was a pilot study that provided the first overview of gene mutations in Indonesian patients with CRC, due to the unavailability of data about Indonesian CRC gene mutations. The analysis of genetic mutations among patients with CRC might be important for future targeted therapy in CRC.\n\n\nConclusions\n\nOur pilot study of the genomic profile of patients with CRC showed that gene and SNVs in at least 90% of all samples consisted of a total of 43 genes comprising 286 variants, with most variants being STK11, SMAD4, EGFR, ERBB4. Genes with the most non-synonymous variants were SMDA4, TP53, FGFR3, CDKN2A, STK11. Our study found that all the patients with CRC had genetic mutations in the CIN pathway. Analysis of genetic mutation in Indonesian patients with CRC might be crucial for advanced targeted therapy and for better clinical outcomes.\n\n\nData availability\n\nOpen Science Framework: Genomic Profile of Indonesian Colorectal Cancer Patients.\n\nhttps://doi.org/10.17605/OSF.IO/JYPMA.32\n\nThis project contains the following underlying data:\n\n• Genomic Profile Raw Data.xlsx (This file contains clinicopathological data of patients recruited in this study)\n\n• Genomic Profile Sequencing Data (This file contains raw genomic data of sequenced DNA from tissue samples)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nCompeting interests\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThis study was supported by the Indonesian Ministry of Research, Technology, and Higher Education through the World Class Research (WCR) 2019 Program Contract NKB-1086/UN2.R3.1/HKP.05.00/2019.",
"appendix": "Acknowledgement\n\nWe thank Dr. Agustinus Wiraatmadja for assisting our research in refining the manuscript.\n\n\nReferences\n\nBray F, Ferlay J, Soerjomataram I, et al.: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018 Nov; 68(6): 394–424.\n\nMoghimi-Dehkordi B, Safaee A: An overview of colorectal cancer survival rates and prognosis in Asia. World J. Gastrointest. Oncol. 2012 Apr; 4(4): 71–75. PubMed Abstract | Publisher Full Text\n\nOnyoh EF, Hsu W-F, Chang L-C, et al.: The rise of colorectal cancer in Asia: Epidemiology, screening, and management. Curr. Gastroenterol. Rep. 2019 Jul; 21(8): 36. PubMed Abstract | Publisher Full Text\n\nParramore JB, Wei JP, Yeh KA: Colorectal cancer in patients under forty: presentation and outcome. Am. Surg. 1998 Jun; 64(6): 563–567. discussion 567–8. Reference Source\n\nLee PY, Fletcher WS, Sullivan ES, et al.: Colorectal cancer in young patients: characteristics and outcome. Am. Surg. 1994; 60(8): 607–612. PubMed Abstract\n\nSehbai AS, Hossain A, Kurian S, et al.: Epidemiologic characteristics of colon cancer in Asian Indian and Pakistani population living in the USA compared to US White population in SEER database from 1988 to 2002. J. Clin. Oncol. 2006; 24(18_suppl): 20112. Publisher Full Text\n\nSudoyo AW: Karakteristik molekular kanker kolorektal pada usia muda: Ekspresi MLH1 dan MSH2 sebagai indikator instabilitas mikrosatelit. Dep. Ilmu. Penyakit. Dalam. Univ. Indones. Jakarta. 2004.\n\nAbdullah M, Sudoyo AW, Utomo AR, et al.: Molecular profile of colorectal cancer in Indonesia: is there another pathway?. Gastroenterol. Hepatol. Bed Bench. 2012; 5(2): 71–78.\n\nKeum N, Giovannucci E: Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat. Rev. Gastroenterol. Hepatol. 2019 Dec; 16(12): 713–732. PubMed Abstract | Publisher Full Text\n\ndo Canto LM , Larsen SJ, Catin Kupper BE, et al.: Increased Levels of Genomic Instability and Mutations in Homologous Recombination Genes in Locally Advanced Rectal Carcinomas. Front. Oncol. 2019; 9: 395. PubMed Abstract | Publisher Full Text\n\nMik M, Berut M, Dziki L, et al.: Right- and left-sided colon cancer – clinical and pathological differences of the disease entity in one organ. Arch. Med. Sci. 2017 Feb; 13(1): 157–162. PubMed Abstract | Publisher Full Text\n\nAbdullah M, Rani AA, Sudoyo AW, et al.: Expression of NF-kB and COX2 in colorectal cancer among native Indonesians: The role of inflammation in colorectal carcinogenesis. Acta Med. Indones. 2013 Jul; 45(3): 187–192. PubMed Abstract\n\nMakmun D, Simadibrata M, Abdullah M, et al.: Changing trends in gastrointestinal malignancy in Indonesia: The Jakarta experience. J. Cancer Res. Ther. 2014; 2(9): 160–168. Publisher Full Text\n\nVuik FE, Nieuwenburg SA, Bardou M, et al.: Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years. Gut. 2019 Oct; 68(10): 1820–1826. PubMed Abstract | Publisher Full Text\n\nRosato V, Bosetti C, Levi F, et al.: Risk factors for young-onset colorectal cancer. Cancer Causes Control. 2013 Feb; 24(2): 335–341. Publisher Full Text\n\nFitzmaurice C, Dicker D, Pain A, et al.: The global burden of cancer 2013. JAMA Oncol. 2015 Jul; 1(4): 505–527. PubMed Abstract | Publisher Full Text\n\nSiegel RL, Miller KD, Jemal A: Cancer statistics, 2017. CA Cancer J. Clin. 2017 Jan; 67(1): 7–30. PubMed Abstract | Publisher Full Text\n\nGrady WM, Carethers JM: Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 2008 Oct; 135(4): 1079–1099. PubMed Abstract | Publisher Full Text\n\nCarethers JM, Jung BH: Genetics and genetic biomarkers in sporadic colorectal cancer. Gastroenterology. 2015 Oct; 149(5): 1177–1190.e3. PubMed Abstract | Publisher Full Text\n\nDel Vecchio F, Mastroiaco V, Di Marco A, et al.: Next-generation sequencing: recent applications to the analysis of colorectal cancer. J. Transl. Med. 2017; 15(1): 246. PubMed Abstract | Publisher Full Text\n\nSiegel RL, Miller KD, Goding Sauer A, et al.: Colorectal cancer statistics, 2020. CA Cancer J. Clin. 2020; 70(3): 145–164. Publisher Full Text\n\nHalpern MT, Pavluck AL, Ko CY, et al.: Factors associated with colon cancer stage at diagnosis. Dig. Dis. Sci. 2009 Dec; 54(12): 2680–2693. Publisher Full Text\n\nShah YM, van den Brink GR : c-Kit as a novel potential therapeutic target in colorectal cancer. Gastroenterology. 2015; 149: 534–537. PubMed Abstract | Publisher Full Text\n\nWang H, Boussouar A, Mazelin L, et al.: The proto-oncogene c-Kit inhibits tumor growth by behaving as a dependence receptor. Mol. Cell. 2018 Nov; 72(3): 413–425.e5. PubMed Abstract | Publisher Full Text\n\nMohammad Rezaei F, Hashemzadeh S, Ravanbakhsh Gavgani R, et al.: Dysregulated KDR and FLT1 Gene Expression in Colorectal Cancer Patients. Reports Biochem. Mol. Biol. 2019 Oct; 8(3): 244–252.\n\nNakayama M, Oshima M: Mutant p53 in colon cancer. J. Mol. Cell Biol. 2019 Apr; 11(4): 267–276. PubMed Abstract | Publisher Full Text\n\nNguyen HT, Duong H-Q: The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy. Oncol. Lett. 2018 Jul; 16(1): 9–18. PubMed Abstract | Publisher Full Text\n\nWilliams CS, Bernard JK, Demory Beckler M, et al.: ERBB4 is over-expressed in human colon cancer and enhances cellular transformation. Carcinogenesis. 2015 Jul; 36(7): 710–718. PubMed Abstract | Publisher Full Text\n\nLuo Y, Tsuchiya KD, Il Park D, et al.: RET is a potential tumor suppressor gene in colorectal cancer. Oncogene. 2013 Apr; 32(16): 2037–2047. PubMed Abstract | Publisher Full Text\n\nSantos C, Sanz-Pamplona R, Salazar R: RET-fusions: A novel paradigm in colorectal cancer. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2018; 29(6): 1340–1343. PubMed Abstract | Publisher Full Text\n\nMoreira RB, Peixoto RD, de Sousa Cruz MR : Clinical response to sorafenib in a patient with metastatic colorectal cancer and FLT3 amplification. Case Rep. Oncol. 2015; 8: 83–87. PubMed Abstract | Publisher Full Text\n\nAbdullah M: Genomic profiles of Indonesian colorectal cancer patients [Dataset]. OSF. 2022. Publisher Full Text"
}
|
[
{
"id": "135274",
"date": "04 May 2022",
"name": "Ahmad Rusdan Handoyo Utomo",
"expertise": [
"Reviewer Expertise cancer genetics",
"immunology"
],
"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 describing numbers of genetic variants found in frozen tissues of 13 CRC patients undergoing surgical procedures. They found many genetic variants in many genes using Illumina NGS 50-gene panel. This is an interesting article providing preliminary results of genetic variants found using NGS. There are several issues that the authors need to address before the manuscript can be accepted for indexing.\nThe authors should cite previous papers describing mutations in KRAS genes (Levi et al., 20181) and MIN pathways (Susanti et al., 20212) in Indonesia. The authors may discuss these papers and compare the results with the current manuscript.\nThe methods should describe the percentage of tumor content of the specimens. This can be done by looking at the corresponding FFPE (formalin fixed paraffin embedded) block. This quality control check is to ensure that specimens being tested for NGS contained high percentage of tumor cells.\nThe study design should describe the purpose of the study more clearly. The authors had described that indonesian colorectal patients may have different genetic and clinicopathological profiles (age, tumor locations) from western patients. Therefore, they should describe in their paper the prevalence of genetic mutations in different categories such as age and tumor locations as well. The paper should also analyse what is the percentage of transition and transversion mutations in order to gain insight and speculate the roles of local diet and pollutants. For instance the KRAS tranversion mutation has been associated with smoking (Dogan et al., 20123). There is no need for statistical analysis. A descriptive percentage table should be sufficient.\nThe authors should also describe how many patients have pathogenic mutations of these genes since not all variants are pathogenic. KRAS G12D and BRAF V600E are certainly pathogenic mutations, but EGFR G765V is not. Describing the prevalence of clinically actionable genetic mutations using NGS may also demonstrate the utility of NGS in cancer genetic studies especially in developing countries like Indonesia.\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? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8337",
"date": "08 Jun 2022",
"name": "Saskia Aziza",
"role": "Author Response",
"response": "The study was designed to investigate potential biomarkers as biomarker candidates for Indonesia patients with colorectal cancer. A previous study on the clinical epidemiology of Indonesian patients with CRC found that the majority of patients were diagnosed between 45 and 50 years old, with a mean age around 47 years old. Immunohistochemical studies showed that patients with negative mismatch repair proteins were 43.5% for MSH2 and 83.5% for MLH1.1 KRAS has been used as a potential tumor marker and its expression was reported to be as high as 30%-40% worldwide, but only 16.3% of 43 Indonesian patients with sporadic CRC cases have KRAS mutation and no BRAF mutation. This low KRAS mutation may indicate a different pattern of genetic instability in these colorectal tumors.1,2 Along the sporadic colorectal carcinogenesis pathway, the cyclooxygenase-2 (COX-2) enzyme played a specific role during the polyp formation. COX-2 expression was reported in about 80% of CRC cases worldwide.3 An Indonesian study found only 49% of COX-2 expression among CRC patients. Based on anatomical location, early-onset CRCs in developed countries most commonly occur in the rectum (35-37%), followed by the distal colon (25-26%) and proximal colon (22-23%) and showed a low pathological stage, rarely metastasize, and has a better prognosis.4,5 However, Indonesian patients with CRC showed otherwise characteristics, i.e., commonly occur in the rectum (61.7%), distal (21.5%), proximal (16.7%), have a high clinical stage, and poor survival.1,6-7 The paper should also analyse what is the percentage of transition and transversion mutations in order to gain insight and speculate the roles of local diet and pollutants. For instance the KRAS tranversion mutation has been associated with smoking (Dogan et al., 20123). There is no need for statistical analysis. A descriptive percentage table should be sufficient. The percentage of transition and transversion mutation and the roles of local diet are indeed necessary and should be considered for our further study."
}
]
},
{
"id": "150607",
"date": "20 Sep 2022",
"name": "Wei Zhang",
"expertise": [
"Reviewer Expertise Cancer biomarker discovery",
"human genetics",
"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\nUnderstanding genomic/genetic landscapes of CRC from different populations is critical for elucidating health disparities. The authors collected 13 tumor samples from Indonesian patients with CRC and generated genetic variant profiles using a candidate gene approach. The study design was straightforward and the manuscript was concisely written. The level of analysis and depth of description can be further improved though:\nMajor comments:\n1. The results section is largely \"direct\" description of what was observed from the 13 tumor samples. It will be more interesting to add some description about comparisons for example early onset vs. late onset, early stages vs. late stages, as well as for example males vs. females, smokers vs non-smokers etc.\n2. The discussion section has a lot of redundant description of the results. The authors can improve the discussion by comparing with what is available in the literature for other populations (e.g., Eastern Asians, European Americans etc.).\n3. Also, the current discussion repeats too much about CRC epidemiology. The authors can try to be more focused by discussing their major findings as suggested in 2).\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": "9330",
"date": "13 Feb 2023",
"name": "Murdani Abdullah",
"role": "Author Response",
"response": "We have revised the paper according to your comments. We have added the early onset and late onset proportions in our paper. We have also added comparisons of the mutated genes in our results with few literatures from different populations, namely US, China, European and African descendants, and Australians."
}
]
}
] | 1
|
https://f1000research.com/articles/11-443
|
https://f1000research.com/articles/11-1292/v1
|
11 Nov 22
|
{
"type": "Research Article",
"title": "Analysis of energy storage materials for developments in solar cookers",
"authors": [
"Rahul Khatri",
"Rahul Goyal",
"Ravi Kumar Sharma",
"Rahul Goyal",
"Ravi Kumar Sharma"
],
"abstract": "Solar energy is accessible freely and can be utilized for many household and industrial applications. The consumption of solar energy for cooking applications has found significant success. Various innovations have been employed in facilitating cooking during off-sunshine hours. Thermal energy storage helps in overcoming the fluctuations in the supply of energy required for cooking during different time periods of the day. This study focuses on the different types of thermal energy storage mediums that are currently utilized in solar cooking. Primarily, oils and pebbles are most commonly used as sensible heat storage (SHS) while organic phase change materials (PCMs) are used as latent heat thermal energy storage materials (LHTES).\nThe properties and performances of various SHS and latent heat storage (LHS) mediums have been compared for their suitable utilization. SHS materials are cost-effective but have lower thermal gradient compared to LHTES materials. The energy storage capability of LHTES is high while degradation with the increasing number of charging and discharging cycles is also considerable. The melting point should be close to the utilization temperature for being used as LHTES as thermal diffusivity of the materials greatly influences the performance of solar cookers. The cooking time is lower for solar cooking systems equipped with energy storage compared to non-equipped cooking systems. It is recognized that the use of energy storage has been proved as a huge advantage to solar cooking systems, however, the design, and heat transfer characteristics of the cooking vessel along with the storage material type and volume must be optimized in order to make this technology more influential.",
"keywords": [
"Solar Energy",
"Solar Cooker",
"Energy Storage",
"Sensible Heat",
"Latent Heat",
"Storage Capacity",
"Thermal Performance and Phase Change Materials"
],
"content": "Introduction\n\nThe future belongs to renewable energy, as the demand and supply gap of fossil fuel is increasing day by day. Solar energy seems to have the potential to cater to the energy needs of the world as they have grown strongly over the last few decades in terms of energy collected. Solar thermal energy systems have higher efficiencies, but they lack in the aspect of energy backup. Many applications of these systems require a continuous supply of energy, but the unavailability of energy during off-sunshine hours limits their use. Energy storage systems bridge this gap and maintain the required energy supply, which increases the performance and reliability of these systems.\n\nSolar energy is one of the simplest green energy options to meet the cooking energy needs. It not only reduces health hazards caused by the use of traditional fuels but it is also eco-friendly. Two types of commonly used direct solar cookers are box type and concentrating type. These may have reflectors for enhancing optical performance or can work without reflectors. In indirect-type solar cooking arrangements, the system may be integrated with flat plate collector (FPC), evacuated tube collector (ETC) or with a concentrating collector.1\n\nThe social importance of solar cookers was explored by Escobar.2 The unavailability of energy during off-sunshine hours is its major drawback. Solar cookers with thermal energy storage (TES) are a good alternative to the traditional cooking methods and also reduce CO2 emissions in a significant manner.3\n\nSolar energy systems will be highly productive and reliable with the integration of energy storage mediums.4–6 Use of TES enhances the performance with low running and operating expenses. This also permits the use of solar cooking systems during off-sunshine hours.\n\nUse of energy storage in solar energy systems improves their efficiency and reliability. For high temperature applications, phase change materials (PCM) are most useful, however, their economic feasibility is still unattended. As suggested by Gautama et al.,7 sensible heat storage (SHS) combined with PCM can improve the performance of energy storage systems.\n\nUtilization of water and dodecanoic acid as energy storage in solar collector was carried out by Joseph et al.8 Water has high charging and discharging rates but low storage capacity while LHES was reported to be potentially better for reducing energy storage volumes.\n\nThe properties of a good TES medium are, melting point of PCM should be same as the working temperature, high energy storage density, high latent heat, and high heat capacity. These are required to have high thermal conductivity for faster heat transfer rates.9 High mass to volume ratio and high specific heat are two common desirable properties of energy storage mediums while working with solar energy systems.\n\n\nMethods\n\nThis paper categorizes various research works carried out on solar cooking with thermal energy storage mediums. Classification of thermal energy storage medium along with a discussion on sensible heat storage mediums and latent heat storage mediums is presented. The advantages of SHS and latent heat storage (LHS) mediums for suitability in solar cooking applications are also reviewed. Various thermo-physical properties of these materials are also discussed to analyze their use as per the end-user needs.\n\nThe storage of energy during the daytime for supply during off-sunshine hours is possible if it is stored in one or other form. TES can be classified under SHS and LHS mediums. SHS mediums do not have a change in their physical state while LHS mediums absorb energy, converting their physical state from solid to liquid, and from liquid to vapor. The heat and temperature variations in LHS and SHS have been presented in Figure 1. The detailed classification of energy storage mediums is presented in Figure 2.\n\nThe heat storage capacity of latent heat thermal energy storage (LHTES) mediums is high as compared to SHTES medium. As the latent heat of fusion (Qlatent) does not have any temperature change, the charging and discharging include both temperature change and phase change in LHTES.\n\nSHS mediums\n\nSHS mediums store energy in the form of heat creating temperature difference. Materials having a high specific heat are more useful as SHS as they can store higher energy for a unit change of temperature difference. They are relatively cheaper and easily available as compared to other materials, which increase their usefulness.\n\nSHS mediums can be in solid or liquid form. In liquid, water is used in many applications as it is cheaply available and has high specific heat. For high temperature applications, various SHS liquid mediums like oils, liquid metals, or salts can be used. In a few articles,11,12 working of SHS mediums to up to 180°C has been reported, but the increase in the total weight of the system is a concern with these mediums. Economic analysis for different solar concentrating devices used in cooking applications has been carried out by Widjaja et al.,12 with SHS medium, the payback period for solar cooking system was half of the payback period without SHS.\n\nSaxena et al.13 experimentally investigated the use of grainy carbon powder as an SHS medium in box-type solar cookers (BTSC); the best output was reported with a composite prepared with LHS i.e. paraffin wax. The use of palm oil as an energy storage medium was studied14 and it was reported that the heating efficiency was doubled with the use of energy storage mediums. A low cost SHS medium was prepared with sand and carbon for testing with solar cooker.15 The cooker was found viable for off-sunshine hours cooking with an efficiency of around 37%.\n\nUse of bayburt stone as an SHS medium in BTSC as shown in Figure 3 resulted in efficient cooking during off-sunshine hours. The efficiency improvement of about 40% was achieved with this SHS medium.16 The temperature in solar cooker with Lapland granite rocks used as SHS during experimentation was maintained above 40°C for almost 225 minutes, while without SHS material, it was above 40°C for only 45 minutes. The author17 concluded that, when using TES, the cooking capability of the solar cookers can be extended for a longer duration.\n\nAn oil-pebble bed-based energy storage medium for solar cookers was studied by Mawire et al.18 Methods of charging and discharging the energy storage medium also play an important role in its performance. Engine oil as an energy storage medium with BTSC systems was studied by Nahar.19 A temperature difference of 23°C was achieved with energy storage compared to a system without energy storage. Food was cooked perfectly during off-sunshine hours where it was not cooked without energy storage medium. The various materials used as SHS medium in solar cooking system along with their thermal and physical properties are presented in Table 1.\n\nLHS mediums\n\nLHS mediums generally have a phase change during energy interactions. During energy exchange, i.e. charging and discharging, the energy can be absorbed in raising the temperature as well as changing the physical state. They are also referred to as PCM. It is desirable to use LHS mediums where uniform temperature needs to be maintained for a longer duration, however, PCM increases the initial cost of the system.20 Chemically, the PCMs must be stable, compatible with materials, should be non-toxic and non-flammable.21\n\nOrganic PCMs are the most commonly used energy storage medium in solar cooking. Nitrate salts are mostly used in high temperature applications, while for low and moderate temperatures, organic materials are used. The systems with working temperatures lower than 120°C do not effectively utilize the latent heat storage mediums.22 The various materials used as LHS medium in solar cooking system along with their thermo-physical properties are presented in Table 2.\n\n* Mixture of sodium nitrate and potassium nitrate.\n\n** Mixture of NaNO2, NaNO3, and KNO3.\n\n# (Mg (NO3)2 6H2O).\n\nUse of organic PCM\n\nOrganic PCMs are a group of paraffins and non-paraffin materials. Fatty acids, alcohols, glycols and esters are classified under non-paraffin phase change materials. They have low thermal conductivity in solid phase and are relatively cheap. Paraffin wax is the most commonly used organic PCM as it has comparable thermal properties, i.e., high density and high latent heat.\n\nThe cooking efficiency up to 54% can be achieved and cooking time reduced with the use of paraffin as an energy storage medium in BTSC. It was concluded by Saxena et al.13 that the composite of SHS and LHS performed better than the SHS and LHS individually. The cooking time was reduced by one hour when paraffin wax used as an energy storage medium.23 Comparative studies between solar cooker with and without energy storage was reported by Reddy et al.2 Paraffin PCM was used and a temperature difference of 17 °C was maintained during evening time in the cooker with TES compared to the cooker without TES.\n\nUse of erythritol as an energy storage medium was investigated24 using a box-type solar cooker and it was reported that both the charging and discharging time was increased using PCM. Thermal stability of the system was better with PCM during off-sunshine hours. Use of acetanilide as PCM with box-type solar cooking system was investigated by Buddhi et al.,25 showing high temperature for well-cooked food. Use of benzoic acid and stearic acid as LHS medium was studied by Adetifa et al.14 and it was concluded that the high temperature of water was realized with energy storage, i.e., 80°C, and 50°C was maintained without solar radiations.\n\nSolar cooker with PDC was studied by Senthil26 using paraffin wax as an energy storage medium. Heating time for water was reduced to 90 min compared to 120 min without PCM. Improved productivity and thermal performance of the cooker were observed with PCM. Solar cooking using solar salt as PCM for high temperature application was carried out by Bhave et al.27 An indoor experiment was carried out and 170–180°C was easily achieved with this system. The device was found convenient for cooking inside the kitchen and with minor geometrical modifications it can serve different end user needs.\n\nGalactitol as PCM was utilized for medium temperature solar cooking applications by John et al.28 The lifespan of Galactitol as PCM was reported to be less than 100 days if utilized every day for cooking application. Stability at high temperatures of 150°C was reported, but due to the short life span, the author concluded that it is unstable for energy storage applications.\n\nStearic acid as a PCM using a collapsible parabolic solar cooker was studied by Keith et al.29 PCM integrated cooking pot is shown in Figure 4 which was used to cook food and subsequently kept it warm for longer duration. The payback period of the developed solar cooking system was found to be less than 53 weeks.\n\nParaffin and erythritol were used as energy storage mediums in a parabolic concentrating- type solar cooking system. Lecuona et al.30 concluded that the use of PCM and insulating the utensil after energy storage allows cooking of dinner and next day breakfast. The study also concluded that higher latent heat and conductivity of erythritol are advantageous for faster indoor cooking.\n\nUse of inorganic PCM\n\nInorganic PCMs are salts, salt hydrates and metal alloys. Salts and salt hydrates have the highest latent heat to volume ratio, thermal conductivity and smooth phase transition. Drawbacks of inorganic salts as reported by Khan et al.20 are change of volume, low thermal conductivity and high cost.\n\nSolar salt was used as an energy storage medium with a box-type solar cooker by Coccia et al.31 It was concluded that thermal stability was improved and heat retention was increased 1.86 times than that without a storage medium. Mussard et al.32 concluded that the use of inorganic PCM like nitrate salt has potential of replacing traditional cooking methods. These systems are slower for traditional cooking but the quality of heat transfer is better in these systems.\n\nMagnesium chloride hexahydrate was used as PCM with parabolic dish solar collector (PDSC) by Bhave et al.33 The cooker with PCM tubes is presented in Figure 5. The PCM was heated upto 130°C i.e., 12°C above the melting point of the PCM. 32.66% utilization was achieved by the developed system.\n\nMagnesium nitrate hexahydrate was used as PCM for indirect solar cooking unit by Hussein et al.34 The developed cooker was found suitable for heating or keeping the food hot during off-sunshine hours till the next morning. Box-type solar cooker incorporating acetamide as PCM was experimentally compared with solar cooker without PCM by Sharma et al.35 The results concluded that cooking during off-sunshine hour is possible with cooker incorporated with PCM. Due to heavy weight, metallic PCMs are rarely considered as an energy storage medium in solar cooking.\n\nHeat transfer fluids (HTFs)\n\nSolar energy systems while having energy concentration can store thermal energy in direct or indirect cooking arrangements. HTFs are used to transfer the heat from the source to the indirect cooking system. The heat transfer fluid, while having a major role in transferring the heat, can also behave as an energy storage medium. Few articles suggested that the storage medium can also be used as an HTF.36 The high specific heat and thermal conductivity appraise it to behave as energy storage and transfer medium. Low viscosity for minimum pumping power is desirable for heat transfer fluids. Table 3 lists HTFs used in solar cooking and their properties.\n\nUse of therminol-55 as an HTF for energy modelling of cooking systems was carried out by Bade et al.37 and proposed this for water scarce regions. It also enhances the heat transfer capability and has a very minimal payback period. Therminol-55 (synthetic oil) was used as heat transfer fluid by Singh38 for realizing indoor cooking using solar energy. Vegetable oil was used as HTF in solar cooking system for big families and positive results have been obtained by Schwarzer et al.11\n\n\nDiscussion and conclusions\n\nSolar cooking can be a potential replacement for traditional cooking systems. This will lead to environmental, economic and health benefits to the end user. Use of solar cookers in conjunction with energy storage mediums to enhance their performance is analyzed for its use during off-sunshine hours. The role of energy storage materials, their importance and advantages in solar cooking application are discussed in detail.\n\nSolar cooking systems using both SHS and LHS have been reviewed and discussed. Use of SHS found limited applications, however, optimized used of these mediums resulted in better thermal output. Pebbles are most commonly used SHS as they have comparable thermal properties, are readily available and are available free of cost.\n\nMost of the studies reviewed used LHTES mediums with solar cooking. The results suggested promising improvement in the performance of solar cooking especially during off-sunshine hours. With moderate melting point and high latent heat of fusion, paraffin wax and erythritol are the most commonly used latent heat storage mediums.\n\nHeat transfer fluids are generally used to integrate the direct and indirect cookers. The feasibility of indoor cooking has been found in a few studies where HTF is highly recommended. Therminol-55 is the most commonly used HTF.\n\nThe following conclusions can be drawn from the present study:\n\n• Box-type and parabolic dish-type solar cooker are commonly used solar cooking devices.\n\n• The use of energy storage mediums shows remarkable progress in the thermal output of solar cooking systems.\n\n• Working of solar cooker during evening and till next morning has been found feasible with the use of energy storage.\n\n• Thermal performance improvement with PCM is high whereas economically SHS was found more viable.\n\n• Use of inorganic PCMs i.e. salts and salt hydrates are associated with drawbacks like corrosion, poor heat transfers and phase separation\n\n• Use of PCM reduces the energy storage volumes compared to SHS mediums.\n\n• SHS can be used for low temperature applications while PCM is recommended for high temperature applications.\n\n• Use of SHS in powder form will be highly advantageous as thermal diffusivity will be high.\n\n• PCM’s having low melting point will have lower life cycle as the number of charging and discharging cycles will be high.\n\n• In indirect solar cooker, TES is efficient and safe to use. However, from economic point of view, the use of TES has been found viable for community cooking.\n\n• The composite of SHS and LHS could be a potential area for research in order to improve the performance economically.\n\n• The method of utilization of energy storage mediums also affects their thermal performance.\n\n• Use of HTF can also contribute to the improvements of the performance of solar cooking units, especially with indirect cooking units.\n\n• Various geometrical and design parameters of the cooking vessel and energy storage unit can play a significant role in better output.",
"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\nMuthusivagami RM, Velraj R, Sethumadhavan R: Solar cookers with and without thermal storage-A review. Renew. Sust. Energ. Rev. 2010; 14: 691–701. Publisher Full Text\n\nDe Escobar EM: Low budget solar cookers: An alternative to diminish the use of wood as a source of fuel. Renew. Energy. 1996; 9: 754–757. Publisher Full Text\n\nMallikarjuna Reddy S, Sandeep V, Sreekanth M, et al.: Development and testing of a solar cooker with thermal energy storage system. Int. Energy J. 2017; 17: 185–192.\n\nPandey AK, Hossain MS, Tyagi VV, et al.: Novel approaches and recent developments on potential applications of phase change materials in solar energy. Renew. Sust. Energ. Rev. 2018; 82: 281–323. Publisher Full Text\n\nSenthil R, Cheralathan M: Enhancement of the thermal energy storage capacity of a parabolic dish concentrated solar receiver using phase change materials. J. Energy Storage. 2019; 25: 100841. Publisher Full Text\n\nKashyap V, Sakunkaewkasem S, Jafari P, et al.: Full Spectrum Solar Thermal Energy Harvesting and Storage by a Molecular and Phase-Change Hybrid Material. Joule. 2019; 3: 3100–3111. Publisher Full Text\n\nGautam A, Saini RP: A review on technical, applications and economic aspect of packed bed solar thermal energy storage system. J. Energy Storage. 2020; 27: 101046. Publisher Full Text\n\nJoseph A, Kabbara M, Groulx D: Characterization and real-time testing of phase-change materials for solar thermal energy storage. Int. J. Energy Res. 2015; 40: 61–70. Publisher Full Text\n\nKhatri R, Goyal R, Sharma RK: Advances in the developments of solar cooker for sustainable development: A comprehensive review. Renew. Sust. Energ. Rev. 2021; 145: 111166. Publisher Full Text\n\nHelm M, Keil C, Hiebler S, et al.: Solar heating and cooling system with absorption chiller and low temperature latent heat storage: Energetic performance and operational experience. Int. J. Refrig. 2009; 32: 596–606. Publisher Full Text\n\nSchwarzer K, Vieira da Silva ME: Solar cooking system with or without heat storage for families and institutions. Sol. Energy. 2003; 75: 35–41. Publisher Full Text\n\nWidjaja ASN, Löwe K, Costa FS: Design and simulation of a concentrated solar thermal system with an integrated concrete storage for continuous heat supply. Energy Procedia. 2018; 155: 121–135. Publisher Full Text\n\nSaxena A, Cuce E, Tiwari GN, et al.: Design and thermal performance investigation of a box cooker with flexible solar collector tubes: An experimental research. Energy. 2020; 206: 118144. Publisher Full Text\n\nAdetifa BO, Aremu AK: Computational and experimental study of solar thermal energy store for low-temperature application. J. Energy Storage. 2018; 20: 427–438. Publisher Full Text\n\nSaxena A: Performance Evaluation of a Solar Cooker with Low Cost Heat Storage Material. Int. J. Sustain. Green Energy. 2017; 6: 57. Publisher Full Text\n\nCuce PM: Box type solar cookers with sensible thermal energy storage medium: A comparative experimental investigation and thermodynamic analysis. Sol. Energy. 2018; 166: 432–440. Publisher Full Text\n\nAbate S: Solomon Abate Evaluation of Thermal Energy Storage Materials for Solar Cooker.2014.Reference Source\n\nMawire A, McPherson M, Van Den Heetkamp RRJ: Simulated energy and exergy analyses of the charging of an oil-pebble bed thermal energy storage system for a solar cooker. Sol. Energy Mater. Sol. Cells. 2008; 92: 1668–1676. Publisher Full Text\n\nNahar NM: Performance and testing of a hot box storage solar cooker. Energy Convers. Manag. 2003; 44: 1323–1331. Publisher Full Text\n\nKhan MMA, Saidur R, Al-Sulaiman FA: A review for phase change materials (PCMs) in solar absorption refrigeration systems. Renew. Sust. Energ. Rev. 2017; 76: 105–137. Publisher Full Text\n\nMohamed SA, Al-Sulaiman FA, Ibrahim NI, et al.: A review on current status and challenges of inorganic phase change materials for thermal energy storage systems. Renew. Sust. Energ. Rev. 2017; 70: 1072–1089. Publisher Full Text\n\nNkhonjera L, Bello-Ochende T, John G, et al.: A review of thermal energy storage designs, heat storage materials and cooking performance of solar cookers with heat storage. Renew. Sust. Energ. Rev. 2017; 75: 157–167. Publisher Full Text\n\nArabacigil B, Yuksel N, Avci A: The use of paraffin wax in a new solar cooker with inner and outer reflectors. Therm. Sci. 2015; 19: 1663–1671. Publisher Full Text\n\nCoccia G, Aquilanti A, Tomassetti S, et al.: Design, realization, and tests of a portable solar box cooker coupled with an erythritol-based PCM thermal energy storage. Sol. Energy. 2020; 201: 530–540. Publisher Full Text\n\nBuddhi D, Sharma SD, Sharma A: Thermal performance evaluation of a latent heat storage unit for late evening cooking in a solar cooker having three reflectors. Energy Convers. Manag. 2003; 44: 809–817. Publisher Full Text\n\nSenthil R: Enhancement of productivity of parabolic dish solar cooker using integrated phase change material. Mater Today Proc. 2020; 34: 386–388. Publisher Full Text\n\nBhave AG, Kale CK: Development of a thermal storage type solar cooker for high temperature cooking using solar salt. Sol. Energy Mater. Sol. Cells. 2020; 208: 110394. Publisher Full Text\n\nJohn G, König-Haagen A, King’ondu CK, et al.: Galactitol as phase change material for latent heat storage of solar cookers: Investigating thermal behavior in bulk cycling. Sol. Energy. 2015; 119: 415–421. Publisher Full Text\n\nKeith A, Brown NJ, Zhou JL: The feasibility of a collapsible parabolic solar cooker incorporating phase change materials. Renew. Energy Focus. 2019; 30: 58–70. Publisher Full Text\n\nLecuona A, Nogueira JI, Ventas R, et al.: Solar cooker of the portable parabolic type incorporating heat storage based on PCM. Appl. Energy. 2013; 111: 1136–1146. Publisher Full Text\n\nCoccia G, Di Nicola G, Tomassetti S, et al.: Experimental validation of a high-temperature solar box cooker with a solar-salt-based thermal storage unit. Sol. Energy. 2018; 170: 1016–1025. Publisher Full Text\n\nMussard M, Gueno A, Nydal OJ: Experimental study of solar cooking using heat storage in comparison with direct heating. Sol. Energy. 2013; 98: 375–383. Publisher Full Text\n\nBhave AG, Thakare KA: Development of a solar thermal storage cum cooking device using salt hydrate. Sol. Energy. 2018; 171: 784–789. Publisher Full Text\n\nHussein HMS, El-Ghetany HH, Nada SA: Experimental investigation of novel indirect solar cooker with indoor PCM thermal storage and cooking unit. Energy Convers. Manag. 2008; 49: 2237–2246. Publisher Full Text\n\nSharma SD, Buddhi D, Sawhney RL, et al.: Design, development and performance evaluation of a latent heat storage unit for evening cooking in a solar cooker. Energy Convers. Manag. 2000; 41: 1497–1508. Publisher Full Text\n\nStutz B, Le Pierres N, Kuznik F, et al.: Stockage thermique de l’énergie solaire. Comptes. Rendus. Phys. 2017; 18: 401–414. Publisher Full Text\n\nBade MH, Bandyopadhyay S: Energy Modelling of Thermal Oil Based Cooking System. Energy Procedia. 2015; 75: 1746–1751. Publisher Full Text\n\nSingh OK: Development of a solar cooking system suitable for indoor cooking and its exergy and enviroeconomic analyses. Sol. Energy. 2021; 217: 223–234. Publisher Full Text\n\nKumaresan G, Vigneswaran VS, Esakkimuthu S, et al.: Performance assessment of a solar domestic cooking unit integrated with thermal energy storage system. J. Energy Storage. 2016; 6: 70–79. Publisher Full Text"
}
|
[
{
"id": "155694",
"date": "15 Nov 2022",
"name": "Brian Norton",
"expertise": [
"Reviewer Expertise Solar energy 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\nThis paper provides a review of the use of sensible phase change materials for energy storage in solar cookers. Energy storage is required in solar cookers if their use is to be extended to applications where cooking is either in the evening or at night. Solar cookers used at such times are unlikely to be located outdoors so fluids for the transfer of heat from the outdoor to the indoor environment are also summarized.\n\nThe paper could provide a more comprehensive and complete review of the literature on this topic. In particular on (i) the solar collectors or inverted absorber mirrors used to transfer heat indoors and (ii) the charging/discharging rates of the various heat storage materials when combined with a range of heat transfer enhancements. The conclusions presented need to be linked to specific previous work. Some conclusions seem odd; for example, is it universally true that PCMs with lower melting points have shorter lives as they cycle more often?\nSome conclusions are lacunae, for example \"use of PCM reduces storage volumes compared with SHS medium; true but only if the application requires a large amount of heat stored at the phase transition temperature; for heat stored over wide temperature range the difference in volume is less.\nThe work should be contextualized more realistically, for example, in bulk PCMs the phase transition takes place over a range of temperatures as unmelted PCM material convects within that already melted. The PCM line in Figure 1 thus does not apply to the bulk materials discussed in this paper.\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?\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? Partly",
"responses": [
{
"c_id": "9348",
"date": "21 Feb 2023",
"name": "Rahul Khatri",
"role": "Author Response",
"response": "S.No. 1 Comment The paper could provide a more comprehensive and complete review of the literature on this topic. In particular on (i) the solar collectors or inverted absorber mirrors used to transfer heat indoors and (ii) the charging/discharging rates of the various heat storage materials when combined with a range of heat transfer enhancements. The conclusions presented need to be linked to specific previous work. Some conclusions seem odd; for example, is it universally true that PCMs with lower melting points have shorter lives as they cycle more often? Response The section named “Modified Solar Collectors” is included as per the suggestion. The Conclusion is modified/removed as suggested. S.No. 2 Comment Some conclusions are lacunae, for example \"use of PCM reduces storage volumes compared with SHS medium; true but only if the application requires a large amount of heat stored at the phase transition temperature; for heat stored over wide temperature range the difference in volume is less. Response The conclusion is modified/removed as suggested. S.No. 3 The work should be contextualized more realistically, for example, in bulk PCMs the phase transition takes place over a range of temperatures as unmelted PCM material convects within that already melted. The PCM line in Figure 1 thus does not apply to the bulk materials discussed in this paper. Response Figure 1 is used to compare LHS and SHS over a wide range of temperatures. Specific melting temperature is considered for PCM in this figure."
}
]
},
{
"id": "155692",
"date": "07 Dec 2022",
"name": "Katlego A. Lentswe",
"expertise": [
"Reviewer Expertise Solar cooker with thermal energy storage systems"
],
"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 author could rephrase the topic from “Analysis of energy storage materials for developments in solar cookers” to “Analysis of energy storage materials for solar cookers”\n\nFor Figure 1 I suggest that the author use a different figure similar to that used in “Latent thermal energy storage technologies and applications: A review” by Jouhara et al.\n\nOn the abstract the following sentence “Primarily, oils and pebbles are most commonly used as sensible heat storage (SHS) while organic phase change materials (PCMs) are used as latent heat thermal energy storage materials (LHTES).” Can be modified I suggest the author must also include water because it has been utilized extensively over the years.\n\n“Solar thermal energy systems have higher efficiencies, but they lack in the aspect of energy backup.” I suggest the author must use “storage” than backup.\n\nOn the introduction section the author couldn’t properly link the sentences and paragraphs it was very confusing and not easy to follow.\n\nI think the method section was not supposed to be included because this is a review paper, rather a heading that will indicate or show the classification section.\n\nThis sentence does not sense “TES can be classified under SHS and LHS mediums.” Rather say SHS and LHS mediums are classified under TES.\n\nI suggest a major revision because the format of the manuscript is disorganized.\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?\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": "9349",
"date": "21 Feb 2023",
"name": "Rahul Khatri",
"role": "Author Response",
"response": "S. No 1 Comment The author could rephrase the topic from “Analysis of energy storage materials for developments in solar cookers” to “Analysis of energy storage materials for solar cookers” Response The study was carried out for future developments in solar cookers. However, requested the editor for suggestion. S. No 2 Comment For Figure 1, I suggest that the author use a different figure similar to that used in “Latent thermal energy storage technologies and applications: A review” by Jouhara et al. Response Figure 1 is cited from the following article, “Helm M, Keil C, Hiebler S, et al.: Solar heating and cooling system with absorption chiller and low temperature latent heat storage: Energetic performance and operational experience. Int. J. Refrig. 2009;32:596–606”. 10.1016/j.ijrefrig.2009.02.010 S. No 3 Comment On the abstract the following sentence “Primarily, oils and pebbles are most commonly used as sensible heat storage (SHS) while organic phase change materials (PCMs) are used as latent heat thermal energy storage materials (LHTES).” Can be modified I suggest the author must also include water because it has been utilized extensively over the years. Response Modified as suggested. S. No 4 Comment Solar thermal energy systems have higher efficiencies, but they lack in the aspect of energy backup.” I suggest the author must use “storage” than backup. Response The backup word is replaced with storage. S. No 5 Comment On the introduction section the author couldn’t properly link the sentences and paragraphs it was very confusing and not easy to follow. Response The introduction section is modified as per the suggestion S. No 6 Comment I think the method section was not supposed to be included because this is a review paper, rather a heading that will indicate or show the classification section. Response “Methods” heading is replaced by “Organization of the study” S. No 7 Comment This sentence does not sense “TES can be classified under SHS and LHS mediums.” Rather say SHS and LHS mediums are classified under TES. Response Modified as suggested."
}
]
}
] | 1
|
https://f1000research.com/articles/11-1292
|
https://f1000research.com/articles/12-201/v1
|
21 Feb 23
|
{
"type": "Research Article",
"title": "A Prospective Study on the Transmission dynamics of Corona virus disease (2019) (COVID-19) among Household contacts in Delhi, India.",
"authors": [
"Pragya Sharma",
"Shivani Rao",
"Sonal Saxena",
"Vikas Manchanda",
"Rohit Chawla",
"Warisha Mariam",
"Saurav Basu",
"Anisur Rahman",
"Meghachandra Singh",
"Neha Rana",
"Aditya Athotra",
"Himanshi Sharma",
"Mohammad Ahmad",
"Pragya Sharma",
"Shivani Rao",
"Sonal Saxena",
"Vikas Manchanda",
"Rohit Chawla",
"Saurav Basu",
"Anisur Rahman",
"Meghachandra Singh",
"Neha Rana",
"Aditya Athotra",
"Himanshi Sharma",
"Mohammad Ahmad"
],
"abstract": "Background: This study was conducted to understand the transmission dynamics of COVID-19 virus among the household contacts of RT-PCR confirmed cases to have an insight on key epidemiological characteristics of the infection. Methods: This was a prospective case-ascertained study conducted among the contacts of laboratory-confirmed COVID-19 cases residing in the same household in the Central and North-East districts of Delhi between 28th December 2020, and 28th June 2021. Data and specimen for reverse transcription polymerase chain reaction (RT-PCR) and serology were collected from the primary case and their contacts on day one of the visit, and follow-up collection of data and specimen was done on day 7, 14 and 28. A daily symptom diary was also maintained for all the primary cases and their contacts till 28 days from enrolment in the study. A total of 109 houses were enrolled in the study. Results: The secondary attack rate (SAR) estimated among the household contacts was 13.86% [95% C.I. 9.71%, 19.39%] and the secondary infection rate was 33.16% [95% C.I. 26.97%, 40.00%]. The serial interval and basic reproduction number (R0) within the household were estimated to be 3.6± 5.73 days and 1.26 [95% C.I. 1.21—1.31], respectively. Significant predictors of the infection were location of household in central district (SAR = 20% [13.75, 28.16]) versus North-East District (SAR = 4.87% [1.83-12.35]) p= 0.002, sharing of utensils (SAR= 42.85% [14.26—77.11], p=0.02), and using the room to sleep where a specific case has been isolated (SAR= 25% [12.97—42.71], p=0.047). Transmission from the symptomatic primary case was observed to be five times higher. Conclusion: Our analysis showed that the secondary infection rate was higher among household contacts. This study suggests a dose-response association between severity of the primary case of SARS CoV-2 and infection among contacts.",
"keywords": [
"SARS CoV-2",
"COVID-19",
"Transmission dynamics",
"Epidemiology",
"Household Transmission"
],
"content": "Introduction\n\nA novel coronavirus (n CoV) is a new strain that has not been previously identified in humans. Corona viruses (CoV) are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV).1 The first case was reported in Wuhan, Hubei Province, China, in December 2019 and the World Health Organization (WHO) declared the outbreak a public health emergency of international concern on January 30, 2020.2,3 There has been lot of uncertainty in the detection and spread of this emerging respiratory pathogen as we have little information about the epidemiological, clinical and virological characteristics of this novel pathogen.4 The average incubation period of SARS-CoV-2 is 5– 6 days, but it has been reported up to 14 days also.5 The transmission takes place by various routes such as through contact, droplets, fomite, fecal-oral, blood borne, air borne, mother-to-child, and from animal-to-human. Transmission by contact and droplets may be direct or indirect by close contact with infected people through saliva and respiratory secretions or their respiratory droplets, expelled by cough, sneeze, talking or singing, and aerosols generated during medical procedures (“aerosol-generating procedures”). The present information suggests that the transmission of COVID-19 primarily takes place from people having symptoms, and occurs before they show any symptoms, but have close proximity to those people for a prolonged period of time.6 The clinical condition of COVID-19 is highly variable from being asymptomatic to mild and to severe. Headache, fever, cough, fatigue, diarrhoea, and even conjunctivitis are common symptoms. Severe symptoms include SARS-like viral pneumonia, acute respiratory distress syndrome (ARDS), multi organ dysfunction, and even death.6 The infection with SARS-CoV-2 results primarily in respiratory disorders ranging from mild to severe and sometime even death, while many people infected with the virus remain asymptomatic.\n\nA household is a closed setting having a defined population which normally does not mix readily with surrounding bigger communities. Thus, it can work as a tool to track emerging respiratory infections, which in turn can help in determining the pattern of transmission of the virus, as the denominator will be well-defined in a household. The follow-up of household contacts is also very easy in this well-defined setting as compared to an undefined one because the exposure is within the setting. Studies in household settings also give an insight of the transmission dynamics (reproduction number and serial interval) of the virus, as well as help in understanding of the clinical spectrum of illness in secondary cases.7 In a closed setting, the pool of susceptible and exposed individuals is larger, which makes it easy to observe chains of transmission in an epidemic. Further in the case of multiple waves of infection, a study conducted in a closed setting provides unique insight into transmission dynamics in the very early epidemic stage.\n\nTo date, the study has been confined primarily to symptomatic patients with severe illness and as such, the spectrum of the disease, including the extent and fraction of mild or asymptomatic infection that does not require medical attention, is not clear. Infections identified in closed settings may be generalized as naturally acquired infections in contrast to cases presenting for emergency care, among which there would be fewer mild cases. Maintaining a follow-up of close contacts with similar levels of exposure to infection from primary cases can also permit identification of the asymptomatic fraction. Principally, follow-up and testing of respiratory specimens and serum of close contacts can provide useful information about the newly identified cases, as well as the spectrum of illness and frequency (by, for example, age) of asymptomatic and symptomatic infection.\n\nIsolation of cases and quarantine at home are recommended as a disease control measure in India and other countries with COVID-19 outbreaks, but such restrictions are likely to have little or no effect on transmission within households. In close contacts, humans are more susceptible to secondary infection risk and the probability that a susceptible person may get infection (SAR) is very high.8 In epidemiology, a household secondary attack rate (SAR) is defined as the number of household cases occurring within the incubation period upon exposure to a primary case divided by total susceptible household contacts.9 The household contacts are defined as individuals sharing the same residence address with the positive cases and they are more susceptible to infection. It was observed that household contacts are at greater risk as compared to other contacts such as healthcare workers and workplace contacts.10 Various studies show that spouses and elderly population (aged ≥ 60 years) evidently emerged as one of the most susceptible groups for secondary transmission, and the difference in SAR of these groups with other family members was statistically significant.11–13 Therefore, secondary clinical attack in close contact is an important factor in transmission of COVID-19 among the households.\n\nExisting evidence shows that most of the COVID-19 cases are missed by screening due to the absence of symptoms and due to lack of awareness.14 Serial interval and incubation period are the two main epidemiological parameters that determine the transmission dynamics of infectious diseases. Serial interval is defined as the time from illness onset in the primary case to illness onset in the secondary case, while incubation period is the time from infection occurred to the onset of signs and symptoms.15 Previous studies reported that the average serial interval of COVID-19 is shorter than the average incubation period, which suggests occurrence of a substantial proportion of pre-symptomatic transmission.16,17 This makes it difficult to trace contacts due to the rapid turnover of case generations. An observational study that aimed to provide the epidemiological parameters of COVID-19 using seven countries data revealed that the mean incubation period and serial interval were 7.44 days and 6.70 days, respectively.18 To address the knowledge gap on transmission dynamics, this present study investigated the household transmission of the COVID-19 virus among households who were exposed to infection. The study was conducted with the objective to understand the extent of transmission of COVID-19 within a household and to study the factors associated with any variation in the secondary infection risk, range of clinical presentation of secondary cases, risk factors for infection, and the extent and fraction of asymptomatic infections. This study will help in generating timely evidence of estimates of the severity and transmissibility of COVID-19 infection, as well as informing the public health responses and taking policy decisions.\n\n\nMethods\n\nThis was a prospective case-ascertained study which involved the identification of household contacts of a laboratory-confirmed COVID-19 infection. The study was carried out in the northeast and central districts of Delhi and the samples were processed in the laboratory of Microbiology, Maulana Azad Medical College, New Delhi. The non-hospitalized confirmed cases of COVID-19 of age more than five years and their close contacts in their household were enrolled in the study. Once a confirmed COVID-19 case was identified in at least one member of the household such households were included in the study. Households were subsequently followed up to observe development of secondary infections. A household with only one primary case and their identified household contacts were also included in the study after a written informed consent. For the purpose of this investigation, the primary case was identified through the Delhi Government surveillance system. The study was carried out for a duration of six months from 28th December 2020 to 28th June 2021. Enrolled households should have four home visits, including the enrolment visit (Day 1) and three follow-up visits on 7, 14 and 28 days of enrolment. Those who had severe COVID-19 disease or were hospitalized, co-primary cases and those living in congregation settings like hostels, orphanages, old age homes and prisons were excluded.\n\nCentre for Evidence Based Medicine (CEBM), University of Oxford, reported that between 5% and 80% of people testing positive for SARS-CoV-2 were asymptomatic. Various government reports in India had also estimated the proportion of asymptomatic infection to be 70%.19 Thus, considering the prevalence of asymptomatic cases as 0.70, the sample size was calculated by the following formula: N=2×p1−pm2×deff+c; where, t=confidence level at 95% (standard value of 1.96), p=0.70 (prevalence of asymptomatic cases), m=margin of error at 5% (standard value of 0.05), design effect (considered as 1.5 in this case), c=non-response rate (considered as 0.10). The sample size was calculated as 484 and rounded off to 500. Therefore, the total number of study participants included in the study were 500. Considering that the average size of household in Delhi is estimated to be approximately 5, a total of 100 households with a laboratory confirmed COVID-19 infected primary case were covered to achieve the desired sample size (i.e., 100 laboratory confirmed cases and their 400 household contacts).\n\nHousehold: A group of individuals (two or more) living together in the same house with a common household space and shared kitchen was referred to as a household.\n\nHousehold contacts: A household contact was defined as any person who had resided in the same household (or other closed setting) as a confirmed COVID-19 case.19\n\nThe incubation period was defined as the time between an exposure that caused COVID-19 infection and the manifestation of the first clinical symptoms of the disease (from infection or exposure to disease).\n\nThe serial interval was defined as the time between the primary case's development of symptoms and the onset of symptoms in a contact case.\n\nThe average number of infections that an infected person causes during the early stages of an epidemic, when almost all contacts are vulnerable, is known as the basic reproduction number (R0). It should be noted that very little to no immunity to COVID-19 is anticipated.\n\nA positive COVID-19 result determines the secondary infection rate, which is a measurement of the frequency of new COVID-19 infections among contacts of confirmed cases over a certain period of time. In other words, it is the proportion of contacts who contract the infection as determined by polymerase chain reaction (PCR)/serological testing on matched samples.\n\nThe secondary clinical attack rate (SAR) is the measure of the frequency of new symptomatic cases of COVID-19 infection among the contacts of confirmed cases in a defined period of time, as determined by a positive COVID-19 result. In other words, it is the rate of clinical manifestation of the infection in contacts.\n\nThe term “overcrowding” refers to a situation when the number of people exceeds the capacity of the available living space, whether measured in terms of rooms, bedrooms, or floor area, with detrimental effects on both physical and mental health. It depends on the number of people per room, the tenants' age, sex, and floor area.20,21\n\nA pretested semi-structured questionnaire in alignment with the WHO unity protocols was used for the purpose of data collection. Separate questionnaires were used for primary cases and separate for household contacts. Questionnaires for primary cases included sociodemographic details and questions on housing, disease symptoms, comorbidity status and laboratory reporting. Similarly, household contacts were asked questions on their type of contact with the primary case from their day of laboratory confirmation or the manifestation of symptoms. A daily symptom diary for a period of 28 days was also maintained both by the study participants and the field investigators. The detailed algorithm is shown in Figure 1.\n\nList of all the laboratory confirmed cases in the two districts was obtained from the office of the chief district medical officer (CDMO) along with their addresses on day 1 of the initiation after prior approval from the district administration. Once the list of all positive cases was obtained, simple random sampling using a computer-generated random number table was used to select four households for that data collection day. The field investigator then contacted the cases and took the information such as, is the case living with her/his family, how many members are in the family and how many members have confirmed COVID 19 cases. According to exclusion and inclusion criteria, the cases were selected. The selected households were visited by the survey team consisting of a field investigator, phlebotomist or laboratory technician (LT) and the accredited social health activist (ASHA) /auxiliary nurse midwives (ANM) of the respective areas. In case the household members did not give consent, or the phone number was unreachable then the next household from the available list was selected randomly.\n\nThe data collection was done in four phases; in the preparation phase, protocol development, recruitment, training and pretesting in the field were done. The next phase included primary data collection, data quality checking, specimen collection and transportation and refresher training and team meetings at the various intervals. The monitoring and evaluation were conducted at various stages by the investigators for quality assurance. The last phase included data processing. During the study, community engagement was necessitated with the help of ASHA/ANM to convince the patient as some patients were very stubborn and rigid, and initially denied giving the sample.\n\nThe nasopharyngeal swabs and blood samples (3 mL) were collected from the patient’s house on day 1, 7, 14 and 28. The specimen box was carried gently without shaking, preventing jerks in the vehicle and provided to the team. The lab technician checked the name and other details and validated with the questionnaire and also checked the subject ID number in the data tool (questionnaire) and labelled that number on the vials. Then, the sample was transported and promptly transferred to the to the technician on duty of the virology lab and serology lab, Department of Microbiology, MAMC. During the process of field data collection and sample collection, the biomedical waste generated i.e., used PPE kits, gloves, needles, syringes, cotton swabs etc. was disposed of in the associated Delhi government dispensary of the catchment area.\n\nSerology\n\nUpon receipt in the laboratory, the identifiers mentioned on the vacutainer tube were cross-checked with the details mentioned in the sample transportation sheet. A unique laboratory accession ID was assigned to each sample. The blood samples were centrifuged to separate serum. Serum was transferred to a pre-labelled microcentrifuge tube and stored at -20°C until further testing. WANTAI SARS-CoV-2 Ab ELISA, an enzyme-linked immunosorbent assay (ELISA) for qualitative detection of total antibodies to SARS-CoV-2 virus in human serum or plasma specimens was used to check for the presence of antibodies. This assay is a two-step incubation antigen “sandwich” enzyme immunoassay, which uses polystyrene microwell strips pre-coated with recombinant SARS-CoV-2 antigen. The results were analysed and validated and provided as a pdf as “reactive” or “non- reactive”.\n\nReverse Transcriptase Polymerase Chain Reaction (RT-PCR) Testing\n\nThe cold boxes containing nasopharyngeal swabs in viral transport media (VTM) vials were cross-checked for the information mentioned on the line list and sample vial. Any discrepancy was reported immediately i.e., any leaked sample, and name/enrolment number mismatch was informed and rectified at the earliest. The real time process was divided into three parts: reaction plate set up, template and PC addition and amplification. The complete process was carried out between 15–25°C. The RT-PCR was put using ICMR approved National Institute of Virology (NIV) RT- PCR kit according to the literature of kit insert.\n\nFor accuracy, relevancy, and completeness, the data checking was done weekly by project coordinator and all the investigators of study. After that data was managed regularly and double data entry was done in Microsoft Excel (RRID:SCR_016137).\n\nThe data were scrutinized properly by the investigators. All the filled forms were physically verified for their completeness and accuracy. The raw data was entered in MS Excel software and code book for questionnaires on day 1 and follow-up questionnaires for 7, 14 and 28 day was also made. The data was organized and crossed checked twice. The final data were analyzed in SPSS PC Version 26 (RRID:SCR_019096) and STATA16 (RRID:SCR_012763).\n\nQualitative data have been expressed in proportions and percentages while quantitative data have been expressed in mean standard deviation (SD) and median interquartile range (IQR). Each sample in the secondary contact data were assigned a sampling weight, which was equal to the total number of observations made. Similarly, a finite population correction was introduced in the calculation, which is equal to the inverse of sampling weight as sampling was done without replacement. This helped to weigh the population composition of the collected data to account for different composition of the same. Then, a sampling survey module was designed using STATA 16 and accordingly proportions are calculated. For calculation of Ro, the library (Ro) of R software using secondary attack rate was calculated. To find out predictor variables for the occurrence of secondary cases, binary logistic regression was used. p value <0.05 has been considered statistically significant.\n\nThe study was conducted after approval from the WHO ERC and Institutional Ethics Committee of Maulana Azad Medical College with IEC registered as F.1/IEC/MAMC (77/05/2020/No20). Informed consent was taken, and data have been anonymized.\n\n\nResults\n\nA total of 325 households with SARS-CoV-2 primary cases under home isolation were contacted within a span of 6 months. Out of them, 146 households were enrolled in the study while remaining did not give consent for participation for follow-up with 4 samples or were either not eligible. Thus, 146 study participants and a total of 303 household contacts were enrolled at baseline. A total of 109 primary cases and their 202 household contacts who had given samples for RT-PCR and serology in all 4 visits were finally included in the study analysis (Figure 2).\n\nThe total primary cases were 109 in both the districts, of which 53 (48.6%) cases were from central Delhi and 56 (51.4%) cases were from the northeast Delhi. The male primary cases 67 (61.5%) were more than female cases 42 (38.5 %). 82 (75%) cases were in the category of 18–44 years and only 4 (3.7%) cases were ≥60 years of age. The median (IQR) age of primary cases was 32 years (25,40) while median (IQR) age of household contacts was 35 years (24,47). The minimum age of primary case was 7 years while the minimum age enrolled for the contacts was 6 years. Similarly, the maximum age among primary cases and contacts was 68 years and 84 years, respectively. The proportion of household contacts across all the age categories was more in the central district as compared to the northeast district and this difference was statistically significant (p=0.043). The distribution of religion and occupation of household contacts were similar across both the districts (Table 1).\n\nThe mean (±SD) household size was 3.9±1.8 and the median household size was 4 (3,5) across both the districts. Majority (85%) households had less than five family members in their house. The family size of more than five members was observed in north-east district 10(63%) as compared to Central district 6(37%). However, this difference in proportion was not significant (p=0.335). Across both the districts, majority (62%) households had ≥3 rooms with 70% having <3 bedrooms. The median number of rooms and bedrooms was found to be 3(2,4) and 2(1,3) respectively. Overcrowding was observed among 75% of the households which was calculated by persons per room criteria (US AHS criteria). Though, overcrowding was observed marginally higher in the central district (51%) as compared to northeast district (49%) as per the persons per room criteria; the difference in proportion was not statistically significant (p>0.05). However, by using persons per bedroom criteria, overcrowding was observed more in the northeast district (66%) as compared to the central district (34%) and this difference in proportions was statistically significant (p=0.039) (Table 2). About 39% household contacts of primary cases had to share a toilet during the period of illness and difference in proportion was found between those who did not share a toilet in the central (65%) and northeast (35%) districts. This difference in proportion was statistically significant (p=0.031). Majority (79%) of household contacts who took care of the primary case during their COVID-19 illness were from northeast district as compared to only 21% from central district and this difference in proportion was statistically significant (p<0.001). The sharing of utensils and sharing of the same glass with the primary case was seen among 3% of household contacts and all of them belonged to the central district. (p=0.043) Across both the districts, sharing of room (17%), sleeping in the same room (16%) and shaking hands (8%) were the other types of contacts between primary cases and their household contacts (Table 3).\n\n* Chi-squared test.\n\n# Fisher exact test.\n\n* Chi-squared test.\n\n# Fisher exact test.\n\nThe most common symptom of presentation was fever (53%) followed by constitutional symptoms (45%) and respiratory symptoms (37%). Influenza-like illness was seen in 71% of primary cases and gastrointestinal symptoms were present in 15% of the cases. Co-morbidity such as obesity (28%), self-reported diabetes (2%), heart disease (2%) and asthma (1%) were present. Other co-morbidities viz renal disease, autoimmune diseases, liver disease, immunosuppression were not reported by the primary cases. Three out of 42 women were pregnant. Of these, two were in the second trimester while one was in the third trimester.\n\nAll the primary cases who were RT-PCR positive initially, 20 (18.3%) remained laboratory positive by PCR on 7th day from the day of enrolment, while 4 (3.7%) remained positive even on day 28 from the day of enrolment. However, if the virus had a potential for spread, it could not be ascertained since RT-PCR could not differentiate between the live and the dead viral debris (Figure 3).\n\nA total of 69 secondary cases were reported among the household contacts during the study period. This was the cumulative total of the number of infections (RT-PCR positive) amongst the household contacts within the 4-week period of observation. It was found that out of these secondary cases, 24 (34.78%) had symptoms while remaining 45 (65.22%) were asymptomatic. The SAR estimated was 13.86% (95% C.I. 9.71%,19.39%) and the secondary infection rate was 33.16% (95% C.I. 26.97%, 40.00%). The median time taken for symptom onset in primary case to symptom onset in secondary cases is 3.5 (0,5.25) days and mean serial interval is 3.6±5.73 days status. Incubation period was calculated as 3.33±7.99 days for the household contacts to become cases. The generation time from infection in primary case to the development of infection in contacts was 2.13±4.46 days. The number of infections produced by a primary case among their susceptible household contacts was 1.26 [95% C.I. 1.21,1.31]. Thus, on an average, one primary case infected 1.26 persons. It was also observed that one in 89 cases needed hospitalization among the total cases in households (2%) in both the districts. Most of the subjects hospitalized were in the age group between 45–59 years (Table 4).\n\nSAR was higher (20%) in the central district of Delhi than the northeast (4.87%) and the difference was found to be statistically significant (p=0.002), and was higher among females (14.3%) in both the districts combined, however, the difference was not statistically significant. The SAR was maximum in the age groups 45 to 59 year and 18 to 44 years. Those who travelled out for work had a higher SAR as compared to those who stayed indoors, indicating the role of workplace, travelling and social distancing like factors playing a role in transmission too, which might be confounding factors in these households. The risk was 1.58 times as compared to those at home. Those who shared a room, slept in the same room, shared utensils, glasses, kissed and hugged with the primary case had a higher secondary attack rate and these factors were statistically significant. Presence of comorbid conditions and being symptomatic also increased the risk of transmission (OR=2.07 and 29.6 respectively). On univariate analysis, the significant predictors/risk factors of the infection were location of household in the central district (SAR=20% [13.75,28.16]) vs the northeast district (SAR=4.87% [1.83–12.35]) p=0.002, sharing of utensils (SAR=42.85% [14.26–77.11], p=0.02), and using the room to sleep where the case had been isolated (SAR=25% [12.97–42.71], p=0.047). On multivariate analysis, the model correctly predicted 86.79% (goodness of fit), and the only factor which was significant was the presence or absence of symptoms while other factors which were significant in univariate analysis did not predict the SAR.\n\nSecondary attack rate was higher in females in the central district of Delhi, being maximum in the age groups 45 to 59 year and 18 to 44 years. Those who shared a room, slept in the same room, shared utensils, glasses, kissed and hugged with the primary case had a higher secondary attack rate and these factors were statistically significant. Presence of comorbid conditions and being symptomatic also increased the risk of transmission. On univariate analysis, the significant predictors/risk factors of the infection were location of household in the central district (SAR= 20% [13.75,28.16]) vs the northeast district (SAR=4.87% [1.83–12.35]) p=0.002, sharing of utensils (SAR=42.85% [14.26-77.11], p=0.02), and using the room to sleep where the case had been isolated (SAR=25% [12.97–42.71], p=0.047). On multivariate analysis, the only factor which was significant was the presence or absence of symptoms while other factors which were significant in univariate analysis did not predict the SAR (Table 5).\n\nThe household characteristics predicting the occurrence of secondary cases among the households were living in the central district (p=0.006), age of primary case between 18 to 49 years, overcrowding, less no. of rooms, smaller family size and the presence of symptoms in primary case (p=0.009) being associated with higher secondary attack rate among the contacts. On multivariate analysis, the model correctly predicted 71.56% (goodness of fit) and RT-PCR positivity status of primary case and the presence of symptoms was found to be a predictor of occurrence of secondary cases in the household (p<0.001) (Table 6).\n\nThe household contacts who were taking care of the primary case were at a higher risk of secondary infection and this was found to be statistically significant (p=0.019). No other factors like sharing of room or toilet, shaking hands, sleeping in the same room or sharing of the utensils were associated with transmission of infection (Table 7).\n\n* Chi-squared test.\n\n# Fisher exact test.\n\nSecondary cases presented with a varied range of symptoms. The most common presentation fatigue was in 15 (21.7%), cough and sore throat in 13 (18.8%) and constitutional symptoms of fever, headache, myalgia in 9 (13%) of them. Diarrhoea was seen among 5 (7.3%) of them while a few of them suffered from loss of smell or taste 4 (5.8%). Comorbidity was present only in 24 (35%), while the majority did not have any comorbidity. Obesity was present among 37% of them, 4.3% had diabetes and 1.4% had heart disease while none of them had any liver disease, kidney disease, autoimmune disease, rheumatological or hematological disease. The RT-PCR pattern of the secondary cases is shown in Figure 4.\n\nThose who were living in the central district had 2.62 times risk of developing secondary infection. Male gender, age more than 45 years and presence of comorbidity in contacts were also associated with the development of secondary cases. On univariate analysis, living in the central district (p=0.003), absence of antibodies on day 1 (p=0.005), presence of symptoms (p<0.001) and presence of respiratory symptoms 14 days before onset in primary case (p<0.001) had higher odds of developing COVID-19 infection and was found to be significantly associated. On multivariate analysis, model fits 70.8% and presence or absence of symptoms (p=0.024), residing in the central district (p=0.048) and absence of antibodies (p<0.001) were the only significant factors found out to be associated with the secondary cases among the household contacts (Table 8).\n\nIt was observed that symptomatic cases were more in the central district 22 (43.1%) while asymptomatic were more in the northeast district (89%). The risk of symptomatic transmission was 6.07 times in the central district as compared to the northeast district and was found to be statistically significant (p=0.024). Female gender had 1.47 times risk of both symptomatic and asymptomatic transmission. Similarly, age group 18 to 44 years also had higher risk of symptomatic transmission as compared to other groups. Presence of comorbidity among the contacts also determined symptomatic transmission for the occurrence of secondary cases and the risk was 3.02 times compared to those who did not have any comorbidity (p=0.032). Other factors like sharing of room, toilet, utensils and seropositivity status did not determine the presence or absence of symptomatic transmission among the secondary cases (Table 9).\n\n\nDiscussion\n\nThis study was conducted in Delhi among the households of COVID-19 positive patients who were under home isolation. These households were selected randomly without replacement and eventually analyzed 109 households with primary cases and their 202 household contacts.\n\nAn estimated 69 secondary cases were reported from the 109 primary cases over a period of 28 days of follow-up as per the protocol. The estimated SAR was 13.86% (9.71%,19.39%) and the secondary infection rate was 33.16% (26.97%, 40.00%). A study by Rajmohan et al. (2021) in Kerala studied the epidemiology of COVID-19 infection among 101 cases and their 387 contacts. They reported the secondary attack rate as 40.7%.22\n\nThe household transmission of 13.86% for COVID-19 as found in our study as well as other studies is higher as compared to 4% for MERS-CoV (4%), 10% for SARS (10%) and 13% for the 2009 pandemic influenza A (H1N1).23–25\n\nThe average infection produced by one primary case is represented by RO. In this study, Ro was estimated to be 1.26 [95% C.I. 1.21–1.31]. This epidemiological parameter effectively demonstrates how fast an infection can spread. A value of more than 1 indicates that the number of infections have the potential to become an epidemic and pandemic. Zhao et al. observed the mean basic reproduction number (Ro) of SARS-CoV-2 to be between 2.24 to 3.58 while Imai et al. reported it to be 2.6 in the early stages of the outbreak.26,27 In a retrospective study conducted among 391 cases and their 1286 close contacts in Shenzhen, China, reproductive number (R) was found to be 0.4 (95% C.I. 0.3–0.5), with a mean serial interval of 6.3 days (95% C.I. 5.2–7.6). They also reported a similar Ro value of 1.63 (95% C.I. 1.28–1.98).28\n\nOur study suggests that transmission of infection is most likely if contacts were exposed shortly before and after symptom onset among the primary cases (3.5 days). Greater COVID-19 attack rates were observed in contacts exposed less than three days following the onset of symptoms in index patients in a Taiwan, which suggested that the time around symptom onset in primary/index cases is crucial for transmission.29 The factors like those household contacts who shared a room space for sleeping, shared utensils, glasses, kissed and hugged with the primary case had a higher secondary attack rate and these factors were statistically significant. Presence of comorbid conditions and being symptomatic also increased the risk of transmission.\n\nAnother finding is that physical intimacy of contact and case was likely to increase the risk of secondary infection and were also found to be asymptomatic given the mild form of COVID-19 infection. The transmission from the symptomatic primary case was observed to be five times higher. This finding suggests that there may be a dose-response relationship between the severity of the primary COVID-19 case and contacts’ clinical manifestation. Similarly, those primary cases who travelled out for work and male gender had higher risk of transmission to their household contacts.\n\nTherefore, a focused strategy at household contacts at higher risk is probably effective in preventing the spread of illness among susceptible contacts. Not everyone who comes into contact with the primary case will get the illness. In the first instance, viral excretion determines the transmission. The risk of infection might also be increased by factors like sharing utensils. As a result, only one-third of household contacts become infected within 7–10 days of exposure, despite the presence of similar characteristics in those contacts. As a result, individuals with mild to severe COVID disease can receive care in their homes and there is no need to establish specialized COVID care facilities. The hospitalization rate for patients with mild to moderate illness was incredibly low (1.1%), even when they also had comorbid conditions. The only component that was observed to be linked to the progression of the illness was obesity. Therefore, it should continue to be a top priority for primary health care providers to regularly monitor patients in the mild-to-moderate category who have obesity and to make prompt referrals. The hospitals should also maintain a buffer of services for the 1.1% of patients receiving home care who may eventually need hospitalization due to illness, which could result in significant numbers during a pandemic. Since symptomatic cases contribute higher to secondary attack rate (SAR) and secondary infection rate. The mass education programs should focus on immediate testing at the onset of symptoms. Gastrointestinal symptoms were also observed commonly in the cases and contacts; thus, the awareness campaigns should focus on the entire spectrum of symptoms than merely on fever and cough. The mass education programs should also focus on individual behavior. The primary case under home isolation and their household contacts must abide by the home isolation guidelines and following of infection prevention protocols. The study’s result of a secondary infection rate of 33% points to the lack of adherence in following COVID appropriate behavior. Therefore, it is needed that the primary case and their contacts always maintain COVID-19 appropriate behavior. Strengthening of testing capacity and early identification of primary cases through active and passive surveillance will also help in further reduction in transmission. Moreover, free of cost testing facilities need to be provided with less waiting time for reports in the primary health care facilities, in the absence of which, sometimes, the subjects with mild symptoms avoid getting tested and keep on spreading the infection. Thereby in few households, it was observed that the contacts developed symptoms prior to the primary case whereas the primary case was diagnosed prior to the contact. This happens due to cost and long waiting time for the diagnostic test to be conducted.\n\nThe study is one of the first few studies in India conducted at household level to address the knowledge gap on epidemiology of COVID-19 infection in closed community setting. It was a prospective case ascertained study, therefore chances of recall bias and selection bias were minimized. Our study however, had few limitations. Since this was a prospective study, loss to follow-up was observed. We did not consider non-household contacts for this study thus, the risk of transmission or contracting infection outside the household was not accounted for. Only mild cases of home isolation have been enrolled in the study thus, the predictors of severity could not be established from the study. The role of antibodies post vaccination and following exposure to natural infection could not be established as the study was initiated much before vaccine introduction in India.",
"appendix": "Data availability\n\nZenodo. A Prospective Study on the Transmission dynamics of Corona virus disease (2019) (COVID-19) among Household contacts in Delhi, India. (SARS CoV-2 HT Study) (Version 1) [Data set]. Zenodo. https://doi.org/10.5281/zenodo.7317631. 30\n\nThe project contains the following underlying data:\n\n• [https://zenodo.org/record/7317631/files/MAMC_WHO DATASET] (raw data).\n\nZenodo: STROBE checklist for ‘[A Prospective Study on the Transmission dynamics of Corona virus disease (2019) (COVID-19) among Household contacts in Delhi, India]’. SARS CoV-2 HT STROBE CHECKLIST (Version 1). Zenodo. https://doi.org/10.5281/zenodo.7306641. 30\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 acknowledge the guidance and constant support of Dr. Mohammad Ahmad (NPO, WHO Country Office), Dr. Anisur Rahman (Research Officer, WHO Country Office) and the other WHO members from country office, India and SEARO region as well as WHO-HQ. The authors would also like to extend their acknowledgment to the DGHS, Delhi and the study participants for their contribution.\n\n\nReferences\n\nWorld Health Organization: WHO Coronavirus Disease (COVID-19) Dashboard. World Health Organization;2021. [Accessed on 16 June, 2021].Reference Source\n\nZu ZY, Jiang MD, Xu PP, et al.: Coronavirus Disease 2019 (COVID-19): A Perspective from China. Radiology. 2020; 296: E15–E25. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: Statement on the second meeting of the International Health Regulations (2005) Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV). Published January 31, 2020. [Accessed 17 June, 2021].Reference Source\n\nWorld Health Organization: The First Few X cases and contacts (FFX) investigation protocol for coronavirus disease 2019 (COVID-19). Geneva:World Health Organization;2020.\n\nTian S, Hu N, Lou J, et al.: Characteristics of COVID-19 infection in Beijing. J. Infect. 2020; 80: 401–406. PubMed Abstract | Publisher Full Text\n\nTabata S, Imai K, Kawano S, et al.: Clinical characteristics of COVID-19 in 104 people with SARS-CoV-2 infection on the Diamond Princess cruise ship: a retrospective analysis. Lancet Infect. Dis. 2020; 20: 1043–1050. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: Protocol for assessment of potential risk factors for corona virus disease 2019 (COVID-19) among health workers in a health-care setting. Geneva:World Health Organization; 2020. [Accessed 17 June, 2021].Reference Source\n\nKoh WC, Naing L, Chaw L, et al.: What do we know about SARS-CoV-2 transmission? A systematic review and meta-analysis of the secondary attack rate and associated risk factors. PLoS One. 2020; 15(10): e0240205. PubMed Abstract | Publisher Full Text\n\nShah K, Saxena D, Mavalankar D: Secondary attack rate of COVID-19 in household contacts: a systematic review. QJM: Int. J. Med. 2020; 113: 841–850. PubMed Abstract | Publisher Full Text\n\nBi Q, Wu Y, Mei S, et al.: Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study. Lancet Infect. Dis. 2020; 20: 911–919. PubMed Abstract | Publisher Full Text\n\nJing Q-L, Liu M-J, Zhang Z-B, et al.: Household secondary attack rate of COVID-19 and associated determinants in Guangzhou, China: a retrospective cohort study. Lancet Infect. Dis. 2020; 20: 1141–1150. PubMed Abstract | Publisher Full Text\n\nCheng H-Y, Jian S-W, Liu D-P, et al.: Contact Tracing Assessment of COVID-19 Transmission Dynamics in Taiwan and Risk at Different Exposure Periods Before and After Symptom Onset. JAMA Intern. Med. 2020; 180: 1156–1163. PubMed Abstract | Publisher Full Text\n\nLi W, Zhang B, Lu J, et al.: Characteristics of Household Transmission of COVID-19. Clin. Infect. Dis. 2020; 71: 1943–1946. PubMed Abstract | Publisher Full Text\n\nGostic K, Gomez AC, Mummah RO, et al.: Estimated effectiveness of symptom and risk screening to prevent the spread of COVID-19. elife. 2020; 9: e55570. PubMed Abstract | Publisher Full Text\n\nAlene M, Yismaw L, Assemie MA, et al.: Serial interval and incubation period of COVID-19: a systematic review and meta-analysis. BMC Infect. Dis. 2021; 21: 257. PubMed Abstract | Publisher Full Text\n\nNishiura H, Linton NM, Akhmetzhanov AR: Serial interval of novel coronavirus (COVID-19) infections. Int. J. Infect. Dis. 2020; 93: 284–286. PubMed Abstract | Publisher Full Text\n\nViego V, Geri M, Castiglia J, et al.: Incubation period and serial interval of Covid-19 in a chain of infections in Bahia Blanca (Argentina).2020; 25: 3503–3510. Publisher Full Text\n\nMa S, Zhang J, Zeng M, et al.: Epidemiological parameters of coronavirus disease 2019: a pooled analysis of publicly reported individual data of 1155 cases from seven countries. Infectious Diseases (except HIV/AIDS). 2020. Publisher Full Text\n\nNational Centre for Disease Control: Directorate General of Health Services MoHFW, GOI. New Delhi:[Accessed on 26th July, 2021].Reference Source\n\nInformation NC for B, Pike USNL of M 8600 R, MD B, Usa 20894: Household crowding. World Health Organization;2018.\n\nBethesda: Measuring Overcrowding in Housing. Maryland. USA:2007. [Accessed on 21 July 2021].Reference Source\n\nRajmohan P, Jose P, Thodi JA, et al.: Dynamics of transmission of COVID-19 cases and household contacts: A prospective cohort study. J. Acute Dis. 2021; 10: 162. Publisher Full Text\n\nDrosten C, Meyer B, Müller MA, et al.: Transmission of MERS-Coronavirus in Household Contacts. N. Engl. J. Med. 2014; 371: 828–835. PubMed Abstract | Publisher Full Text\n\nPang X, Yang P, Li S, et al.: Pandemic (H1N1) 2009 among Quarantined Close Contacts, Beijing, People’s Republic of China - Volume 17, Number 10—October 2011 - Emerging Infectious Diseases journal - CDC n.d.Publisher Full Text\n\nWilson-Clark SD, Deeks SL, Gournis E, et al.: Household transmission of SARS, 2003. CMAJ. 2006; 175: 1219–1223. PubMed Abstract | Publisher Full Text\n\nZhao S, Lin Q, Ran J, et al.: Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: A data-driven analysis in the early phase of the outbreak. Int. J. Infect. Dis. 2020; 92: 214–217. PubMed Abstract | Publisher Full Text\n\nImai N, Cori A, Dorigatti I, et al.: Transmissibility of 2019-nCoV. Int. J. Infect. Dis. 2019. Report 3.\n\nLi F, Li Y-Y, Liu M-J, et al.: Household transmission of SARS-CoV-2 and risk factors for susceptibility and infectivity in Wuhan: a retrospective observational study. Lancet Infect. Dis. 2021; 21: 617–628. PubMed Abstract | Publisher Full Text\n\nCheng H-Y, Jian S-W, Liu D-P, et al.: Contact tracing assessment of COVID-19 transmission dynamics in Taiwan and risk at different exposure periods before and after symptom onset. JAMA Intern. Med. 2020; 180(9): 1156–1163. PubMed Abstract | Publisher Full Text\n\nMariam W:A Prospective Study on the Transmission dynamics of Corona virus disease (2019) (COVID-19) among Household contacts in Delhi, India. (SARS CoV-2 HT Study) (Version 1). [Data set]. Zenodo. 2022. Publisher Full Text"
}
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[
{
"id": "255916",
"date": "14 May 2024",
"name": "Hong Nghiem",
"expertise": [
"Reviewer Expertise Health economics"
],
"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 provides detailed descriptions of the process in which the authors examine the possibility of being infected by COVID-19 among direct contacts within the same households in India. The quality of the manuscript is very good. I have only a few minor points for improvement 1. Provide a reference for the sample size calculation 2. Provide more details on the sampling methods (e.g., random simple or cluster) 3. What factor determined how many direct contacts in each household were surveyed? 4. On what ground the authors divide to follow-up with participants every seven days?\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": []
}
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https://f1000research.com/articles/12-201
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https://f1000research.com/articles/12-200/v1
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20 Feb 23
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{
"type": "Research Article",
"title": "Genome-wide comparisons reveal broad variations in intraspecific SNP frequencies among species in Agaricomycetes, Basidiomycota",
"authors": [
"Kuan Zhao",
"Jianping Xu",
"Kuan Zhao"
],
"abstract": "Background: Genome sequence analyses can provide crucial information for understanding population history, speciation, and taxonomy. In Class Agaricomycetes where most mushroom-forming fungi belong, most species so far have been defined based on morphological, ecological, and/or molecular features. At present, there is little information on how species defined based on such features reflect their genome sequence diversity. In this study, we investigated genome-wide single nucleotide polymorphism (SNP) frequencies between strains within species to understand the patterns of variation. Methods: A total of 112 species in 72 genera of Agaricomycetes contained the nuclear and/or mitochondrial genome sequences from at least two strains each in public databases. Together, we obtained 398 and 106 available nuclear and mitochondrial genomes respectively from these taxa. Pairwise strain comparisons of the nuclear and mitochondrial genomes within individual species were conducted to obtain their SNP frequencies. Results: The SNP frequencies between nuclear genomes within individual species ranged 0–7.69% while for the mitochondrial genome, the pairwise strain SNP frequencies ranged 0–4.41%. The Spearman’s non-parametric rank correlation test showed a weak but statistically significant positive correlation between the paired nuclear and mitochondrial genome SNP frequencies. Overall, we observed a significantly higher SNP frequency in the nuclear genome than in the mitochondrial genomes between strains within most species. Interestingly, across the broad Basidiomycetes, the ratios of mitochondrial genome SNPs and nuclear genome SNPs between pairs of strains within each species were almost all lower than 1, with a mean of 0.24. Conclusions: Our analyses revealed broad variations among species in their intraspecific SNP frequencies in both the nuclear and mitochondrial genomes. However, there was broad consensus among the examined species in their mitochondrial to nuclear genome SNP ratios, suggesting that such a ratio could potentially serve as an indicator for genome sequence-based species identification.",
"keywords": [
"mitochondrial genome",
"nuclear genome",
"SNP",
"Agaricomycetes",
"mushrooms",
"intraspecific divergence"
],
"content": "Introduction\n\nThe Agaricomycete is the largest Class of fungi within the Division Basidiomycota. More than 100 families, 1,147 genera, and about 21,000 species have been reported in this Class, including many that form mushrooms, the macroscopic fruiting bodies of sexually reproducing fungi.1 Agaricomycete fungi are commonly found around our environments and play important ecological, economic, and medical roles.2 However, our understanding of most Agaricomycetes is still limited and many Agaricomycete mushrooms which seem familiar to us have not been described or were not described until very recently. For example, a local popular golden chanterelle harbored in Newfoundland Island, Canada has been frequently consumed since at least the 1960s, but it was not described until 2017 as a native new species broadly distributed throughout eastern North America.3 On the other side of the globe, several common chanterelle species in China were described only recently4,5\n\nThe increasing identification of new mushroom species has been driven by several factors, including more extensive sampling, better methods for identifying biological differences among specimens, and the changing concepts of fungal species.6–8 Indeed, both the species concepts and species delimitation criteria have been evolving, driven largely by the development of molecular markers, analytic tools and scientific approaches.3–5,9 In the biological literature, over 30 species concepts have been proposed and they can be grouped into eight main types for fungi, namely biological species, evolutionary species, phylogenetic species, morphological species, genotypic species, physiological species, ecological species, and genomic species.1–8,10–12 Dating back to the 18th century, Linnaeus began to name mushrooms based on macro-morphological features just like plants and animals, which developed into the most classic morphological species concept in higher fungi, with the taxonomic history for mushroom-forming fungi largely paralleled those of plants and animals.13 Subsequently, the biological species, ecological species, and phylogenetic species concepts were applied to the taxonomy of mushrooms.9,12,14–17 For example, the biological species concept has been used to determine the species limits based on their ability to mate and produce viable fertile offspring for the commercial button mushroom Agaricus bisporus and the honey mushroom Armillaria mellea.14,15 However, over the last 20 years, the phylogenetic species concept has become increasingly popular among mycologists for species identification, including recognizing a range of cryptic species within originally-defined individual species/species complexes.16–20 For example, the world-wide consumed porcini mushrooms (Boletus sensu stricto) share common characteristics such as “stuffed pores”, white context, reticulated stipe surface and the absence of color change after injury.21 However, it is not easy to accurately recognize individual species within the genus through morphological analyses alone. In addition, species within the genus can’t be cultured, thus limiting the application of the biological species concept. Even E.M. Fries, well-known as the “Linnaeus of fungal taxonomy” could not help sighing, “Nullum genus quam Boletorum magnis me molestavit (no genus has given me more trouble than that of the boleti)”.22 In contrast, molecular phylogenetic studies based on DNA sequences revealed its abundant genetic diversity and elucidated the relationships among Boletus edulis and its allies, including identifying several new taxa that subsequently revealed differences in macro- and micro- morphological features, ultrastructure, chemical composition, and ecological niche.21,23 While the combined features have helped resolve the species boundaries, overlapping values and conflicting signals were commonly found among many of the species for most features. Indeed, there is no universally agreed similarity cutoff for any feature for any fungal group. Consequently, there have been many new species reported in the literature for both Boletus and other fungi, with some of the species defined based on relatively few nucleotide differences.16,21\n\nA recently proposed genome sequence-based fungal species concept can potentially unify and standardize the fungal taxonomy framework.24 However, at present, little is known about the distributions of whole-genome sequence divergence within and between closely related species.25 The rapid development in genomics technology and in associated data depository and analyses platforms such as Genome Taxonomy Database (GTDB) have accelerated the development of bacterial and archaeal taxonomy, leading to a standardized bacterial taxonomy based on genome phylogeny.26 Though less abundant than those in Bacteria, the number of sequenced fungal genomes is increasing rapidly.27–29 The presence of such resources allows us to evaluate the amount of whole-genome sequence divergence within fungal species that were defined based on different species concepts and different species delimitation criteria.\n\nSpecifically, in this study, we aimed to identify the patterns of genome-wide single nucleotide polymorphisms (SNPs) within species based on publicly available genomes in the fungal Class Agaricomycetes. A SNP is a variation at a single nucleotide position between homologous genes of different organisms.30 At the population level, SNPs are the most common form of genetic variation. SNPs have been used as markers for quantitative trait loci mapping, strain identification, and phylogenetic lineage separation.31–33 Here, we explored the genome-wide SNPs for both the nuclear and the mitochondrial genomes, as well as the ratios between the nuclear and mitochondrial genomes between strains within each species of Agaricomycetes where whole-genome sequence data from ≥ two strains are available.\n\n\nMethods\n\nThe assembled nuclear and mitochondrial (mt) genome data of Agaricomycetes were downloaded from the National Center of Biology Information (NCBI) and the Joint Genome Institute (JGI) genome database deposited up to August 31, 2022. For each analyzed genome, the sequencing technology used, assembled genome size, sequencing read coverage depth, number of scaffolds and/or contigs, N50 (the minimum scaffold/contig length needed to cover 50% of the genome, L50 (the number of contigs required to reach N50), the mitogenome size and the related references were all retrieved when available. The species containing sequences from at least two nuclear genomes and/or two mitochondrial genomes were selected for our analyses.\n\nThe genome-wide SNP analyses within individual species were determined by the alignment-based program MUMmer 3.23,34 with longer assemblies (larger genome and better assembled genomes/fewer scaffolds) in each pairwise comparison serving as the reference for each analyzed species. Our alignments used the following specific commands: “-mum -p” parameter for aligning each pair of assembled genomes and identifying overlapping regions between two profiles (maxgap = 500, mincluster = 100), followed by “delta-filter -1” processing to filter out repeated comparisons, then “show-snps -CHITrl” to detect base substitutions. Insertions and deletions (InDels) in those overlapping regions were excluded from SNP frequency calculations. The series of commands were completed through two remote servers from Compute Canada. For each pair of genomes, their SNP frequency was calculated as the total number of observed SNPs between them over the reported smaller genome size of the genome pair. Density plots were generated from R package ggplot235 to show the distribution of the calculated SNP frequencies for all pairwise comparisons. The plots were exported to and modified manually by Adobe Photoshop CS6.\n\nStatistical significance for the observed differences in SNP frequencies was determined using the non-parametric test for paired data. Specifically, SNP frequencies derived from the nuclear and mitochondrial genome comparisons were exported to the online data analysis platform SPSSPRO (Scientific Platform Serving for Statistics Professional). Spearman’s non-parametric rank correlation procedure was used to detect the potential correlation between the paired nuclear and mitochondrial datasets. Only p values below 0.05 were considered statistically significant. The Spearman R values were used to infer the strength of the correlations (0–0.2, very weak; 0.2–0.4, weak; 0.4–0.6, moderate; 0.6–0.8, strong; 0.8–1.0, very strong). Furthermore, the Shapiro-Wilk test was used to check whether the SNP frequency data conformed to a normal distribution. A T-test was conducted to determine the statistical significance of the difference between two datasets if both datasets conformed to a normal distribution. Alternatively, the Wilcoxon signed-rank test was used if the SNP frequency distribution did not conform to a normal distribution.36\n\nFor species where genome sequences from multiple (more than three) strains were available, we analyzed the relationships between inter-strain SNP frequencies and their geographic distances if the strains spanned at least two continents. The quantitative relationship between the inter-strain SNP frequencies within species and their geographic distances was investigated through the online data analysis platform SPSSPRO based on Spearman’s non-parametric rank correlation procedure.\n\n\nResults\n\nAmong the Agaricomycetes, 112 species from 72 genera contained whole genome-sequenced and assembled nuclear and/or mitochondrial genomes from at least two strains within each of the species. In total, 398 nuclear genomes and 106 mt genomes from these 112 species were downloaded and their genome-wide SNP frequencies were analyzed (Underlying data: Supplementary Table 1, sheet 1).37 When available, the whole-genome SNP frequencies were calculated between all pairs of nuclear genomes and all pairs of mitochondrial genomes separately within each of the 112 species. Of the 112 species, 22 species contained at least two strains each with assembled whole genome sequences from both the nuclear and mitochondrial genomes. The genome information of the 72 strains in these 22 species is listed separately in the Underlying data: Supplementary Table 1, sheet 2.37 For these 22 species, the relative divergences of their nuclear and mitochondrial genomes among strains within each species were determined and compared. The original GenBank accession numbers of the compared genomes are presented as underlying data.37\n\nThe nuclear genome SNP frequencies varied greatly among strain pairs from within the same species (Table 1). The highest inter-strain SNP frequency based on the nuclear genome data (7.69%) was found within Rhizoctonia solani (between strains AG1-1C & AG-1 IB O8/2), followed by Schizophyllum commune (7.35%, between strains 14-112_S77 & Loenen D) and Hericium coralloides (6.93%, between strains FP-101451 & tvtc0002). The lowest inter-strain nuclear genome SNP frequency was found between two samples of Heterobasidion irregulare (between strains SAMEA6501289 & SAMEA6501290) where no SNP was found between their nuclear genomes. In addition, only one SNP was detected between two strains within Hypsizygus marmoreus (between strains HM62 & NN12) (Table 1).\n\nWithin the listed 72 genera, the nuclear and/or mitochondrial genome sequences are available from two or more strains within at least one species of each of these 72 genera.\n\nSimilar to those observed from the nuclear genome comparisons, the mitochondrial genome SNP frequencies varied greatly among strain pairs from within the same species (Table 1). The top three highest mitochondrial genome SNP frequencies within species were found in Hericium coralloides (4.41%, between strains FP-101451 & tvtc0002), Schizophyllum commune (2.83%, between strains 225.1 & 5334) and Suillus brevipes (2.79%, between strains FC45 & Sb2). However, there was no SNP within four of the 31 species where multiple mitochondrial genomes were available, namely Armillaria borealis (between strains AB13-TR4-IP16 & 47425), Schizophyllum commune (between strains ZB1 & X44, among strains 227.1, 227.2 and UNK), Trametes coccinea (between strains CIRM-BRFM 310 & 158605), and Taiwanofungus camphoratus (between strains W1 & W2, M8 & W2, V5 & V7).\n\nWe compared the inter-strain SNP frequencies between the nuclear and mitochondrial genomes within 22 Agaricomycete species. Only strains with both the nuclear and mitochondrial genome sequence information were included in this comparison. Our analyses revealed that overall, the nuclear genome SNP frequency was higher than the mitochondrial genome SNP frequency in the intraspecific comparisons (Table 1 and Figure 1).\n\nThe SNP frequencies for both the nuclear and mitochondrial genomes rejected the hypothesis of normal distribution. Thus, the non-parametric Wilcoxon signed-rank test was conducted to identify whether the difference between the paired data was statistically significant. Specifically, we included 147 paired SNP frequencies in this comparison. The result indicated a significant difference between the nuclear and mitochondrial genome SNP frequencies, with the nuclear genome showing an average of more than 300% greater SNP frequency than the mitochondrial genome SNPs (p < 0.01; 2.86% vs 0.59% on average) (Figure 1).\n\nFrom the 147 strain pairs within the 22 species with both nuclear genome and mitochondrial genome SNP frequency data, we found a weak but statistically significant positive correlation between nuclear genome and mitochondrial genome SNP frequencies (R = 0.391, p < 0.01).\n\nAmong these strains and species, the average inter-strain nuclear genome SNP frequency within species was 2.86% and the standard deviation was 1.62%. By comparison, the average inter-strain mitochondrial genome SNP frequency was 0.59% and the standard deviation was 0.65%. The coefficient of variation (standard deviation/mean) for the two datasets were 0.57 and 1.11, respectively. Thus, overall, the nuclear genome SNP frequency within species had a relatively tighter distribution than that of the mitochondrial genome. The distribution and relationship of the two group datasets are shown in Figure 2a.\n\nBased on the paired inter-strain nuclear vs mitochondrial SNP frequency comparisons in the 22 divergent species, the mitochondrial genome showed less difference than the nuclear genome in 144 of the 147 paired comparisons that covered 20 of the 22 species. For the remaining three paired comparisons representing two species, the mitochondrial genome showed more difference than the nuclear genome. Among the 22 species, the average ratio of mitochondrial genome SNP frequency and nuclear genome frequency was 0.24 with the standard deviation 0.35, the coefficient of variation for the dataset was 1.47 (Figure 2b). Detailed data, including the intraspecific SNP frequencies from all the paired genomes and their ratios, are shown in the Underlying data: Supplementary Table 1, sheet 3.37 A clear majority (95%) of the values are below 0.6 and only three values were more than one (which are not shown in Figure 2b). The highest ratio (3.14) was found between strains RHP3577 ss4 and RV95-379 of Lentinula lateritia, a close relative of the Shiitake mushroom. This pair of strains had a nuclear genome SNP frequency of 0.63% while the mitochondrial genome SNP frequency was1.99%. The lowest value of the inter-genome SNP frequency ratio was 0.00, found in several pairs of strains where their mitochondrial genomes were identical to each other.\n\nFor the intraspecific nuclear genome SNP frequency analyses, there were 42 species with each containing at least three nuclear genome sequences in NCBI/JGI. Among these, we found eight broadly distributed species with nuclear genome sequences from at least four strains and whose geographical site data were available. Among the eight species, the following six showed statistically significant positive correlation between geographical distance and inter-strain SNP frequency: namely Agaricus bisporus, Boletus edulis, Pleurotus eryngii, Pyrrhoderma noxium, Schizophyllum commune and Serpula lacrymans. The relationships between geographical distances and nuclear genome SNP frequencies within each of these six species are shown in Figure 3 with the original data used for the figure listed in the Underlying data: Supplementary Table 1, sheet 4.37 The two species that showed no significant correlation between nuclear genome SNP frequency and geographic distance were Laetiporus sulphureus and Pleurotus ostreatus.\n\nEach species is represented by a different color as shown at the bottom of the figure.\n\n\nDiscussion\n\nIn this study, we investigated the inter-strain genomic SNP frequencies within species in Agaricomycetes and revealed broad variations in their genome sequence divergence between strains for both the nuclear and the mitochondrial genomes. Overall, we found a positive correlation between the nuclear and mitochondrial genome SNP frequencies within these analyzed taxa, and with the nuclear genome SNP frequencies being about four times of that in the mitochondrial genomes. In addition, positive correlations between geographical distance and SNP frequencies were found in six of the eight species where strains from multiple continents were sequenced. Below we discuss the implications of these results with regard to genome evolution and taxonomy in Agaricomycetes.\n\nThe positive correlation between geographical distance and SNP frequencies in six of eight species are indicative of the effect of long-distance geographical separation on sequence divergence within species. Indeed, geographic separation is known to play a significant role in genome divergence and speciation in many mushroom-forming fungi.16–18,38 Interestingly, within the eight individual species where strains from multiple continents were sequenced and compared, two failed to show a strong positive correlation between geographic distance and SNP frequencies. Both species are widely distributed and consumed: the chicken mushroom Laetiporus sulphureus has both edible and medicinal values, and the oyster mushroom Pleurotus ostreatus is broadly cultivated throughout the world. Thus, their lack of correlation between geographic distance and genome-wide SNP frequencies is not surprising given the widespread collection, cultivation, consumption, and trade of germplasm of the two species among geographic regions, contributing to recent gene flow and reduced differences among geographic populations.2 Gene flow due to anthropogenic influences have been reported in multiple fungal species, including Agaricus bisporus and Amanita exitialis.39–42 For A. bisporus, even though it’s a widely cultivated and globally consumed mushroom and gene flow has been reported, the sequenced strains were chosen to represent the indigenous germplasms within each region for comparative studies.43–46 Such a strain selection bias contributed to the positive correlation between nuclear genome SNPs and geographic distances in A. bisporus.\n\nMitochondrial genes and genomes have been used extensively for phylogeographic and phylogenetic studies in a variety of eukaryotes, including fungi. Indeed, due to the small genome size and multicopy nature of the mitochondrial genomes, it’s typically much easier to obtain gene sequences from the mitochondrial genome and to assemble full mitochondrial genomes than those of the nuclear genomes. Within several Agaricomycete species such as the commercial button mushroom A. bisporus and the pine mushroomTricholoma matsutake,47,48 the mitochondrial genomes have also shown evidence of geographic differentiation. Interestingly, within 20 of the 22 analyzed species, the paired nuclear and mitochondrial genome SNP frequencies revealed overall significantly greater SNP frequencies in the nuclear genome than in the mitochondrial genome. Such a pattern is consistent with earlier observations in selected fungi49 but different from those observed in animals where mitochondria typically evolve significantly faster than nuclear genomes.50\n\nThe broad variations in both nuclear and mitochondrial genome sequence divergence observed here are consistent with what was described in an earlier review showing a range of nuclear and mitochondrial genome divergence rates in fungi.49 However, for most inter-strain comparisons within most species, the ratios of mitochondrial genomes SNP frequency over the nuclear genome SNP frequency within species were low, with a mean of 0.24 across the 22 species. This ratio is very close to the theoretical ratio predicted for a dioecious diploid species with maternal mitochondrial inheritance where the effective gene number in mitochondria is one-fourth of that in the nucleus in idealized populations.51 Assuming an equal mutation rate for the nuclear and mitochondrial genomes, we would expect that the mitochondrial genome divergence within species to be about one-fourth of that for the nuclear genome in such organisms.51 The mean observed ratio (0.24) among the 22 Agaricomycete species being close to the expected ratio (one-fourth) for a dioecious diploid species forms a contrast to that in animals. In the majority of animals, despite having a higher effective gene number in the nuclear genome (four times of that over the mitochondrial genome), sequence variation in the mitochondrial genome is often significantly higher than that in nuclear genomes, primarily due to high mutation rates in their mitochondrial genomes. In our 147 pairwise comparisons, three showed high ratios of inter-strain mitochondrial/nuclear genome SNP frequencies exceeding one: Lentinula lateritia (3.14, between strains RHP3577 ss4 & RV95-379) and Leucoagaricus gongylophorus (1.72, between strains AL2 & AS2; 1.64, between strains AB2 & AL2). At present, the reasons for such high ratios in these three comparisons are not known. A high mitochondrial mutation rate for a couple of the strains, similar to that observed in animals, could have contributed to the high ratios. Alternatively, hybridization between divergent taxa could have caused mitochondrial genome(s) from different species being associated with nuclear genome(s) of one species. In such cases, the compared mitochondrial genomes represented different species/varieties while the nuclear genomes were from the same species, resulting in such high ratios of inter-strain mitochondrial/nuclear genome SNP frequencies. Additional analyses of closely related species are needed to test the second possibility.\n\nAt present, morphological, sexual compatibility, ecological, and geographic features are often combined with phylogenetic analyses of DNA sequences at one or a few genes to differentiate existing species and describe new species. In this study, we observed broad variations in genome-wide SNP frequencies for both the nuclear and the mitochondrial genomes. Thus, our findings highlight the difficulty in applying one threshold of genome-wide SNP frequency to define species among broad taxonomic groups within Agaricomycetes. Indeed, almost any threshold value we apply will lead to changes in existing taxonomy. While setting such a threshold may be desirable in the long run, in the short term, one potential solution is to acknowledge the differences in intraspecies genome divergence among taxonomic groups and use the current intraspecific sequence divergences within individual genera as references to define new species within each corresponding genus.\n\nOn the other hand, the ratios of inter-strain mitochondrial genome SNP frequency vs nuclear genome SNP frequency showed a tight distribution, with overwhelming majority values being close to or smaller than the theoretic value of 0.25. We believe such ratios represent a promising indicator in species delineation in Agaricomycetes. In Agaricomycetes, most species are dikaryotic, their mushroom-forming ability represents their sexual cycle and mitochondrial inheritance is primarily uniparental.52 Together, these features predict that within an inter-breeding population in nature, the effective mitochondrial gene number is about one-fourth of that in the nuclear genome. And, assuming a similar base substitution rate between the mitochondrial and nuclear genomes, the observed SNP frequencies among strains within species should approach 0.25. In contrast, between reproductively isolated species and assuming a similar mutation rate, the smaller effective gene number within species means that between species, the mitochondrial genomes should diverge from each other faster than the nuclear genomes. The different patterns of mitochondrial and nuclear divergences within and between species could potentially result in a larger gap between species than within species, ideal for species delineation. In addition, using a ratio for species delineation has the advantage of being relatively independent of the mutation rate of individual species. Indeed, in S. commune, due to its high mutation rate, both the nuclear and mitochondrial genomes showed very high sequence divergence among strains.53 However, their mean ratio was 0.06 (± SD of 0.029; range 0.00–0.10; Underlying data: Supplementary Table 1, sheet 3),37 a much tighter distribution than the inter-strain SNP frequencies for both the nuclear and the mitochondrial genomes. Additional analyses of more taxa, including those of sister species and broad sampling within individual taxa, are needed in order to determine the usefulness of this measure in fungal taxonomy.\n\n\nConclusions\n\nThrough analyzing 398 nuclear and 106 mitochondrial genomes representing 112 species within 72 genera, we found broad inter-strain SNP frequencies among species in Agaricomycetes. Overall, we found a weak but statistically significant positive correlation between the paired nuclear and mitochondrial genome SNP frequencies. Different from those in animals, we observed an overall significantly higher SNP frequency in the nuclear genome than in the mitochondrial genomes between strains within most species. Interestingly, across the broad Basidiomycetes, the ratios of mitochondrial genome SNPs and nuclear genome SNPs between pairs of strains within each species were almost all lower than 1, with a mean of 0.24. Our analyses suggest that the ratio of mitochondrial genome SNP frequency to nuclear genome SNP frequency could potentially serve as an indicator for genome sequence-based species identification.",
"appendix": "Data availability\n\nDryad: Underlying data for’Genome-wide comparisons reveal broad variations in intraspecific SNP frequencies among species in Agaricomycetes, Basidiomycota’. Intraspecific genome SNP frequencies comparison. https://www.doi.org/10.5061/dryad.kh18932b1. 37\n\nThis project contains the following underlying data:\n\n• Supplementary Table 1, sheet 1: Information about all the genome data in our SNP analyses.\n\n• Supplementary Table 1, sheet 2: Information about the 147 paired nuclear genomes and mitochondrial genomes.\n\n• Supplementary Table 1, sheet 3: The original data including the intraspecific SNP frequencies from the 147 paired genomes and their ratios.\n\n• Supplementary Table 1, sheet 4: The original data of the geographical distances and SNP frequencies within six globally distributed species.\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 thank all individuals who have contributed to the assembled genome sequence data for Agaricomycetes.\n\n\nReferences\n\nHibbett DS, Binder M, Bischoff JF, et al.: A higher-level phylogenetic classification of the Fungi. 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Plant Prot. 2022; 49: 283–297.\n\nZhao K, Korfanty GA, Xu J, et al.: Genetic analyses of discrete geographic samples of a golden chanterelle in Canada reveal evidence for recent regional differentiation. Genes. 2022; 13: 1110. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXu J, Kerrigan RW, Callac P, et al.: Genetic structure of natural populations of Agaricus bisporus, the commercial button mushroom. J. Hered. 1997; 88: 482–488. Publisher Full Text\n\nZhong J, Xu J, Zhang P: Diversity, Dispersal and mode of reproduction of Amanita exitialis in southern China. Genes. 2021; 12: 1907. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMorin E, Kohler A, Baker AR, et al.: Genome sequence of the button mushroom Agaricus bisporus reveals mechanisms governing adaptation to a humic-rich ecological niche. Proc. Natl. Acad. Sci. 2012; 109: 17501–17506. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSonnenberg ASM, Gao W, Lavrijssen B, et al.: A detailed analysis of the recombination landscape of the button mushroom Agaricus bisporus var. bisporus. Fungal Genet. Biol. 2016; 93: 35–45. PubMed Abstract | Publisher Full Text\n\nO’Connor E, McGowan J, McCarthy CGP, et al.: Whole genome sequence of the commercially relevant mushroom strain Agaricus bisporus var. bisporus ARP23. G3: Genes Genomes Genet. 2019; 9: 3057–3066. Publisher Full Text\n\nSun L, Fu Y, Yang Y, et al.: Genomic analyses reveal evidence of independent evolution, demographic history, and extreme environment adaptation of Tibetan plateau Agaricus bisporus. Front. Microbiol. 2019; 10: 1786. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXu J, Kerrigan RW, Sonnenberg AS, et al.: Mitochondrial DNA variation in natural populations of the mushroom Agaricus bisporus. Mol. Ecol. 1998; 7: 19–33. Publisher Full Text\n\nZhang S, Bai X, Ren LY, et al.: Dynamic evolution of eukaryotic mitochondrial and nuclear genomes: a case study in the gourmet pine mushroom Tricholoma matsutake. Environ. Microbiol. 2021; 23: 7214–7230. PubMed Abstract | Publisher Full Text\n\nSandor S, Zhang Y, Xu J: Fungal mitochondrial genomes and genetic polymorphisms. Appl. Microbiol. Biotechnol. 2018; 102: 9433–9448. Publisher Full Text\n\nXia X: Rapid evolution of animal mitochondria. Evolution in the Fast Lane: Rapidly Evolving Genes and Genetic Systems. Singh RS, Xu J, Kulathinal RJ, editors. Oxford, UK: Oxford University Press; 2012; pp. 73–82.\n\nBirky-Jr CW, Maruyama T, Fuerst P: An approach to population and evolutionary genetic theory for genes in mitochondria and chloroplasts, and some results. Genetics. 1983; 103: 513–527. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXu J, Wang P: Mitochondrial inheritance in basidiomycete fungi. Fungal Biol. Rev. 2015; 29: 209–219. 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}
|
[
{
"id": "291977",
"date": "03 Sep 2024",
"name": "Alexandra Dallaire",
"expertise": [
"Reviewer Expertise Fungal genomics and epigenomics"
],
"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\nZhao & Xu investigate SNP frequencies in nuclear and mitochondrial genome of a large collection of strains from 112 species of Agaricomycetes, covering 72 genera. In the context of an ever-debated array of species concepts, this work explores how genetic variation, calculated using whole-genome sequences, could help develop taxonomy frameworks.\nThis is the first study with a taxonomic scope this large, and the authors draw comprehensive conclusions regarding correlations between nuclear SNP frequencies, mitochondrial SNP frequencies and geographical distance.\nThe authors propose that ratios of inter-strain nuclear/mitochondrial SNP frequencies could potentially be used as a scalable measure for species delimitation in Agaricomycetes. This idea is innovative and, I believe, promising.\nThe methods are simple, solid and well-described. The data used for the analyses and the raw results are provided in Supplementary Tables. The discussion is thorough and includes interesting comparisons between fungi and the animal kingdom. I don’t see any specific point that would help improve the manuscript.\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
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https://f1000research.com/articles/12-200
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https://f1000research.com/articles/12-197/v1
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20 Feb 23
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{
"type": "Research Article",
"title": "Development and implementation of self-supportive intervention on post-traumatic stress symptoms and quality of life among battered wives of Madhya Pradesh, India: A pilot study",
"authors": [
"Joji Joseph",
"Rodel P. Canlas",
"Rodel P. Canlas"
],
"abstract": "Background: In India, intimate partner violence against women is a major problem that leads to terrible physical, sexual, emotional, psychological and economic consequences. In 55-92% of women who have a history of being abused wives, high levels of symptoms of post-traumatic stress disorder have been discovered. Therefore, the quality of life is significantly low among them regardless of regions and countries. The purpose of the current study was to create and evaluate the effectiveness of a self-supportive intervention on the quality of life and post-traumatic stress symptoms among abused wives in Madhya Pradesh, India. Methods: The post-traumatic Symptoms Scale Interview version for DSM-5 (PSS-I-5) and WHO Quality of Life-BREF (WHOQOL) were used in this study as assessment tools. The Need assessment results showed that 51% of battered wives met the criteria of PTSD symptoms from moderate to severe and 83% experienced low quality of life. This study utilized a mixed research method and was executed in three phases, based on the main three elements of Conklin’s (1997) program development model, namely (1) planning; (2) design and implementation; and (3) evaluation of the newly created Self-Supportive Intervention program (SSI). The SSI program consisted of six modules, focused on addressing the issues that emerged through qualitative data and need assessments. Results: Excellent inter-rater reliability (.845) was found in the expert evaluation's findings, which supported the recommendation to use the SSI as it is with minor modification. The SSI was further pilot-tested for its feasibility with 10 battered wives and validated through the paired sample t-test, which showed a substantial decrease in post-traumatic stress symptoms and enhanced quality of life at 0.05 level of significance. Conclusion: This is an indication that the SSI program can be recommended as a psychological intervention in eliminating the PTSD symptoms and improving the quality of life.",
"keywords": [
"battered wives",
"post-traumatic stress symptoms",
"quality of life",
"self-supportive intervention"
],
"content": "Introduction\n\nThe state of women who are victims of intimate partner violence is denoted by the word ‘battering’. This kind of violence against women is considered a worldwide health issue (Habigzang et al., 2018). Intimate partner violence which affects millions of women throughout the world every year can take the form of physical, sexual, or psychological harm (Liu et al., 2020). Intimate partner violence (IPV) is a serious form of abuse that affects both urban and rural parts of India, with negative consequences for the woman’s mental and physical health and a lower quality of life (Achchappa et al., 2017). According to the World Health Organization, approximately one-quarter of women will be subjected to experience severe physical and psychological violence during their lifetime by an intimate partner, such as being slammed, hit, or beaten (Breiding et al., 2014). As the country with the second-largest population in the world, India records many intimate partner violence cases across the country (Shubina, 2015).\n\nWomen who have been experiencing battering have various mental health issues than non-victims, including post-traumatic stress disorder. Increased physical, psychological, and social morbidity have been related to intimate partner violence, causing battering to be the most significant cause of female injuries (Shubina, 2015). According to Tirone and his colleagues (2021), among battered women, post-traumatic stress disorder is one of the most frequently diagnosed mental health conditions. The reenactment of traumatic events through recollections and dreams is a common sign of PTSD. Flashbacks and nightmares typically leave victims overly stirred, easily startled, and quick to anger as a result of which they are continually re-traumatized (APA, 2013). Further, the previous study suggests that traumatic relationship experiences can impact an individual’s personality, coping mechanisms, strength, and empowerment (Jojo & Sathiyaseelan, 2019). Furthermore, women who have been abused have been found to have chronic post-traumatic stress disorder, with symptoms continuing even after the assault has stopped.\n\nIn the context of India, due to many reasons such as fear, shame, and lack of understanding, victims of battering may not report these abuses. Moreover, women are impaired by loneliness, cultural differences, and inadequate information of services available to protect the rights and safety of women (White & Satyen, 2015). Women’s sorrow is exacerbated by a strong patriarchal household structure in which they have little control, limited opportunities for education, and unemployment. Thus, being a ‘good wife’ and ‘good mother’ is crucial and deeply ingrained in the minds of Indian women, which might make these women more vulnerable to ongoing battering, and most women who experience battering do not seek help outside their families (Evans et al., 2020). The cross-sectional data from India show a strong association between battering and self-reported post-traumatic stress disorder among battered women. Furthermore, battering leads to suicide; therefore, the need for psychological interventions is recommended (Malhotra & Shah, 2015).\n\nBased on these findings, the current study developed a self-supportive intervention (SSI) program to lessen the symptoms of post-traumatic stress and to improve the quality of life among battered wives in India by combining mindfulness-based cognitive and emotional processing theories. Self-support is viewed as a tool that people can use to address their own challenges in daily life and advance their own growth (Das et al., 2020). A pilot study was conducted on the newly created SSI program to measure its viability and effectiveness.\n\n\nMethods\n\nA mixed method approach was adopted for the current study’s research, particularly a sequential exploratory design, to build the program, evaluate the feasibility of the study, and analyze the program’s impact on the target group. A qualitative information phase is introduced first in the sequential exploratory technique, and then quantitative information is presented (Creswell & Plano, 2011). Additionally, sequential design is ideal for finding out a new research problem where few studies have been conducted previously (Creswell & Plano, 2007).\n\nSince it is recommended that a pilot study has between 10 and 30 participants (Hill, 1998; Isaac & Michael, 1995), we chose 10 battered wives to take part in the current study. Ten battered wives who met the criteria of PSS-I-5 symptoms and poor Quality of Life were chosen at random for the pilot study according to the following standards: wives who lived with their husbands for more than one year and wives between the ages of 20 to 49.\n\nPersonal Data Sheet. The personal data sheet is a demographic questionnaire created by the researcher to ascertain the respondent’s social-demographic characteristics. We used it to assist in the inclusion and exclusion of participants. Name, age, length of the marriage, economic position, types of abuse suffered by the spouse (physical violence, emotional violence, sexual violence), number of children, and other pertinent information were included.\n\nPosttraumatic Symptom Scale Interview Version for DSM-5 (PSS-I-5). Post-traumatic stress disorder symptoms severity is measured by the 24-item PTSD symptom Scale-Interview for DSM – 5 (Foa & Capaldi, 2013). The most reliable and valid results of standard administration and scoring can be achieved with the help of PSS-I-5 (Foa & Capaldi, 2013). On a five-point scale, the severity of PTSD symptoms is scored as follows: 0=not at all; 1=once per week or less/ a little; 2=indication of three times per week/somewhat; 3=indication of four to five times per week/a lot; and 4=evidence of six times or more per week/severe. PTSD diagnosis depends upon the number of symptoms endorsed per symptoms cluster. The severity of PTSD symptoms is estimated using the first 20 questions of the PSS-I-5 scale, which has a score range of 0-80. The following clinical recommendations are made regarding PTSD symptoms intensity: no symptoms from 0 to 8, mild symptoms from 9 to 18, moderate symptoms from 19 to 30, severe symptoms from 31 to 45, and extremely severe symptoms from 46 to 80. The remaining four questions measure the duration and difficulties in everyday life. PSS-I-5 demonstrates good internal consistency of .89, test-retest reliability of .87, and strong inter-rater reliability for the diagnosis of PTSD (Foa et al., 2016). The current study obtained a Cronbach’s alpha coefficient of .93.\n\nWorld Health Organization Quality of Life (WHO-QOL)-BREF. It consists of 26 items for self-report that assesses the impact of sickness and impairment on everyday activities and behavior, as well as perceived health, disability, and functional capacity. It considers four domains: environment, social interactions, mental health, and physical health (Kumar et al., 2020). The internal consistency results for the questionnaire and the domains have a Cronbach’s alpha of .70. Higher numbers signify higher levels of quality of life on the scale, which spans from 26 to 156 overall. Examining the four domain scores yields a quality-of-life profile. The responses of the respondents are recorded using a Likert scale with a range of 1 to 5, and the scores of each domain vary from 4 to 20. This scale has been widely used by several researchers and clinicians (Kim et al., 2013). Quality of Life BREF scale’s each domain in the current study shows a high internal consistency with its Cronbach alpha value of .731 in physical, .798 in psychological, .696 in social, .778 in environmental, and .794 in the total score of quality of life.\n\nIn light of the research and after reviewing the relevant articles, the researcher created the interview methods. The pool of experts, which included a clinical psychologist, a psychiatrist, and two family counsellors validated the semi-structured interview protocol. According to the expert’s evaluation feedback, the interview questions were re-arranged. The interview group consisted of ten battered wives from the group study subjects that were eligible and met the study’s inclusion requirements. The interview/topic guide(s) can be found in the Extended data (Joseph, 2023).\n\nThe current study obtained ethical approval from the University of Santo Tomas (UST) Nursing School Ethics Review Committee with the protocol code USTCON ERC - 2022-OR31 on May 24, 2022. As part of the development of the Self-Supportive Intervention Program, we approached 300 battered women from the Social Work Center of the Diocese of Ujjain, Madhya Pradesh, India. These data were gathered between May and June of 2022. Among them, 23 were not interested in participating in the study due to fear, shame and personal issues. Participants were interviewed at various social work facilities to ensure data quality. Prior to data collection, all participants were told about the study’s goal and nature, and informed consent was obtained from them. A copy of the informed consent form was given to the participants, and upon getting a signed copy of the written consent form, it was returned. They were also told that their information would be kept confidential and that they could terminate their participation at any time. The PTSD Symptom Scale-Interview for DSM-5 (PSS-I-5) and World Health Organization Quality of Life (WHO-QOL)-BREF and demographic questions were given to those who indicated their willingness to participate. The final sample consisted of 277 participants in the study. Among them, 10 were chosen for interviews. The duration of each interview was between 40 and 50 minutes, and all of them were audio recorded so that they could be transcribed verbatim. The field notes were made during the interview. No repetition of the interview was done, and data saturation was discussed. Finally, the transcript was returned to the participants for correction. Participants’ feedback on findings was collected to improve the information and better decision.\n\nThis study organized two sets of Focus Group Discussion (FGD) participants: 1) FGD with battered wives; 2) FGD with experts. The members of the battered wives FGD comprised of eight battered wives from the research participant pool. The FGD Expert consisted of six members, including one family counselor, two psychologists, one psychiatrist, and two social work directors. The focus group schedule was designed to encourage an open and in-depth discussion of the subject. Necessary permission was requested, prior to the study, and a copy of the written informed consent form was distributed to the participants for their signature to get their willingness to participate in the study. The informed consent form stated that participants’ privacy would be guaranteed. The discussion in each focus group lasted for more than an hour (65 minutes), and they were documented and recorded. The collected data from interviews and focus group discussions with battered wives and experts underwent thematic analysis. Qualitative data were analyzed by three coders.\n\nFinally, 10 battered wives who met the inclusion and exclusion criteria were chosen randomly to participate in the current study and were further interviewed by a psychiatrist to confirm the symptoms according to the study’s protocol. Ten participants with moderate to severe post-traumatic stress symptoms and low Quality of Life received an 11-week Self-Supportive intervention (SSI) program, and the current pilot study was delivered face-to-face in the group. The intervention was done at one of the social work centers of the Ujjain diocese, Madhya Pradesh, India. The 11-week intervention program’s timetable for the 3-hour module is shown in Table 1. The current study used the paired sample t-test to analyze the data obtained through pre-test and post-test before and after the program’s implementation. In Table 2, the findings of the pilot study are presented in detail.\n\n\nResults\n\nThe goal of the current study was to target post-traumatic symptoms and quality of life among abused wives by developing a self-supportive intervention program that incorporated mindfulness-based theory and emotion processing theory. The newly designed self-supportive intervention program was assessed for its content and suitability in clinical practice by six specialists currently employed in mental health facilities and other associated medical and counseling sectors. The expert group consisted of one clinical psychologist, two family counselors, one psychiatrist, and two social work directors. The evaluators were given an adapted version of a standardized evaluation instrument created and used by the United States Agency for International Development (2006) to evaluate the content and validate its appropriateness in clinical practice. The evaluators were requested to validate the entire program and its suitability in clinical practice. One of the evaluators stated that the facilitator should be aware of the confidentiality of personal difficulties when administering it in group settings. If any of the participants inquire about counselling for personal clarification, that should be facilitated for them. The Self-Supportive Intervention (SSI) program received an overall grade of “A” from the experts, demonstrating its soundness, applicability, and viability. We carried out an inter-rater reliability test to ascertain the inter-rater dependability of the expert’s evaluation of the SSI program. The results indicated that the SSI program scored an inter-rater coefficient Alpha Value of .845 and an intra-class correlation coefficient value of .859. It shows that various factors of the SSI program were highly reliable and consistent. The six modules and their goals are listed in Table 1 for the Self-Supportive Intervention Program.\n\nTable 2 displays the pretest-posttest mean scores and standard deviation values of the participants of the pilot study in terms of post-traumatic stress symptoms measured by the post-traumatic symptoms scale interview version for DSM-5 (PSS-I-5) and Quality of Life measured by the World Health Organization Quality of Life (WHO-QOL-BREF). The results showed that after the intervention program, the participant’s level of post-traumatic stress symptoms reduced, and their Quality of Life increased.\n\nTable 2 also shows the paired sample t-test result of the variables. The pilot study demonstrated that after five weeks, a twice-weekly SSI intervention program resulted in a statistically significant decrease in the participants’ post-traumatic stress symptoms and increased Quality of Life. The total PSS-I-5 scores between the pre-test and post-test varied significantly (t=27.813; p=.001) and all the sub-variables of Quality of Life. The pretest and posttest scores in psychological (t=-31.231; p=.001), physical (t=-18.358; p=.001), social (t=-16.432; p=.001), environmental (t=-14.600; p=.001) and total scores of WHOQOL-BREF scale (t=-32.284; p=.001) also shown a substantial difference.\n\nTen battered wives who took part in the 11-week-long six-modular self-supportive program reported happiness and appreciation for participating in the pilot study. Furthermore, participants qualitatively reported improved mindful attention, improved quality of life and decreased symptoms of posttraumatic symptoms. One participant said that “The program significantly helped in my return to mental tranquility. I felt as though I were carrying a large stone in my chest. I was so sad, but now I’m joyful and free.” Another said; “It was really moving for me to realize the meaning and purpose of life. I’ll live and love my life.” All these results showed that the SSI program impacted participants’ lives and was an effective program to improve battered wives’ Quality of Life and reduce post-traumatic stress symptoms.\n\n\nDiscussion\n\nThe pilot study of the SSI program was a six-modular intervention program adopting mindfulness-based cognitive theory and emotion processing theory. This intervention program sought to evaluate its viability and determine its effects on the participants’ symptoms of posttraumatic stress and enhancing quality of life, as they performed all of the activities in each module. The current study’s results were supported by a previous study, stating traumatic relationship experiences might affect a person’s personality, coping skills, strength, and sense of empowerment (Jojo & Sathiyaseelan, 2019). In this perceptive, the newly developed self-supportive intervention results statistically supported and validated battered women’s quality of life and sense of empowerment by reducing the PTSD symptoms. An earlier study demonstrated that domestic violence is a serious public health issue that necessitates handling measures (Habigzang et al., 2018). Furthermore, intervention has severe influence on women’s ability to establish and maintain relationships, avoid social isolation, increase their self-acceptance and access social support (Jonker et al., 2019). According to American Psychological Association, due to flashbacks and nightmares, victims are regularly retraumatized, which causes them to be quickly startled, overly sensitive, and easily enraged (APA, 2013). The outcome of this intervention strongly suggests that the self-supportive intervention program is effective and has met the goals of the program. The findings of the pilot study support the assessments and evaluations made by the six mental health specialists, demonstrating the scientific validity of the self-supportive intervention program.\n\nTo ensure the homogeneity of the research circumstances, we thoroughly analyzed the demographic profile of the participants before the pilot-test. The results showed that the participants had frequently been battered and severely suffering from posttraumatic stress symptoms and had a need for supportive intervention as early as possible. Previous research supports that mindfulness-based cognitive techniques give relief from stress and foster a nonjudgmental awareness of one’s mental processes. By doing so, one can create a positive, healthy attitude toward the surroundings and develop the necessary coping mechanisms for dealing with difficult emotions (Tomfohr et al., 2016). The participants were able to admit that they lack the ability to significantly alter their environment, but they also learnt to be more accepting of their limitations and the realities of life after the program.\n\n\nConclusion\n\nThe Self-Supportive Intervention program had a significant positive effect on participants and it improved the quality of life among female victims of domestic violence by decreasing post-traumatic stress symptoms. Furthermore, the concepts and design of this program are reliable, feasible and effective for evaluating a larger population of female victims of domestic violence who have been suffering from posttraumatic stress symptoms. The findings of this research will be valuable for mental health professionals, particularly psychiatrists and clinical psychologists to recognize women’s post-traumatic stress symptoms in the early stage.\n\nThe study is limited to female victims of domestic violence between the ages of 20 to 49 who had symptoms of post-traumatic stress and low quality of life. The research is limited solely to the information collected through a self-reported survey and intervention that was held in 6 weeks, which was a relatively short-term period. The Self-Supportive Intervention may therefore be tested further on a broader population with extensive planning and across various cultures in order to optimize its effects.",
"appendix": "Data availability\n\nThe data underlying the findings of this study including a mixed research method cannot be made publicly available due to sensitive issues related to battering and ethical considerations regarding participants’ confidentiality. Data will be provided to the readers upon reasonable request to the corresponding author through +63 9954668826 or joji.joseph.gs@ust.edu.ph.\n\nFigshare: Focus Group discussion. https://doi.org/10.6084/m9.figshare.22012565.v1 (Joseph, 2023).\n\nThis project contains the following extended data:\n\n- Interview guide.docx.\n\n- PSSI-5.pdf (a copy of the Posttraumatic Symptom Scale Interview Version for DSM-5)\n\n- whoqol.pdf (a copy of the World Health Organization Quality of Life (WHO-QOL)-BREF)\n\n- Focus Group discussion.docx (interview and focus group discussion protocol guide conceptualization)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAchchappa B, Bhandary M, Unnikrishnan B, et al.: Intimate Partner Violence, Depression, and Quality of Life among Women Living with HIV/AIDS in a Coastal City of South India. J. Int. Assoc. Provid. AIDS Care. 2017; 16(5): 455–459. PubMed Abstract | Publisher Full Text\n\nAmerican Psychiatric Association: Diagnostic and statistical manual of mental disorders Fifth Edition (DSM-5). Washington, D.C.:American Psychiatric Association;2013.\n\nBreiding MJ, Smith SG, Basile KC, et al.: Prevalence and characteristics of sexual violence, stalking, and intimate partner violence victimization--national intimate partner and sexual violence survey, United States, 2011. MMWR Surveill. Summ. 2014; 63(8): 1–18. PubMed Abstract | Free Full Text\n\nCreswell J, Plano Clark V: Designing and Conducting Mixed Methods Research. Book Review: Thousand Oaks, CA: Sage. Organ. Res. Methods. 2007; 12(4): 801–804. Publisher Full Text\n\nCreswell JW, Plano Clark VL: Designing and conducting mixed methods research. 2nd ed.Los Angeles, CA:Sage;2011.\n\nDas M, Das A, Mandal A: Examining the impact of lockdown (due to COVID-19) on Domestic Violence (DV): Evidence from India. Asian J. Psychiatr. 2020; 54: 102335. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nKumar P, Sen RK, Aggarwal S, et al.: Assessment and reliability of the World Health Organisation quality of life (WHO QOL-BREF) questionnaire in total hip replacement patients. J. Clin. Orthop. Trauma. 2020; 11: S756–S759. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu LY, Bush WS, Koyutürk M, et al.: Interplay between traumatic brain injury and intimate partner violence: Data driven analysis utilizing electronic health records. BMC Womens Health. 2020; 20(1): 269. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMalhotra S, Shah R: Women and mental health in India: An overview. Indian J. Psychiatry. 2015; 57(6): 205–S211. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShubina I: Cognitive-behavioral Therapy of Patients with Ptsd: Literature Review. Procedia. Soc. Behav. Sci. 2015; 165: 208–216. Publisher Full Text\n\nTirone V, Orlowska D, Lofgreen AM, et al.: The association between social support and posttraumatic stress symptoms among survivors of betrayal trauma: a meta-analysis. Eur. J. Psychotraumatol. 2021; 12(1): 1883925. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTomfohr L, Campbell T, Giesbrecht G, et al.: Mindfulness-based cognitive therapy for psychological distress in pregnancy: Study protocol for a randomized controlled trial. Trials. 2016; 17. PubMed Abstract | Publisher Full Text | Free Full Text\n\nUnited States Agency for International Development: USAID evaluation policy. USAID’s Bureau for Policy, Planning, and Learning’s Office of Learning, Evaluation, and Research (PPL/LER). 2016.Reference Source\n\nWhite ME, Satyen L: Cross-cultural differences in intimate partner violence and depression: A systematic review. Aggress. Violent Behav. 2015; 24: 120–130. Publisher Full Text"
}
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[
{
"id": "207345",
"date": "29 Sep 2023",
"name": "Sudharani Banappagoudar",
"expertise": [
"Reviewer Expertise OBG",
"COMMUNITY health",
"Yoga"
],
"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\nWhy is the research conducted in MP only is not mentioned.\n\nPilot study is conducted among the study participants which is not recommended as biases would be there.\n\nNo clarification from the place of sample collection.\n\nWere the authors present during data collection is also not clear.(we approached, how, when and where)\n\nThey have returned the consent back to samples? why?\n\n55-92 % has been discovered? not clear\n\nThe study is sensitive as its basically on abused or battered women and the data may become contradictory to the state\n\nWe approached (How) 300 battered women from the Social Work Center of the Diocese of Ujjain, Madhya Pradesh, India. 300 samples were considered are all suffered violence?\n\nWas the reason behind violence identified only with the women or any other family member was also enquired.\n\nHave these women approached the center\n\nWives who lived with their husbands for more than one year and wives between the ages of 20 to 49. Not clear\n\nData underlying the findings of this study including a mixed research method cannot be made publicly available due to sensitive issues related to battering and ethical considerations regarding participants’ confidentiality.(A copy of the informed consent form was given to the participants, and upon getting a signed copy of the written consent form, it was returned)\n\nTen battered wives who took part in the 11-week-long six-modular self-supportive program reported happiness and appreciation for participating in the pilot study. Furthermore, participants qualitatively reported improved mindful attention, improved quality of life and decreased symptoms of posttraumatic symptoms.(Had the women had thought of going back to the family)\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?\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": "207256",
"date": "02 Oct 2023",
"name": "Kathryn Anne Nel",
"expertise": [
"Reviewer Expertise Neuropsychology",
"GBV",
"Sport Psychology and social psychology"
],
"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 work needs editing - for instance, for the use of 'journalistic' English (see for instance, 'terrible' in the abstract). Throughout the grammar is poor (too many instances to note) so a language editor should be used to correct this. As it is mixed methods it is more usual to write the researchers not 'we.'\n\nthink the discussion needs to tie in better with the actual results - please integrate properly. \"10 battered wives were chosen randomly\" How? What was the process and why would you need random selection for an FGD? Needs clarification and explanation. Overall 277 women but if this was a purposive sample then you cannot run inferential stats (t-test etc). You need to sort this out and if not a random sample run appropriate stats. Also what steps were followed in the TA and according to who (Braun & Clarke, for instance). What themes and sub-themes if any emerged? Where is your quality criteria for this section and the quantitative area where is the reliability and validity.\nThis is important work but the article needs a lot of work before indexing. It is not a limitation that female victims were used as that is what you were studying.\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? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-197
|
https://f1000research.com/articles/11-1417/v1
|
02 Dec 22
|
{
"type": "Research Article",
"title": "Entry of the antipsychotic drug, olanzapine, into the developing rat brain in mono- and combination therapies",
"authors": [
"Yifan Huang",
"Fiona Qiu",
"Mark Habgood",
"Shuai Nie",
"Katarzyna Dziegielewska",
"Norman Saunders",
"Yifan Huang",
"Fiona Qiu",
"Mark Habgood",
"Shuai Nie",
"Katarzyna Dziegielewska"
],
"abstract": "Background: Olanzapine is used to treat schizophrenia and bipolar disorder in women of childbearing age. Continuation of psychotropic medications throughout pregnancy and lactation is often required as cessation could be dangerous for both mother and child. However, there is a lack of information on the transfer of these drugs into the developing brain. Methods: Sprague Dawley rats at three developmental ages: embryonic day E19, postnatal day P4 and non-pregnant adult females were administered unlabelled or radiolabelled (3H) olanzapine (0.15 mg/kg) either as monotherapy or in combination with each of seven other common medications. Similar injections were administered to pregnant E19 females to investigate placental transfer. Olanzapine in plasma, cerebrospinal fluid (CSF) and brain was measured by liquid scintillation counting after a single dose (acute) or following 5 days of treatment (prolonged). Results: Olanzapine entry into brain and CSF was not age-dependent. Prolonged olanzapine treatment reduced placental transfer from 53% to 46% (p<0.05). Co-administration of digoxin or lamotrigine with olanzapine increased its entry into the fetal brain, whereas paracetamol decreased its entry into the CSF. Placental transfer of olanzapine was increased by co-treatment with cimetidine and digoxin, whereas co-treatment with lamotrigine, paracetamol or valproate led to a substantial decrease. Repeated co-treatment of digoxin and olanzapine increased olanzapine transfer into the brain and CSF, but not across the placenta. Overall entry of olanzapine from maternally administered drugs into the fetal brain was higher after combination therapy with cimetidine and digoxin. Conclusions: Co-administration of olanzapine with some commonly used drugs affected its entry into the fetus and its developing brain to a greater extent than in adults. It appears that protection of the fetal brain for these drugs primarily comes from the placenta rather than from the fetal brain barriers. Results suggest that drug combinations should be used with caution particularly during pregnancy.",
"keywords": [
"blood brain barrier",
"placental barrier",
"P-glycoprotein",
"cerebrospinal fluid",
"choroid plexus",
"drug transfer",
"olanzapine",
"drug interaction"
],
"content": "Abbreviations\n\nABC: ATP-binding cassette\n\nBCRP: breast cancer resistance protein\n\nCSF: cerebrospinal fluid\n\nMRP: multidrug resistance protein\n\nPgp: P-glycoprotein\n\nSLC: solute carrier\n\n\nIntroduction\n\nPsychological and neurological problems are becoming more prevalent and require a concerted approach to develop more effective and safe treatment regimes. During pregnancy, women are hesitant to take medications for fear of harming their unborn child. Clinicians have the difficult task of weighing up maternal benefit provided by the treatment versus potential risks to the developing baby. This is complicated by limited knowledge of drug safety due to lack of clinical trials conducted in pregnant women for obvious ethical reasons. The evidence base available to clinicians and their patients is limited to clinical experience, expert opinion, data bases (e.g. The Royal Women’s Hospital, Melbourne) and guidance from up-to date reports on child and maternal outcomes of women prescribed drugs during pregnancy (Briggs et al., 2021). Recently the inclusion of pregnant women in clinical trials has been advocated for newly developed medications (van der Graaf et al., 2018; Stock and Norman, 2019) but is unlikely to occur for established treatments because of the cost involved. For current therapies the risk remains as cessation of treatment during pregnancy could be harmful for both mother and child.\n\nFor anti-psychotic drugs such as olanzapine, many women are recommended to continue taking their medication during pregnancy as maternal benefits are deemed to outweigh any potential fetal risks. A review of olanzapine exposure during the first trimester of pregnancy revealed a congenital malformation rate of 3.5%, which is the same as the background malformation rate in the general population (Ennis and Damkier, 2015); this indicates that olanzapine does not appear to increase the risk of congenital malformations. However, there are potential neurological problems that need to be considered. It is not known to what degree olanzapine is able to cross the placenta and enter the fetal brain although a few studies have investigated placental transfer in ex vivo (Schenker et al., 1999) and in vivo (Newport et al., 2007) in human material.\n\nIn the present study we investigated the entry of olanzapine from the mother’s blood across the placenta and into the late gestation fetal brain and into the brain of postnatal rats exposed to the drug acutely and over several days. Effects of co-administration of several commonly used therapeutics (digoxin, cimetidine, lamotrigine, fluvoxamine, lithium, paracetamol, valproate) on olanzapine transfer were also investigated. Results showed that prolonged exposure to olanzapine affected its brain entry in postnatal but not fetal animals and co-administration of several of the drugs tested significantly affected the placental transfer and fetal brain entry. These results are discussed in the context of potential application to clinical care.\n\n\nMethods\n\nAll animal experimentation was approved by the University of Melbourne Animal Ethics Committee (Ethics Approval AEC: 10270 approved 30.12.2019) and conducted in compliance with Australian National Health and Medical Research Guidelines. All animals were assessed as healthy prior to commencement of experiments. All surgeries were short term and conducted under terminal anaesthesia. Animals were handled only by experienced researchers in such a way as to minimise their stress and every effort was made to ameliorate any suffering. For animals treated over several days they were monitored before and after every treatment ensuring that there were no abnormalities in weight (>15%), appearance (fur, wounds) or behaviour (vocalisation, respiration, movements). All aspects of the study conformed to the ARRIVE guidelines (Huang et al., 2022)\n\nThe Sprague–Dawley (RRID: RGD_728193) strain of Rattus norvegicus was used in this study supplied by the University of Melbourne Biological Research Facility. Animals were housed in groups of 2–4 (adults) or full litters per cage (25cm x 35cm x 25cm on Breeders Choice paper bedding, made from 99% recycled paper and biodegradable with no added chemicals), on a 12h light/dark cycle with ad libitum access to food (dry pellets of a fixed formulation for rats (Speciality Feeds, Western Australia) and water.\n\nThe ages studied were: fetuses from time-mated females (all primigravida) at embryonic day (E)19, pups at postnatal day (P)4 and non-pregnant adults. Dating of animals was based on taking E0 as the day a vaginal plug was identified and P0 as the day of birth. E19 was chosen as it is a fetal stage of development where adequate volumes of blood and cerebrospinal fluid (CSF) can be obtained for analysis without pooling (Dziegielewska et al., 1981), and individual pups can be injected intraperitoneally (i.p.) while still inside the uterine horn and kept viable for periods of time (Koehn et al., 2019; Koehn et al., 2020). P4 was chosen because its stage of brain development is similar to that of very premature but viable human infants of 22–24 weeks gestation (Clancy et al., 2001; Workman et al., 2013). Additionally, the results in this paper can be compared with data from previous studies using other drugs at these ages (Koehn et al., 2019; Koehn et al., 2020; Toll et al., 2021). Animal numbers (Table 1) were based on previous experience of such experiments and were the minimum number required to detect a significant difference between groups at p<0.05. Animals were selected for treatment groups to ensure weights were statistically similar between groups that were being compared. Animals were allocated to experiments by the Animal House staff, who had no knowledge of the particular experiments to be performed; experimenters were blind to this allocation.\n\nNumber of animals and route of administration used at each age for (A) olanzapine monotherapy and modulation studies for both liquid scintillation counting and LC-MS (liquid chromatography coupled with mass spectrometry) or (B) [3H] olanzapine drug competition for liquid scintillation counting. Drugs used in drug competition experiments include: cimetidine (CIM), digoxin (DIG), fluvoxamine (FLX), lamotrigine (LTG), lithium (Li), paracetamol (PARA) and valproate (VPA). Note in pregnant experiments route of drug administration was either i.p. (intraperitoneal) or i.v. (intravenous). Value in brackets indicates number of litters used in E19 and P4 animals. Note the number of cerebrospinal fluid (CSF) samples (20) differs from brain samples (21) in A E19 acute i.v. to dam [3H] olanzapine group.\n\nDrug doses were selected based on levels used in clinical practice (Australian Medicines Handbook, 2021) and adjusted for body weight of the animal, summarised in Table 2. Cimetidine, fluvoxamine, lithium, paracetamol and valproate were dissolved in sterile 0.9% sodium chloride solution (B. Braun, Catalogue number: 352 1370). Olanzapine was dissolved in ethanol. Digoxin and lamotrigine were dissolved in ethanol before dilution in sterile 0.9% sodium chloride solution.\n\nIn the acute treatment group, a single dose of 0.15 mg/kg olanzapine containing traces of [3H]-labelled olanzapine (10–20 μCi E19 dams, 1 μCi P4s, 2 μCi adults) was administered to rats by injection at E19, P4 or adult and blood, CSF and brain cortex samples were taken 30 min later. Postnatal and non-pregnant adult animals were administered olanzapine via i.p. injection. Pregnant animals were administered a final intravenous (i.v.) dose as drug transfer from an i.p. injection to the fetus stops as soon as the peritoneal cavity is exposed (Koehn et al., 2019; Koehn et al., 2020).\n\nIn prolonged experiments, doses of unlabelled drug were administered once (olanzapine) or twice (digoxin, i.p. injections, Kohen et al. 2019) daily for 4 days, with a final dose on the 5th day containing [3H]olanzapine. Samples were collected 30 min post i.p. injection as described for the acute treatment group.\n\nFor drug competition experiments, a single injectate contained both olanzapine and one another commonly used medication: cimetidine, digoxin, fluvoxamine, lamotrigine, lithium, paracetamol or valproate together with the radiolabelled tracer [3H] olanzapine was administered and samples were collected 30 min post i.p. injection as described for the acute treatment group.\n\nNo animals died before completion of experiments and no results were discarded.\n\nPostnatal and non-pregnant adult animals were terminally anaesthetised 30 min after final drug injection using inhaled isoflurane (IsoFlo 100% w/w, Abbott Laboratories). Blood, brain and CSF samples were collected. Blood was collected directly from the right ventricle of the heart and CSF from the cisterna magna. Two brain samples were dissected out: cortical samples were obtained from the frontal/parietal lobes dorsal to the lateral ventricles as described previously (Koehn et al., 2019) and the brainstem.\n\nAs previously described (Koehn et al., 2019, 2020), pregnant animals were anaesthetised with i.p. urethane injection (25% w/v urethane, Sigma, 1 ml/100g body weight). Animals were then placed on a temperature-controlled heating pad in a supine position and an endotracheal catheter inserted to maintain a clear airway. A catheter was also inserted into the femoral artery for maternal arterial blood sampling time-matched to individual fetal collections. The cannula was flushed with 0.5 ml of heparinised saline (Hospira Inc, 5 units/ml) following each arterial blood sample. Fetal animals were exteriorised and samples serially collected starting 30 min post maternal injection. Viability of each fetus was assessed at the time of collection by observing the colour of the umbilical vessels. A final maternal blood sample was taken directly from the left cardiac ventricle and brain and CSF samples were taken following terminal exsanguination, as described above.\n\nSamples were processed immediately after collection as previously described (Toll et al., 2021). Plasma was separated from whole blood by centrifugation (2,000xg, 5 min; Eppendorf 5453 Mini-Spin Plus centrifuge). CSF samples were also centrifuged (2,000xg, 5 min), then microscopically examined for traces of red blood cell contamination (Habgood et al., 1992). For every experiment, a sample of injectate was also measured to confirm uniformity of injected material and indicate the effectiveness of injections. Samples were weighed and transferred to scintillation vials. To solubilize brain samples, 0.5 ml Soluene350 (PerkinElmer) was added and incubated overnight at 36°C. Glacial acetic acid (2 drops, Sigma) was added to neutralize the alkaline Soluene350. All samples were mixed with 5 ml scintillant (Emulsifier-safe, PerkinElmer) and counted for 5 minutes each on a liquid scintillation counter (Tri-Carb 4910 TR, PerkinElmer) with luminescence correction on. Counts were expressed as radioactivity disintegrations per minute (DPM), blank samples containing the same tissues with no radioactivity were run alongside the samples to establish the background counts. The corresponding background counts were always subtracted from sample counts.\n\nSample activities were expressed as DPM/μl or mg of plasma, CSF and brain cortex tissue to normalise the values. The following equations were used to indicate the brain cortex, brainstem, CSF transfer (Equation 1) or placental transfer (Equation 2).\n\nEquation 1:\n\nEquation 2:\n\nThe method was similar to that which has been described previously for valproate (Toll et al., 2021). Its application for measuring olanzapine is detailed here. Olanzapine-d8 (Cambridge Isotope Laboratories) and N-demethyl olanzapine-d8 (Toronto Research Chemicals) were dissolved in methanol at 100 μg/ml and 1 mg/ml as stock respectively. All stock solutions were stored at -20 °C. The internal standard mixture containing 100 pg/μl of each standard in methanol was prepared from diluting stock solutions using methanol immediately before use. To each 10 μl plasma sample, 10 μl of internal standard mixture and 80 μl of methanol were added. After mixing for 30 seconds, the sample was centrifuged at 14,000×g for 10 min and the top 50 μl of supernatant was transferred to a glass vial for liquid chromatography coupled with mass spectrometry (LC–MS) analysis using a Vanquish ultrahigh performance liquid chromatography (UHPLC) coupled with an Orbitrap Fusion Lumos mass spectrometer (Thermo Fisher Scientific, San Jose, CA, USA) operated at positive ion mode. Solvent A was 10 mM ammonium formate with 0.1% formic acid in water and solvent B was acetonitrile. Then, 5 μl of each sample was injected into an RRHD Eclipse Plus C18 column (2.1×1000 mm, 1.8 μm, Agilent Technology, Santa Clara, CA, USA) at 50°C at a flow rate of 350 μl/min for 1 min using 1% solvent B. During separation, the percentage of solvent B was increased from 1% to 40% in 4 min, 40% to 80% in 0.5 min, maintained at 80% for 2 min before dropping back to 1% in 0.1 min and staying at 1% for 2.4 min.\n\nAll MS experiments were performed using a heated electrospray ionization (HESI) source. The spray voltage was 3.5 kV in positive ionisation mode. The flow rates of sheath, auxiliary and sweep gases were 20 and 6 and 1 arbitrary unit(s), respectively. The ion transfer tube and vaporizer temperatures were maintained at 350°C and 400°C, respectively, and the S-Lens RF level was set at 50%. Targeted higher-energy collisional dissociation (HCD)-tandem mass spectrometry (MS/MS) scans of unlabelled and labelled olanzapine at normalized collision energy (NCE) of 35% as well as unlabelled and labelled N-demethyl olanzapine at NCE of 42% were acquired with isolation width of 4 Da, Orbitrap resolution at 15,000 (at m/z 200), maximum injection time of 22 milliseconds and automatic gain control (AGC) target of 2.5E5.\n\nPeak areas in extracted ion chromatogram of monitored product ions from olanzapine (m/z 313.1487 to 256.0904) at 3.8 min, olanzapine-d8 (m/z 321.1989 to 260.1156) at 3.8 min, N-demethyl olanzapine (m/z 299.1330 to 198.0245) at 4.2 min and N-demethyl olanzapine-d8 (m/z 307.1833 to 198.0245) at 4.1 min were extracted using Skyline 21.2 (RRID:SCR_014080) for quantitative analysis of drugs in each sample. Linear response range in untreated control rat plasma was tested for both unlabelled and d8-labelled olanzapine at 0.1, 1, 10, 50, 100, 200, 400 and 800 ng/ml. The ranges of linear responses were 1–800ng/ml for olanzapine and 50–800ng/ml for olanzapine-d8. (Extended data Figure 1). The main olanzapine metabolite, N-demethyl olanzapine, was not detected in any of the samples tested.\n\nData from all experiments are expressed as mean±standard deviation (SD). Statistical differences between cortex/plasma, CSF/plasma and fetal/average maternal plasma ratios and olanzapine measurements in plasma, CSF and brain cortex were determined using one-way ANOVA with Tukey’s posthoc test for multiple comparisons (GraphPad Prism 9) (an open-access alternative that can perform an equivalent function is R). P≤0.05 was considered statistically significant.\n\n\nResults\n\nLC-MS was used to confirm that the injection protocol was achieving expected clinical concentrations of olanzapine in the rats’ circulating blood (Huang et al., 2022). Results are shown in Figure 1. Concentrations of olanzapine in the plasma ranged between 10 ng/ml to over 100 ng/ml with the majority of samples falling between 20–40 ng/ml. These values are within clinically accepted limits (shaded area), which in humans are 20–80 ng/ml (Hiemke et al., 2011).\n\nAt E19, P4 and adult 30 min after a single intraperitoneal injection of 0.15 mg/kg olanzapine its concentration was measured using liquid chromatography coupled with mass spectrometry (LC-MS). Shaded area indicates clinical therapeutic range of olanzapine (20–80ng/ml; Hiemke et al. 2011). Bars are means±SD. Note each point is an individual animal (n=4–10).\n\nTo determine the time course of olanzapine entry into the brain and CSF, P4 pups from a single litter of 13 animals were injected individually i.p. with a single dose of olanzapine (0.15 mg/kg) and brain, CSF and blood samples were collected at 30 min, 60 min, 90 min and 120 min. The concentration of the drug was measured by LC-MS as described in the Methods. Results are illustrated in Figure 2 and detailed in Extended data Table 2. Olanzapine concentrations in plasma and CSF decreased over time (Figure 2A). In plasma, concentrations fell significantly from 34±4 ng/ml at 30 min to 11±5 ng/ml at 120 min post injection (p<0.01). CSF concentrations did not change significantly with increased exposure, remaining stable at around 9 ng/ml. CSF/plasma ratios (Figure 2B) increased initially from around 35% to 50% then remained relatively stable between 60 and 120 min. The highest olanzapine concentration in plasma was detected at 30 min, therefore all subsequent acute experiments were performed 30 min following drug injection as in previous similar experiments (Koehn et al., 2019; Toll et al., 2021).\n\n(A) Olanzapine concentration (ng/ml) in CSF and plasma 30 –120 min after a single intraperitoneal (i.p.) injection of olanzapine (0.15 mg/kg) measured using LC-MS (liquid chromatography coupled with mass spectrometry). (B) CSF/plasma olanzapine concentration ratios (%). Note each point represents results from an individual animal (n=3–4 at each time point).\n\nTo establish if the entry of olanzapine into the brain and CSF changed depending on its dose, dose-response experiments were conducted in P4 animals. The entry of [14C]-olanzapine (Table 2) was tested at 5 doses: 0.015 mg/kg, 0.03 mg/kg, 0.075 mg/kg, 0.15 mg/kg and 0.375 mg/kg 30 min after a single i.p. injection (Extended data Figure 2). There were no significant differences in brain and CSF entry between the doses investigated; 0.15 mg/kg was chosen for subsequent experiments as this was shown to achieve clinically relevant plasma concentrations (Figure 1).\n\nEntry of olanzapine into the CSF and brain was estimated at three ages: E19, P4 and adult using liquid scintillation counting and two injection protocols: a single dose (acute group) and multiple doses over 5 days (prolonged group) as described in the Methods. Concentration ratios (%) between the brain (cortex and brainstem) and plasma, and CSF and plasma (expressed as DPM/μl or DPM/mg of sample) were used as an index of drug’s entry (Davson & Segal, 1996).\n\nResults of experiments measuring the entry of [3H]-olanzapine into the brain and CSF in acute experiments are illustrated in Figure 3 and numerical values are shown in Extended data Table 2. Brain entry of the drug into both the cortex and brainstem was highly variable, especially in fetal brains, and therefore no significant difference between the ages was detected. The values ranged from under 10% to over 100% at E19 and around 50% in postnatal animals (Figure 3). In contrast, values obtained for the CSF’s entry were more stable at around 25% and were similar at all three ages.\n\n(A) Brain cortex (B) brainstem and (C) cerebrospinal fluid (CSF) at three ages: E19, P4 and adult, 30 min after a single intraperitoneal (i.p.) injection of 0.15 mg/kg olanzapine containing a radioactive tracer ([3H]olanzapine). Bars are means±SD. Note each point represents results from an individual animal (n=3–14).\n\nEntry of olanzapine was also investigated in animals that received doses of the drug over several days. Olanzapine (0.15 mg/kg) was given once daily i.p. for 5 days and on the final day trace amounts of [3H]-olanzapine) were added to the dose (see Methods). For the fetal animals, dams were given the olanzapine treatments i.p. starting at E15, then on the final day at E19, the last dose was given i.v.. Results are displayed in Figure 4 and numerical values shown in Extended data Table 3. In postnatal animals, prolonged treatment resulted in some significant changes in olanzapine entry into both the brain and CSF. At P4 olanzapine entry into the cortex increased from 56±19% in the acute group to 99±7% in the prolonged group (p<0.01), while transfer into the adult CSF increased from 28±15% in the acute group to 45±6% in the prolonged group (p<0.0.5). There were no significant changes in the E19 pups following prolonged olanzapine exposure (p>0.05).\n\n(A) Brain cortex/plasma, (B) brainstem/plasma and (C) cerebrospinal fluid (CSF)/plasma olanzapine concentration ratios (%) in the rat at three ages: E19, P4 and adult. Final injection included a radioactive tracer ([3H]olanzapine). Final intravenous (i.v.) dose was given maternally for E19 animals. Bars are means±SD. Note each point is an individual animal (n=3–10). *p<0.05, **p<0.01.\n\nPlacental transfer of olanzapine between the dam and the fetus at E19 was estimated by comparing levels of the drug in fetal and maternal plasma (Equation 2) in both the acute and prolonged (Extended data Table 3) experiments. Results are displayed in Figure 5.\n\n(A) A single intravenous (i.v.) injection of 0.15 mg/kg olanzapine with a radioactive tracer ([3H]olanzapine) to each dam and (B) counts (DPM/μl) in plasma after 4 daily intraperitoneal (i.p.) injections of 0.15mg/kg olanzapine followed by olanzapine with a radioactive tracer ([3H]olanzapine) i.v. on the 5th day. (C) Placental transfer as calculated by fetal/average maternal plasma ratio (%) using results from A and B. Bars are means±SD. Note dam values are serial plasma samples taken between 30–160 min post maternal injection from one or two individual dams, fetal values and ratios are from individual animals (n=10–25). *p<0.05.\n\nIn acute experiments the transfer of olanzapine across the placenta from maternal into the fetal circulation was 53±10% (n=25).\n\nPlacental transfer of olanzapine following prolonged treatment was 49±4% (n=10). Thus, prolonged olanzapine treatment significantly decreased placental drug transfer compared to the acute treatment group (p<0.05) but only to a small extent. Results are presented in Figure 5 and Extended data Table 3.\n\nTwo approaches were used to investigate if transfer of olanzapine across brain and placental barriers can be influenced by (i) modulating the function of an ABC transporter, P-glycoprotein (Pgp) that has been suggested to be involved in olanzapine transfer (Boulton et al., 2002; Wang et al., 2004) or (ii) by co-treatment with other drugs that could compete with olanzapine for the same transporter, including digoxin, a substrate for Pgp (Mayer et al., 1997) and cimetidine, a substrate for breast cancer resistant protein (BCRP, Pavek et al., 2005; Staud et al., 2006).\n\nTransfer of olanzapine across the placenta at E19 and its entry into the brain and CSF was investigated following either single (acute, data from Figure 4) or repeated (prolonged) administration including co-administration with digoxin, a known ABC transporter modulator. It was shown previously that this treatment regime in rats was able to upregulate pgp expression and reduce digoxin entry into the brain (Koehn et al., 2019). In the fetal animals, prolonged digoxin treatment significantly increased olanzapine transfer into the brain (152±27%, n=10) compared to prolonged olanzapine alone (128±18%, n=10, p<0.05). At P4, compared to acute treatment, prolonged administration of either olanzapine or digoxin increased olanzapine transfer into the brain (from 56±19% to ~95%, p<0.01 and p<0.05 respectively) whereas only repeated digoxin treatment increased transfer in the CSF (from 24±3% to 39±7%, p<0.05). In the adult, prolonged treatment with either olanzapine (61±11%) or digoxin (66±15%) increased olanzapine transfer into the CSF compared to acute treatment alone (35±10%, p<0.05 and p<0.01 respectively). Results are illustrated in Figure 6 and listed in Extended data Table 4.\n\n(A) Brain cortex/plasma, (B) brainstem/plasma and (C) cerebrospinal fluid (CSF)/plasma at E19, P4 and adult after a single intravenous (i.v.) injection of 0.15 mg/kg olanzapine (acute, white bar), with five day daily intraperitoneal (i.p.) 0.15 mg/kg olanzapine treatment (prolonged, grey bars) or 0.03 mg/kg digoxin i.p. twice daily for 5 days (digoxin, yellow bars). In all experiments samples were collected 30–185min after the final maternal i.v. injection containing olanzapine with a radioactive tracer ([3H]olanzapine). Bars are means±SD. Note each point is an individual animal (n=3–10). *p<0.05, **p<0.01\n\nTransfer of olanzapine across the placenta from dam to fetus was unchanged in the prolonged digoxin treated animals with placental transfer remaining at around 50%. Results are presented in Figure 7 and Extended data Table 4. Entry of olanzapine following either prolonged olanzapine or digoxin treatment appeared to follow a similar pattern, potentially suggesting a shared mechanism of entry.\n\n(A) Plasma counts (DPM/μl) after twice daily intraperitoneal (i.p.) injections of 0.03mg/kg digoxin for 4 days and olanzapine with a radioactive tracer ([3H]olanzapine) intravenous (i.v.) on the 5th day. (B) Placental transfer displayed as fetal/average maternal plasma ratio in the E19 rat after i.v. injection of 0.15 mg/kg olanzapine (acute, white bar; data from Figure 6), four day daily i.p. 0.15 mg/kg olanzapine treatment (prolonged, grey bars; data from Figure 7) or 0.03 mg/kg digoxin i.p. twice-daily for 4 days (digoxin, yellow bars). Samples collected 30–185 min after the final maternal i.v. injection containing olanzapine with a radioactive tracer ([3H]olanzapine) for all groups. Bars are means±SD. Note each point is an individual animal (n=10).\n\nTo investigate the effects of co-administration of several common medications on olanzapine transfer, seven drugs (cimetidine, digoxin, fluvoxamine, lamotrigine, lithium, paracetamol and valproate, Table 2) were given acutely each in combination with olanzapine. Transfer of olanzapine into the rat brain, CSF and across the placenta was measured at E19, P4 and adult. All drug competition results are shown in Figures 8–10 and in Extended data Table 5.\n\nSingle intraperitoneal (i.p.) injection either as monotherapy or in combination with: cimetidine (CIM, 11 mg/kg), digoxin (DIG, 0.03 mg/kg), lamotrigine (LTG, 6 mg/kg), paracetamol (PARA, 15 mg/kg) or valproate (VPA, 30 mg/kg). Bars are means±SD. Note each point is an individual animal (n=3–4).\n\nIn postnatal animals, there was no significant difference in olanzapine transfer after combination therapy with any of the drugs investigated. In the non-pregnant adults, olanzapine transfer remained at around 30–50% in both brain and CSF (Figure 8). At P4 there was also no significant difference in olanzapine transfer after combination therapy and its entry into the brain and CSF remained stable at around 30–40% and 10–20% respectively (Figure 8).\n\nHowever, in fetal animals at E19 co-treatment with either digoxin (192±31%, n=8) or lamotrigine (209±49%, n=10) increased olanzapine transfer into the fetal brain cortex compared to olanzapine alone (128±26%, n=21, both p<0.0001). This trend was also seen in the brainstem, where digoxin and lamotrigine combination therapy also increased olanzapine permeability compared to olanzapine monotherapy (from 129±25%, n=21, to 187±27%, n=8, or 232±49%, n=10 respectively, both p<0.0001). In the CSF, combination therapy with paracetamol decreased olanzapine transfer from 81±9% (n=20) in olanzapine monotherapy to 53±5% (n=4) in combination therapy, p<0.05 (Figure 9). The other drugs co-administered with olanzapine did not appear to affect its entry at this age.\n\n(A) Brain cortex, (B) brainstem and (C) cerebrospinal fluid (CSF) after a single intravenous (i.v.) injection either as monotherapy or in combination with: cimetidine (11 mg/kg), digoxin (DIG, 0.03 mg/kg), lamotrigine (LTG, 6 mg/kg), lithium (Li, 3.2 mg/kg), paracetamol (PARA, 15 mg/kg) or valproate (VPA, 30 mg/kg). Bars are means±SD. Note each point is an individual animal (n=4–21). *p<0.05, ****p<0.0001.\n\nTransfer of olanzapine across the placenta from maternal to fetal circulation changed significantly following co-administration with all of the drugs investigated (Figure 10). Cimetidine and digoxin co-treatment increased olanzapine transfer across the placenta from 53±10% to around 70% (both n=8, p<0.0001 and p<0.001 respectively) whereas lamotrigine, paracetamol or valproate all decreased olanzapine placental transfer to 24±5%, 20±2% and 33±4% respectively (n=4-12, all p<0.0001; Figure 10). Thus, it appears that both influx and efflux transporters are involved in olanzapine transfer across the placental barrier and these can be influenced by different therapeutics (see Discussion).\n\nCalculated by fetal/average maternal plasma ratio (%) after a single intravenous (i.v.) injection either as monotherapy or in combination with: cimetidine (CIM, 11 mg/kg), digoxin (DIG, 0.03 mg/kg), lamotrigine (LTG, 6 mg/kg), paracetamol (PARA, 15 mg/kg) or valproate (VPA, 30 mg/kg). Bars are means±SD. Note each point is an individual animal (n=4–26). ***p<0.001, ****p<0.0001.\n\n\nDiscussion\n\nIn this study, we aimed to determine the extent of olanzapine transfer across the placenta during late pregnancy and its entry into the brain at different stages of development in monotherapy as well as in combination with several medications that are often prescribed with olanzapine. Olanzapine transfer was determined by measuring radiolabelled tracers in plasma, CSF, brain cortex and brainstem in the rat at three developmental ages: late-gestation fetus (E19), early postnatal pup (P4) and adult following either single or repeated doses of the drug. Levels of the drug in blood plasma were confirmed by LC-MS.\n\nDrug transfer into the brain and CSF in vivo is determined by multiple factors including protein binding, lipid solubility and cellular transport mechanisms. Olanzapine has been reported to be ~93% protein bound in humans with binding being concentration independent (Kassahun et al., 1997). However, in our preliminary rat studies we found that olanzapine appears to be less protein bound (~40%) at all ages tested from E19 to adults, but was also concentration independent (F.Qiu, personal communication). As the unbound drug is able to pass across brain and placental barriers more readily than their protein-bound counterparts (Robinson & Rapoport, 1986; Griffiths & Campbell, 2015; Polin et al., 2017) the increase in available free drug potentially indicates that more olanzapine is available for transport/transfer across barriers in rats. Olanzapine is highly lipid soluble with a predicted LogD of 1.9–2.8 at pH 7.4 (Tetko et al., 2005; ChemSpider, 2022). However, it appears that olanzapine permeability does not solely depend on its protein binding capacity or lipophilicity as its brain entry is higher compared to another antipsychotic drug, risperidone, which has lower protein binding and a similar logD (Mannens et al., 1994; Dave and Morris, 2016).\n\nThe major transporters involved in mediating drug movement across placental and brain barriers include adenosine triphosphate binding cassette (ABC) efflux transporters as well as selective bi-directional solute carriers (mostly influx transporters, SLCs). ABC efflux transporters of note include P-glycoprotein (Pgp), breast cancer resistance protein (BCRP) and multidrug resistance proteins (MRPs); the SLCs facilitating drug transfer include the SLC22A and SLCO superfamilies (Ghersi-Egea et al., 2018). Olanzapine has been classified as an intermediate P-glycoprotein (Pgp) substrate with high specificity, but low maximal capacity (Boulton et al., 2002). The entry of olanzapine into brain was tested by Wang et al. (2004) using Pgp knockout mice. In that study, mice were injected i.p. with 2.5 mg/kg of olanzapine, with samples collected one hour after injection. Whilst the plasma concentration remained relatively constant, brain concentrations increased in the knockout group compared to wildtype, implicating a link between Pgp and olanzapine.\n\nEffectiveness of these transporters can also be modulated by inducers and inhibitors. In the case of efflux transporters inducers increase the capacity of the transporter thereby reducing drug entry whereas inhibitors decrease transporter- mediated efflux therefore increasing drug entry. The inverse is true for influx transporters. One such example of transporter inhibition includes competition for the same transporter via drug-drug interactions when more than one substrate drug is present (Ekford and Sharom, 2006; Wessler et al., 2013). In the present study, olanzapine entry into brain was also assessed when challenged with other therapeutics in both single or repeated administration to confirm its relationship with Pgp and investigate any potential interactions with other transporters (see below).\n\nIn monotherapy, entry of olanzapine into the brain or CSF was similar in all three age groups when the drug was administered acutely (i.p.) to individual rats (Figure 3). There was also no difference in its entry into different parts of the brain (cortex and brainstem). Prolonged treatment increased olanzapine entry into both brain and CSF in postnatal animals (P4 and adult), but not at E19 (Figure 4). However, at E19, brain entry was already at 100% of plasma levels in the cortex, brainstem and CSF, indicating entry was not limited by ABC transporter efflux (Kohen et al., 2019).\n\nThe levels of olanzapine measured were variable between individual animals making statistical age-comparisons difficult. Such variability has previously been reported by Aravagiri et al., 1999, who showed that olanzapine passes through the blood brain barrier and accumulates in the brain. Rats chronically exposed to 0.25 to 6 mg/kg/day oral or i.p. doses of olanzapine were reported to have brain/plasma concentration ratios which ranged from 540% to 1,760% following i.p. injections and 630% to 1,310% following oral administration (Aravagiri et al., 1999). In contrast, in a human study involving patients who had taken 2.5–25 mg/day oral doses of olanzapine for 0.2 to 11 years, entry into the CSF was only 12% of serum levels (Skogh et al., 2011). This pattern of higher brain entry compared to CSF was also observed in this study, especially in the younger animals (Figure 4).\n\nDigoxin has previously been used to determine if brain entry of olanzapine is affected by co-administration with a known Pgp substrate (Mayer et al., 1997). In a more recent study, repeated digoxin treatment increased abcb1a (Pgp) expression in the adult cortex by 1.21-fold and was accompanied by a 7% decrease in digoxin entry into the adult brain compared to a single dose treatment group (Koehn et al., 2019). In the present study, the same prolonged dosing protocol was utilised to induce Pgp expression and [3H]-olanzapine was included with the final dose to measure its transfer. An increase in olanzapine transfer into the P4 brain and adult CSF was observed following both prolonged olanzapine and prolonged digoxin treatments, potentially indicating that these drugs share the same mechanism of limiting entry; this supports previous studies suggesting their role as Pgp substrates (Mayer et al., 1997; Boulton et al., 2002; Wang et al., 2004). However, in this case, the effect was an increase in olanzapine transfer, which may be a consequence of the dose of drugs used being too high and thus exceeding the efflux capacity of the transporter at the brain barriers in spite of its increased expression. A similar observation was described previously for paracetamol (Koehn et al., 2019)\n\nOlanzapine is routinely prescribed as a monotherapy to treat psychiatric disorders, but in many patients, additional medications are also used. Drugs are commonly taken in combination with other therapeutics to either increase their efficacy of treatment (e.g. Tohen et al., 2002) or to treat co-existing conditions. To investigate the potential effects of other therapeutics on olanzapine brain entry, a combinatory approach was taken. When considering the effects of drug combination therapy on permeability, increased entry is generally interpreted to reflect competition for the same efflux transporter (Ekford & Sharom, 2006; Wessler et al., 2013), whereas a decrease is thought to reflect competition for the same influx mechanism (Kell, 2021). Olanzapine transfer into the brain and CSF at three developmental ages was measured following co-administration with one of seven medications (see Methods) selected for their peripheral (cimetidine and digoxin) or central nervous system (fluvoxamine, lamotrigine, lithium, paracetamol and valproate) mode of action.\n\nTransport of drugs is multifaceted with their transfer limited by multiple transporters with effectiveness being both barrier- and age-dependent (Ek et al., 2010). Two peripherally acting drugs, cimetidine and digoxin are known to be BCRP and Pgp substrates respectively (Mayer et al., 1997). The antidepressant fluvoxamine, a serotonin reuptake inhibitor (SSRI), also appears to be a Pgp substrate although with some discrepancy between studies (O’Brien et al., 2012). Currently, transport mechanisms for the analgesic paracetamol are yet to be determined. However, its metabolites: glucuronide-, sulfide- and glutathione-conjugated paracetamol have been found to be transported by MRP1, 2 and 4 in the liver (Koenderink et al., 2020). Lamotrigine and valproate are both used to treat epilepsy and bipolar disorder, but the mechanisms limiting their entry into brain differ. Lamotrigine, has been indicated as a substrate for efflux transporters Pgp (Potschka et al., 2002) and BCRP (Römermann et al., 2015) as well as the influx transporter slc22a1 (OCT1; Dickens et al., 2012). Valproate efflux appears to be mediated by Pgp and MRP4 in the placenta (Jinno et al., 2020), but not in the brain (Baltes et al., 2007). Valproate shows limited entry into brain, especially in the adult (Toll et al., 2021), which is likely due to its polar nature (LogD at pH 7.4 is 0.1-0.5, Chemspider, Tetko et al., 2005). However, there is evidence of some inward transport mediated via slc16a1 (MCT1; Vlieghe and Khrestchatisky, 2013).\n\nLithium, commonly used to treat bipolar disorder, was also included in the drug competition group as a biological internal control. Being an ion, lithium enters the brain by a combination of passive diffusion (Wraae, 1978), transfer through ion channels and by ion transporters (Luo et al., 2018). It is therefore unlikely to compete with olanzapine for facilitated entry into or efflux from the brain. Entry of lithium into the brain and across the placenta has been previously described in Chiou et al., 2021. At postnatal day 4, entry of olanzapine into the brain and CSF was similar when administered as a monotherapy or in combination with lithium confirming no effect of lithium on olanzapine transfer. Furthermore, at P4 and adult there were no significant changes in olanzapine transfer into either brain or CSF when administered in combination with any of the other drugs investigated. These findings are in agreement with studies by Jann et al. (2006) and Sidhu et al. (2006) who reported that co-administration of olanzapine and lamotrigine in healthy human adults did not influence the entry of either drug.\n\nIn contrast to the postnatal animals, at E19 co-administration of olanzapine with other medications did affect olanzapine entry. Digoxin and lamotrigine co-treatment both increased olanzapine entry into the fetal brain, indicating competition for the same efflux transporter(s). On the other hand, co-treatment with paracetamol decreased olanzapine entry into the fetal CSF, suggesting competition for the same influx transporter(s). The observed increased olanzapine entry into the fetal brain following combination with fellow Pgp substrates digoxin and lamotrigine, is consistent with our previous findings of lower expression of abcb1a (pgp) in fetal rats compared to adult animals (Ek et al., 2010; Koehn et al., 2021), implying less capacity of the fetal brain to efflux Pgp substrates.\n\nSome human studies have investigated the placental transfer of olanzapine, either using ex vivo models or at birth using maternal and umbilical blood. Placental passage of olanzapine from the maternal to fetal compartment was reported to be 5–14% in a study using human placental explants perfused with 10 ng/ml olanzapine over a 4-hour period (Schenker et al., 1999). In contrast, an in vivo human study analysing the olanzapine concentration in the mother’s plasma compared to plasma from the umbilical cord of the baby at delivery reported 72% transfer. Mothers in this study took olanzapine (mean 8.9 mg/day at delivery) for a minimum of 2 weeks before delivery (Newport et al., 2007). Previous studies have reported that the rate of congenital malformation in babies whose mothers have taken olanzapine during pregnancy is no different from the background incidence (Brunner et al., 2013). However, there are still no controlled studies investigating the use of olanzapine during pregnancy in humans probably due to ethical concerns.\n\nIn this project, using an animal model, transfer of olanzapine across the placenta was measured by comparing its concentration in fetal plasma and maternal plasma in time matched sample pairs (Methods). Following a single dose, olanzapine placental transfer was around 55% and decreased to around 45% following repeated treatment, suggesting an upregulation of efflux mechanisms induced by repeated exposure to the drug. In acute combination experiments, decreased transfer of olanzapine across the placenta was observed following co-treatment with lamotrigine, paracetamol or valproate (Figure 10). However, in a reverse experiment observing the effects of olanzapine co-treatment on transfer of other medications, paracetamol and valproate transfer across the placenta was increased following olanzapine combination therapy (unpublished work, Huang et al., 2023 in preparation). These increases in fetal drug exposure with co-treatment could be of clinical concern due to recent controversies surrounding paracetamol’s safety during pregnancy (Masarwa et al., 2020; Parker and Werler, 2020), while valproate is a known teratogen (Tomson et al., 2018; Abou-Khalil, 2019; Vajda et al., 2012).\n\nEntry of olanzapine into the fetal brain can be estimated by measuring amounts of radioactivity-traced olanzapine in fetal brain compared to its levels in maternal plasma (Figure 11). This appears to be predominantly determined by placental transfer. For example, inclusion of lamotrigine decreased olanzapine entry from fetal blood into the cortex slightly but significantly (from 66±10%; n=21 to 58±6%, p<0.001; n=10) but there was an overall decrease due to the more substantial decrease in placental transfer (from 53±10% to 24±5%; n=10-21). Paracetamol or valproate combination therapy also decreased olanzapine transfer across the placenta to 19±1% (p<0.0001; n=4) and 34±3% (p<0.0001; n=7) respectively. In contrast to the decrease in placental olanzapine transfer that occurred in the presence of paracetamol or valproate, co-treatment with cimetidine or digoxin resulted in increased olanzapine placental transfer exceeding 100%, indicating olanzapine accumulates to a higher level in fetal brain than in maternal plasma.\n\nCalculated by fetal cortex/average maternal plasma ratio (%) after a single intravenous (i.v.) injection either as monotherapy or in combination with: cimetidine (CIM, 11 mg/kg), digoxin (DIG, 0.03 mg/kg), lamotrigine (LTG, 6 mg/kg), paracetamol (PARA, 15 mg/kg) or valproate (VPA, 30 mg/kg). Bars are means±SD. Note each point is an individual animal (n=4–21). ***p<0.001, ****p<0.0001.\n\n\n\n1. Drug levels contained within the blood vessels of brain tissue (i.e. residual vascular space) were not taken into account in the present study. Vascular space in the rat brain from E16 to adult has been reported to be around 2–4% (Toll et al., 2021, Qiu et al., 2022) and is particularly important in experiments where entry of drugs into the brain is at low levels. Due to the high degree of olanzapine entry into the brain, final interpretation of results would not be expected to be affected.\n\n2. Olanzapine metabolites were not included in measurements of overall radioactivity. We did consider this potential problem but having established by LC-MS that the main olanzapine metabolite in rodents, demethyl olanzapine, (DMO; Mattiuz et al., 1997) was not detected in the samples, we concluded that this metabolite did not play a large role in our experiment, likely due to short experimental times (30 min). Another metabolite of olanzapine, 2-hydroxyolanzapine, has been reported to be present in plasma to a similar extent to DMO, although it does not seem to have any pharmacological activity at clinically relevant doses (Callaghan et al., 1999). Therefore, we assumed that the measurements of radioactivity represent the parent olanzapine.\n\n3. Concentration of the drug injected can be estimated from radioactivity counts by calculating the known amount of added radioactivity per mg of the cold drug in the injectate and refer this calculation to radioactivity in blood samples after 30 min of the experiment. Using this calculation, the concentrations in plasma at the three ages were compared with data obtained using LC-MS. This is illustrated in Extended data Figure 3 and shows a reasonably good correlation between the two methods reinforcing the validity of using the radioactive compound in our experiments. An additional advantage of using radioactivity is the very high sensitivity of this method allowing measurements to be performed even in very small volumes of samples such as CSF in fetal rats.\n\nMore than 1200 medications have been prescribed to pregnant and breastfeeding women (Briggs et al., 2021). As outlined in the Introduction there are little data available from clinical trials upon which clinicians and their patients can make evidenced-based decisions about use of medications during pregnancy and breastfeeding. Even though clinical trials in pregnant women are becoming more accepted (van der Graaf et al., 2018; Stock and Norman, 2019) it is unlikely that this acceptance will extend to drugs currently in use because of the expense and lack of compensatory profits for the pharmaceutical industry. Our approach is to study drugs used in clinical practice in pregnant and neonatal rats. An important consideration is the extent to which results from studies in rats can be extrapolated to humans. A substantial amount is known about brain development in rats and humans, which allows detailed regional comparisons to be made (Workman et al., 2013). The placentas in both species are haemochorial; although there are some morphological differences, and are much more similar than many other species that are used for developmental studies (Ek et al., 2010; Studdert et al., 2020; Møllgård et al., 2017). Of particular importance is the similarity of cellular distribution of ABC efflux transporters in rat and human placenta and brain barriers (Ek et al., 2010; Saunders & Dziegielewska, 2020; Koehn et al., 2021).\n\nThe most striking findings in the present study that may have clinical relevance were the results for transfer of olanzapine across the placenta. Prolonged (longer term) treatment of dams reduced fetal/maternal plasma concentration ratio from 53±10% to 46±6% (p<0.05). If the results are presented as fetal cortex/maternal plasma concentration ratios (Figure 11) the ratios are not much different from those in Figure 10, indicating that most of the protection of the fetal brain from administration of maternally derived drugs occurs at the placental barrier. If similar measurements can be made in human maternal and umbilical cord blood at birth this would provide confirmation of the protective effect of the drug combinations and would provide some reassurance to both clinicians and their patients that these particular drug combinations would be less likely to harm the baby. In addition, the effect of various drug combinations on olanzapine transfer into maternal brain was quite small, indicating little diminution in the important clinical effect of this therapeutic in the mothers. In contrast, the increase in transfer of olanzapine in the presence of cimetidine and digoxin (Figure 11) suggests that these combinations should be used with caution, at least until it has been determined if olanzapine does have any deleterious effect on the developing brain. The finding for the combination of olanzapine and paracetamol may be particularly important because of the high rate of self-medication with paracetamol that has been reported in many countries (Zafeiri et al., 2021).",
"appendix": "Data availability\n\nFigshare: Underlying data for ‘Entry of the antipsychotic drug, olanzapine, into the developing rat brain in mono- and combination therapies’. https://doi.org/10.26188/c.6273693 (Huang et al., 2022)\n\nThe project contains the following underlying data:\n\n• LC-MS raw data\n\n• LC-MS raw data.xlsx (Raw data for LC-MS measurements)\n\n• LC-MS Skyline template.sky (Skyline template: used to extract peak area from raw data)\n\n• Liquid scintillation counting raw data\n\n• Olanzapine combination therapy.xlsx (CPM, DPM, weight for all samples as well as sex of all animals)\n\n• Olanzapine monotherapy.xlsx (CPM, DPM, weight for all samples as well as sex of all animals)\n\nFigshare: Extended data for ‘Entry of the antipsychotic drug, olanzapine, into the developing rat brain in mono- and combination therapies’. https://doi.org/10.26188/c.6273693 (Huang et al., 2022)\n\nThis project contains the following extended data:\n\n• Extended data figures.docx (Additional supplementary figures)\n\n• Olanzapine Extended data tables.xlsx (Tables of numerical values for each figure)\n\nFigshare: ARRIVE checklist for ‘Entry of the antipsychotic drug, olanzapine, into the developing rat brain in mono- and combination therapies’. https://doi.org/10.26188/c.6273693 (Huang et al., 2022).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAbou-Khalil BW: Update on Antiepileptic Drugs 2019: CONTIN. 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PubMed Abstract | Publisher Full Text\n\nMannens G, Meuldermans W, Snoeck E, et al.: Plasma protein binding of risperidone and its distribution in blood. Psychopharmacology. 1994; 114: 566–572. PubMed Abstract | Publisher Full Text\n\nMasarwa R, Platt RW, Filion KB: Acetaminophen use during pregnancy and the risk of attention deficit hyperactivity disorder: A causal association or bias?. Paediatr. Perinat. Epidemiol. 2020; 34: 309–317. Publisher Full Text\n\nMattiuz E, Franklin R, Gillespie T, et al.: DISPOSITION AND METABOLISM OF OLANZAPINE IN MICE, DOGS, AND RHESUS MONKEYS. Drug Metab. Dispos. 1997; 25: 573–583. PubMed Abstract\n\nMayer U, Wagenaar E, Dorobek B, et al.: Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. J. Clin. Invest. 1997; 100: 2430–2436. PubMed Abstract | Publisher Full Text\n\nMøllgård K, Dziegielewska KM, Holst CB, et al.: Brain barriers and functional interfaces with sequential appearance of ABC efflux transporters during human development. Sci. Rep. 2017; 7: 11603. PubMed Abstract | Publisher Full Text\n\nNewport DJ, Calamaras MR, DeVane CL, et al.: Atypical Antipsychotic Administration During Late Pregnancy: Placental Passage and Obstetrical Outcomes. Am. J. Psychiatry. 2007; 164: 1214–1220. PubMed Abstract | Publisher Full Text\n\nO’Brien FE, Dinan TG, Griffin BT, et al.: Interactions between antidepressants and P-glycoprotein at the blood–brain barrier: clinical significance of in vitro and in vivo findings. Br. J. Pharmacol. 2012; 165: 289–312. PubMed Abstract | Publisher Full Text\n\nParker SE, Werler MM: Prenatal exposure to acetaminophen and neurodevelopment. Paediatr. Perinat. Epidemiol. 2020; 34: 225–226. PubMed Abstract | Publisher Full Text\n\nPavek P, Merino G, Wagenaar E, et al.: Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5- b)pyridine, and Transport of Cimetidine. J. Pharmacol. Exp. Ther. 2005; 312: 144–152. Publisher Full Text\n\nPolin RA, Abman SH, Rowitch DH, et al.: Fetal and neonatal physiology. Philadelphia, PA:Elsevier;Fifth edition.2017.\n\nPotschka H, Fedrowitz M, Löscher W: P-Glycoprotein-mediated efflux of phenobarbital, lamotrigine, and felbamate at the blood–brain barrier: evidence from microdialysis experiments in rats. Neurosci. Lett. 2002; 327: 173–176. PubMed Abstract | Publisher Full Text\n\nQiu F, Huang Y, Saunders NR, et al.: Age dependent contribution of entry via the CSF to the overall brain entry of small and large hydrophilic markers (preprint). In Review.2022. Publisher Full Text\n\nRobinson PJ, Rapoport SI: Kinetics of protein binding determine rates of uptake of drugs by brain. Am. J. Phys. 1986; 251: R1212–R1220. PubMed Abstract | Publisher Full Text\n\nRömermann K, Helmer R, Löscher W: The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2). Neuropharmacology. 2015; 93: 7–14. PubMed Abstract | Publisher Full Text\n\nSaunders NR, Dziegielewska KM: Medications for pregnant women: A balancing act between the interests of the mother and of the fetus. Prenat. Diagn. 2020; 40: 1156–1167. PubMed Abstract | Publisher Full Text\n\nSchenker S, Yang Y, Mattiuz E, et al.: Olanzapine Transfer By Human Placenta. Clin. Exp. Pharmacol. Physiol. 1999; 26: 691–697. PubMed Abstract | Publisher Full Text\n\nSidhu J, Job S, Bullman J, et al.: Pharmacokinetics and tolerability of lamotrigine and olanzapine coadministered to healthy subjects. Br. J. Clin. Pharmacol. 2006; 61: 420–426. PubMed Abstract | Publisher Full Text\n\nSkogh E, Sjödin I, Josefsson M, et al.: High Correlation Between Serum and Cerebrospinal Fluid Olanzapine Concentrations in Patients With Schizophrenia or Schizoaffective Disorder Medicating With Oral Olanzapine as the Only Antipsychotic Drug. J. Clin. Psychopharmacol. 2011; 31: 4–9. PubMed Abstract | Publisher Full Text\n\nStaud F, Vackova Z, Pospechova K, et al.: Expression and Transport Activity of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Dually Perfused Rat Placenta and HRP-1 Cell Line. J. Pharmacol. Exp. Ther. 2006; 319: 53–62. PubMed Abstract | Publisher Full Text\n\nStock SJ, Norman JE: Medicines in pregnancy. F1000Res. 2019; 8: 911. PubMed Abstract | Publisher Full Text\n\nStuddert VP, Gay CC, Hinchcliff KW: Saunders Comprehensive Veterinary Dictionary. Philadelphia, PA:Saunders Ltd.;5th ed2020.\n\nTetko IV, Gasteiger J, Todeschini R, et al.: Virtual Computational Chemistry Laboratory – Design and Description. J. Comput. Aided Mol. Des. 2005; 19: 453–463. PubMed Abstract | Publisher Full Text\n\nTohen M, Chengappa KNR, Suppes T, et al.: Efficacy of Olanzapine in Combination With Valproate or Lithium in the Treatment of Mania in Patients Partially Nonresponsive to Valproate or Lithium Monotherapy. Arch. Gen. Psychiatry. 2002; 59: 62. Publisher Full Text\n\nToll SJ, Qiu F, Huang Y, et al.: Entry of antiepileptic drugs (valproate and lamotrigine) into the developing rat brain. F1000 Res. 2021; 10: 384. PubMed Abstract | Publisher Full Text\n\nTomson T, Battino D, Bonizzoni E, et al.: Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 2018; 17: 530–538. PubMed Abstract | Publisher Full Text\n\nVajda FJE, Horgan D, Hollingworth S, et al.: The prescribing of antiepileptic drugs for pregnant Australian women: Antiepileptic drug prescribing for pregnant women. Aust. N. Z. J. Obstet. Gynaecol. 2012; 52: 49–53. PubMed Abstract | Publisher Full Text\n\nVlieghe P, Khrestchatisky M: Medicinal Chemistry Based Approaches and Nanotechnology-Based Systems to Improve CNS Drug Targeting and Delivery: IMPROVING CNS DRUG TARGETING AND DELIVERY. Med. Res. Rev. 2013; 33: 457–516. PubMed Abstract | Publisher Full Text\n\nWang J-S, Taylor R, Ruan Y, et al.: Olanzapine Penetration into Brain is Greater in Transgenic Abcb1a P-glycoprotein-Deficient Mice than FVB1 (Wild-Type) Animals. Neuropsychopharmacol. 2004; 29: 551–557. Publisher Full Text\n\nWessler JD, Grip LT, Mendell J, et al.: The P-Glycoprotein Transport System and Cardiovascular Drugs. J. Am. Coll. Cardiol. 2013; 61: 2495–2502. Publisher Full Text\n\nWorkman AD, Charvet CJ, Clancy B, et al.: Modeling Transformations of Neurodevelopmental Sequences across Mammalian Species. J. Neurosci. 2013; 33: 7368–7383. PubMed Abstract | Publisher Full Text\n\nWraae O: THE PHARMACOKINETICS OF LITHIUM IN THE BRAIN, CEREBROSPINAL FLUID AND SERUM OF THE RAT. Br. J. Pharmacol. 1978; 64: 273–279. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZafeiri A, Mitchell RT, Hay DC, et al.: Over-the-counter analgesics during pregnancy: a comprehensive review of global prevalence and offspring safety. Hum. Reprod. Update. 2021; 27: 67–95. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "157201",
"date": "21 Dec 2022",
"name": "Byron Bitanihirwe",
"expertise": [
"Reviewer Expertise Translational Psychiatry/Neuropsychopharmacology"
],
"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 present work explores the level of olanzapine transfer across the placenta and its entry into the developing rat brain. The authors focus on three developmental stages and utilise good quality measures (i.e., liquid scintillation counting), which are important strengths of the study. It was found that prolonged exposure to olanzapine can increase its entry into the brains of postnatal animals. Further, combination therapy models that involved the co-administration of lamotrigine and digoxin with olanzapine increased olanzapine transfer into the fetal brain. Finally, placental transfer of olanzapine between the dam and fetus was affected by combination therapy. Overall, the study is informative and provides important evidence that the placental barrier protects the fetal brain from drugs or medication taken during pregnancy.\nBelow are some general comments for the authors to consider:\n1)The authors mention the choroid plexus in the keywords, but nowhere in the manuscript is any allusion made to this structure and how it relates to the findings reported in the present study.\n2) Be consistent with the use of min or minutes in the Methods section.\n3) Consider separating the concentration values plotted in Figure 2A for the CSF and Plasma in to two separate figures.\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": "9339",
"date": "15 Feb 2023",
"name": "Norman Saunders",
"role": "Author Response",
"response": "On behalf of my co-authors I should like to thank Dr Bitanihirwe for his positive comments about our manuscript and his suggestions for changes. We have added a brief new paragraph to the introduction which emphasizes the distinction between entry of drugs across the cerebral blood vessels and via the choroid plexus and CSF. We would therefore prefer to retain choroid plexus as a key word. \"minutes has been corrected to \"min\" in the Methods section. It is an interesting suggestion that we should display the plasma and CSF data in Figure 2A in separate graphs. However, Figure 2A shows the time course of drug levels following administration and it is informative to be able to directly compare plasma levels that are initially high (as would be expected) with CSF levels in the same animals that are much lower. It also allows direct comparison of the fall in CSF levels which appears slower than the steep fall in plasma levels over time. This is a point being made in the section “Time-course of olanzapine entry into the brain and CSF” which references this figure. We would therefore prefer to retain the figure in its present form."
}
]
},
{
"id": "162762",
"date": "13 Feb 2023",
"name": "Udo Schumacher",
"expertise": [
"Reviewer Expertise drug and antibody delivery in malignant tumors and normal tissues."
],
"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 reports the results of a carefully designed and executed study on the uptake of the antipsychotic drug olanzapine into the developing rat brain. As anti-psychotic drug use is relatively common, this study addresses an important clinical concern about the safe use of these drugs. More importantly, it also addresses the question of drug interaction with other clinically used drugs. These drugs were not randomly chosen as many of them interact with efflux/influx transporters which are also substrates for olanzapine. It would have been helpful to the reader to have been informed about these transporters in the Introduction section and not be introduced to the transport problem in the results section. Maybe even a table showing the interaction of the drugs with specific transporters/pumps may be helpful.\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": "9340",
"date": "15 Feb 2023",
"name": "Norman Saunders",
"role": "Author Response",
"response": "On behalf of my co-authors I would like to thank Dr Schumacher for his kind comments about our manuscript. He makes the interesting suggestion that we should include a mention of efflux/influx transporters in the Introduction section and not be introduced to the transport problem in the results section. Maybe even a table showing the interaction of the drugs with specific transporters/pumps may be helpful. This is a complex and poorly understood area of research in the developing brain. When we were drafting the manuscript we considered including such a summary in the Introduction but decided that it would be clearer to readers if in the Introduction we focused on the problem being studied and left possible explanation for findings to the Discussion."
},
{
"c_id": "9365",
"date": "21 Feb 2023",
"name": "Udo Schumacher",
"role": "Reviewer Response",
"response": "Fine with me."
}
]
}
] | 1
|
https://f1000research.com/articles/11-1417
|
https://f1000research.com/articles/11-676/v1
|
20 Jun 22
|
{
"type": "Research Article",
"title": "The COVID-19 pandemic and mental health outcomes – A cross-sectional study among health care workers in Coastal South India",
"authors": [
"Rekha T",
"Nithin Kumar",
"Kausthubh Hegde",
"Bhaskaran Unnikrishnan",
"Prasanna Mithra",
"Ramesh Holla",
"Darshan Bhagawan",
"Rekha T",
"Kausthubh Hegde",
"Bhaskaran Unnikrishnan",
"Prasanna Mithra",
"Ramesh Holla",
"Darshan Bhagawan"
],
"abstract": "Background: Frontline health care workers (HCWs) are at increased risk of developing unfavourable mental health outcomes and burnout, especially during the COVID-19 pandemic. Recognizing the early warning signs of mental distress is very important to ensure the provision of quality patient care. Methods: In this facility-based cross-sectional study, HCWs of the teaching hospitals affiliated to Kasturba Medical College, Mangalore were assessed regarding their mental health status using a semi-structured questionnaire. All doctors and nurses who were willing to participate from these teaching hospitals were included in the study. Data was collected over a period of four months (1st March -30th June 2021) till the required sample size was reached and analysed using IBM SPSS and expressed using mean (standard deviation), median (interquartile range), and proportions. Univariate analysis was done to identify the factors associated with mental health outcomes among the HCWs and the corresponding unadjusted odds ratio and 95% confidence interval were reported. Results: A total of 245 HCWs [52.2% (n=128) doctors and 47.8% (n=117) nurses] were included in our study. The proportion of participants with depressive symptoms, anxiety, and insomnia assessed using PHQ-9, GAD-7, and ISI-7 scales were 49% (n=119), 38% (n=93), and 42% (n=102) respectively. Depression, anxiety, and insomnia were more likely to be experienced by HCWs aged > 27 years, females, and involved in COVID-19 patient care. (p>0.05) Conclusions: Our findings that 38% of the examined HCWs had clinically relevant anxiety symptoms and 49% had clinically relevant depression symptoms draws attention to the importance of systematically tracking the mental health of HCWs during this ongoing pandemic. HCWs should monitor their stress reactions and seek appropriate help both on a personal and professional level. Appropriate workplace interventions including psychological support should be provided to HCWs, to ensure provision of uncompromised quality patient care.",
"keywords": [
"Mental Health",
"Pandemic",
"Health personnel",
"Depression",
"Patient Health Questionnaire",
"anxiety"
],
"content": "Introduction\n\nThe coronavirus disease of 2019 (COVID-19), first identified in Wuhan, China spread rapidly, crossing geographical boundaries and infecting millions of people. The World Health Organization (WHO) acknowledged this outbreak to be of immediate public health concern and declared it a pandemic on March 11, 2020. Now, after two years of outbreaks and large-scale vaccination of the susceptible population, there is still no sign of end of the pandemic. As of 25th February 2022, WHO estimates close to 430 million confirmed cases and around 59 million deaths due to the severe acute respiratory syndrome coronavirus 2 (SARS-COV2) virus worldwide.1 India, one of the major contributors to the global tally of COVID-19 cases has reported around 42 million confirmed cases and 0.52 million deaths.1,2 Countries around the world imposed a nationwide lockdown for curbing the rapid spread of COVID-19 infections, which was modified to region-specific restriction of movement of people. The social isolation and loss of livelihood brought about by frequent lockdown had a huge impact on the physical and mental wellbeing of the general population.\n\nThe frontline health care workers (HCWs) are at increased risk of developing unfavourable mental health outcomes and burnout. During the pandemic, the HCWs must work relentlessly and for extended hours, attending to huge caseloads and unforeseen medical complications which compounds the mental distress arising out of constant fear of acquiring infection. In India, HCWs involved in COVID-19 care were marginalized and stigmatized. HCWs in many parts of India had to perform their duties under the constant threat of aggression and violence from patient caretakers which heightened their mental distress. Refusal of entry to apartments and residences, resistance to the burial of dead bodies of HCWs,3,4 and abuse of the doctors involved in screening and contact tracing were reported from different parts of the country.5\n\nRecognizing the early warning signs of mental distress is important in any population, more so among HCWs. Unfavorable mental health outcomes like anxiety, depression, insomnia, psychological distress, and burnout can affect their health, and compromise the patient safety and the quality of care provided.6 Adequate interventions and coping strategies can be implemented if the mental health status of HCWs is routinely evaluated. With this background and in the context of the current COVID-19 pandemic in the district, the study was carried out to assess the mental health outcomes among the HCWs in Mangalore and the factors associated with them.\n\n\nMethods\n\nThe Institutional Ethics Committee of Kasturba Medical College, Mangalore approved the study protocol. (IEC KMC MLR 05-2020/164). Electronic written informed consent was obtained from all participants on the google form. Only consenting participants were able to access the online questionnaire.\n\nThe study was conducted in the coastal city of Mangalore, belonging to the District of Dakshina Kannada in the Southern part of India. A major commercial and educational hub, an ivory town of hospitals and medical colleges, Mangalore enjoys a high health care index6 catering to patients not only from the adjoining districts, but also from the neighbouring state of Kerala.\n\nDakshina Kannada is among the top five highly affected districts in the State of Karnataka during the ongoing COVID-19 pandemic with a total of 3.9 million cases reported to date7 with Mangalore being the major contributor to the daily tally of cases.\n\nThis facility-based cross-sectional study was carried out among the health care workers (HCWs) – doctors and nurses of the teaching hospitals affiliated to Kasturba Medical College, Mangalore.\n\nA total of 245 HCWs were included in the study to assess their mental health outcomes during the COVID-19 pandemic. The sample size was calculated using the formulae for cross-sectional study8 design: N=4pq/d2. It was calculated considering the proportion of HCWs experiencing depressive symptoms to be 50.4% (11), absolute precision of 7%, 80% power, 95% confidence interval, and a non-response error of 20%. Applying the population proportion to size strategy, a total of 128 doctors and 117 nurses were included in the study using non-probability (convenience) sampling method. The doctors and nurses who were willing to participate, were included in the study till the required sample size was reached.\n\nThe study was conducted during the second wave of COVID-19 from 1st March 2021 to 30th June 2021. The information related to study variables was collected using a semi-structured questionnaire in English which had the following sections:\n\n• Section A: General participant information\n\nThis section of the questionnaire included age, gender, designation, specialty, work experience, whether involved in COVID-19 care, and other personal details.\n\n• Section B: Patient Health Questionnaire (PHQ-9)10 - assesses the presence of depression-related symptoms. PHQ-9 consists of nine statements reflecting the participants’ state of mind and was scored on a three-point Likert-type scale from “0” (not at all) to “3” (nearly every day). The total score ranges from 0 to 27.\n\n• Section C: Generalised Anxiety Disorder (GAD-7) scale11 - assesses anxiety among the participants. GAD-7 consists of seven statements assessing the level of anxiousness in a participant like feeling nervous, anxious, or on edge and worrying too much about different things. The statements are rated on a four-point Likert-type scale (0 = not at all to 3 = nearly every day and the scores ranged from 0 to 21 with higher scores indicating more severe GAD symptoms.\n\n• Section D: Insomnia Severity Index (ISI)12,13 to assess the presence of insomnia.\n\nThe ISI consists of seven-items assessing the level of insomnia across dimensions like severity of sleep onset, sleep maintenance, and early morning awakening problems, sleep dissatisfaction, interference of sleep difficulties with daytime functioning, noticeability of sleep problems by others, and distress caused by the sleep difficulties. All the items are rated using a five-point Likert scale (0 = no problem; 4 = very severe problem), yielding a total score ranging from 0 to 28.\n\nThe questionnaire was pilot tested and validated for the content. Pilot Testing - The pilot testing was carried out in the month of February 2021 among 30 HCWs (15 doctors and 15 nurses). The participants were selected randomly using non-probability sampling. These participants were excluded from the main study. The pilot was done to evaluate the feasibility of an online survey and to finalize the questionnaire. Based on the pilot testing, questions on participants specialty, department to which they belong, and teaching experience in medical college was removed to make section A uniform for both doctors and nurses. No changes were made to Section B, section C, and section D, since they were standard questionnaires and already pre-validated.\n\nData collection\n\nAfter obtaining the requisite permission from the head of the institution and concerned authorities of the hospitals, a list of doctors and nurses along with their phone numbers and email IDs working in the affiliated hospitals was obtained from the Human Resource department.\n\nTo limit the personal contact with the study participants due to the prevailing pandemic, the questionnaire was prepared in Google forms (https://www.google.co.uk/forms/) and the link was sent to the participants via WhatsApp or email. The Google form questionnaire was pre-tested and validated.\n\nThe information sheet and consent form were included in the Google form questionnaire. Electronic consent was obtained from each respondent on the first page of the Google form questionnaire. Only the consenting participants were able to access the questionnaire and fill out their responses. We did not include any personal identifiers in the questionnaire to ensure confidentiality of the participants. The link for the survey was circulated till the required sample size of 245 was reached and the final spreadsheet downloaded\n\nThe collected data was extracted as a spreadsheet from Google drive and analysed using IBM SPSS (Statistical Package for Social Sciences) Statistics for Windows Version 25.0. Armonk, NY: IBM Corp). The data is expressed using mean (standard deviation), median (interquartile range), and proportions.\n\nThe interpretation of the scales used to assess the various mental health outcomes among the participants is as follows:\n\n• General Anxiety Disorder - 7: Normal (0-4), Mild (5-9), Moderate (10-14), and severe (15-21) anxiety.\n\n• Patient Health Questionnaire - 9: Normal (0-4), mild (5-9), moderate (10-14), and severe (15-27) depression.\n\n• Insomnia Severity Index - 7: Normal (0-7), Subthreshold (8-14), Moderate (15-21), and Severe (22-28) insomnia.\n\nThe cutoff scores were used for detecting symptoms of major depression, anxiety, and insomnia, Participants were categorized to have severe symptoms if they had scored greater than the cutoff threshold.\n\nFor comparison across the groups, (gender, type of HCWs, involved in COVID-19 care) the Mann-Whitney U test was used and a ‘p’ value of <0.05 was considered statistically significant. Univariate analysis was carried out to identify the factors associated with mental health outcomes like presence of depression, anxiety, and insomnia among the HCWs and the corresponding unadjusted odds ratio and 95% confidence interval were reported.\n\n\nResults\n\nA total of 245 HCWs, which included 52.2% (n=128) doctors and 47.8% (n=117) nurses were assessed about their mental health status in our study. The mean age of the doctors was 29.7 (±7.9) years, while that of nurses was 26.3 (± 6.2) years. A higher proportion of participants (n=66, 51.6%) among doctors were females. Majority (n=87, 68%) of the doctors and 47% (n=55) of the nurses were involved in the direct care of COVID-19 patients.\n\nThe mental health status of the study participants is depicted in Table 1. The proportion of participants with depressive symptoms, anxiety, and insomnia assessed using PHQ-9, GAD-7 and ISI-7 scales were 49% (n=119), 38% (n=93) and 42% (n=102) respectively. The proportion of depression was higher among doctors (51.5%) compared to nurses (45.3%). The anxiety-related symptoms were similar among doctors and nurses (doctors 39.0% vs. 36.7% in nurses). A higher proportion of nurses experienced insomnia related symptoms compared to doctors (45.2% vs. 38.2%) (P >0.05).\n\n* Fisher exact test.\n\nComparison of mental health outcome scores as assessed by the various scales is shown in Table 2. The median (IQR) scores for depression (PHQ-9), anxiety (GAD-7), and insomnia (ISI-7) for all the participants were 4.0 (1.0-8.0), 3.0 (0.5-7.0), and 6 (2-10) respectively. The median PHQ-9 and GAD-7 scores were higher among doctors compared to nurses, while nurses had a higher ISI-7 median score. However, no significant difference in mental health scores was observed across categories of HCWs, gender of the participants, and involvement in COVID-19 patients’ care (P>0.05).\n\n* Mann-Whitney U test.\n\nThe risk factors for developing mental health outcomes – depression, anxiety, and insomnia among HCWs is shown in Table 3.\n\nDepression was more likely to be experienced by HCWs aged >27 years (OR,1.19; 95% CI, 0.70-2.05), female HCWs (OR,1.03; 95% CI, 0.58-1.84), and HCWs involved in COVID-19 care (OR 1.22;95% CI,0.73-2.04). Insomnia was more likely to be experienced by HCWs aged >27 years (OR,1.59; 95% CI, 0.91-2.79) and HCWs with work experience of more than 10 years (OR,2.08; 95% CI, 1.10-3.92). Anxiety was more likely to be experienced by HCWs aged >27 years (OR,1.63; 95% CI, 0.92-2.91), nurses (OR,1.10; 95% CI, 0.66-1.85), and HCWs with work experience of more than 10 years (OR,1.53; 95% CI, 0.82-2.92). However, none of these factors was significantly associated with mental health outcomes (P>0.05), except HCWs with work experience of more than 10 years, which was significantly associated with experiencing insomnia symptoms (P<0.05).\n\n\nDiscussion\n\nHealth-care workers (HCWs) have been at the forefront since the beginning of the pandemic providing uncompromising care to those infected with COVID-19. However, the extended period of duty hours and the constant fear of getting infected or spreading the infection to family members has negatively impacted their physical and mental health. Unfavourable mental health outcomes – depression, insomnia and anxiety were also reported among our study participants.\n\nThe prevalence of depression was 51.5% in our study. Anxiety was reported among 38%, while insomnia was present in 42% of the participants. The prevalence of mental health outcomes in our study is high compared to a similar study from another part of India where depression was reported among 47.4% of the HCWs, while anxiety and insomnia were seen among 29.0% and 32.2% of the participants respectively.14 Similar studies conducted among the HCWs during the pandemic from different parts of the world have reported a prevalence of depression ranging from 8.9% to 77.2%,15–25 anxiety 14.5% to 88%,5,15–18,20–23,25,27–30 and insomnia 8.3% to 85.4%.5,16,17,19,20–30\n\nMany factors can contribute to unfavourable mental health outcomes among HCWs. The long duty hours and overflowing outpatient departments (OPDs), along with acute shortage of trained staff and personal protective equipment (PPE), fear of contracting the infection and spreading the disease to their family members, and continuous performance evaluation results in psychological distress in most HCWs, ultimately leading to burnout. HCWs are also faced with several decision-making dilemmas during a pandemic including allocation of resources, care for a severely ill/dying patient, and aligning patient needs with those of family members further resulting in moral distress. All this is compounded by a prolonged period of separation from family members or a lack of any other form of support system.31,32\n\nStudies from different parts of the world have reported a variety of factors contributing to unfavourable mental health outcomes. A study from the Eastern Mediterranean region reported that the presence of a pre-existing mental illness, being isolated for COVID-19, and having children was significantly associated with experiencing depressive symptoms23 while insomnia was significantly associated with HCWs working in an isolation unit in a study in China.21 The absence of psychological support at the workplace as a factor for experiencing poor mental outcomes was reported in studies conducted in China and Albania,21,24 while fear of getting infected and transmitting COVID-19 was associated with experiencing depressive symptoms among HCWs in Switzerland and China.20,21\n\nThe frontline HCWs being directly involved in the examination, diagnosis, and treatment of COVID-19 makes them more vulnerable to contracting the infection. The constant fear of being at risk of getting infected may lead to psychological distress and burnout among them. Several studies have reported that the HCWs involved in direct care for COVID-19 patients were found to have unfavourable mental health outcomes.9,16,21,24\n\nIn our study, unfavourable mental health outcomes – depression, anxiety and insomnia were observed among participants >27 years of age, nurses, and HCWs having work experience of more than 10 years. Similar observations were reported in various studies among HCWs around the world. Nurses were found to have a higher risk of experiencing poor mental outcomes in studies conducted in Asia and Africa9,14,17,29 whereas another study from Africa reported male HCWs and physicians to be more at risk for experiencing distress.24,25 In general, female HCWS were found to be more vulnerable to experiencing depression and insomnia related symptoms.9,14,17,19,20,28,29 Younger HCWs in the age group between 21-30 years were also found to experience unfavourable mental health outcomes in several studies.16,25,29,30\n\nOur study has many clinical implications. Our finding that 38% of the examined HCWs had clinically relevant anxiety symptoms and 49% of the participants had clinically relevant depression symptoms draws attention to the importance of systematically tracking the mental health of HCWs during this ongoing pandemic. The result of our study reiterates the need for periodic monitoring of the mental health status of the HCWs, especially during pandemic and provide appropriate and timely interventions, not only to improve the quality of life of HCWs, but also the quality of patient care provided. It is important that the measures taken address the key concerns of healthcare workers who are working in frontline such as adequate availability of PPE, sufficient time to spend with family, and acceptable compensations to their family in case of death.\n\nThere are certain limitations in our study. Firstly, our study was conducted in and around the healthcare facilities of Mangalore, a tier 2 city in India and, due to the limited geographical reach of the study, it may not be possible to generalize the results obtained. Secondly, we did not assess the mental health of the participants before the pandemic and hence their prior mental condition may act as a confounding factor in our study. Thirdly, we did not take into consideration the socio-economic parameters of the participants of our study. We recommend follow up studies to assess the progression of mental health among the HCWs after implementing workplace intervention measures for the betterment of their mental health.\n\nThe COVID-19 pandemic has had alarming implications for personal and collective health along with social and emotional functioning. The onus of maintaining the health of the society as well as the safety of their loved ones inserts a substantial stressor on the mental health of the frontline workers, especially the doctors and nurses in hospitals. The novel nature of the infection, inadequate testing, unknown long-term sequelae, limited availability of PPE, and extended work hours along with the other emerging concerns summate together potentially overwhelming these workers. Thus, it becomes important that the healthcare workers monitor their stress reactions, seek appropriate help both on a personal and professional level including professional mental health interventions if indicated.\n\n\nConclusions\n\nOur finding that 38% of the examined HCWs had clinically relevant anxiety symptoms and 49% of the participants had clinically relevant depression symptoms draws attention to the importance of systematically tracking the mental health of HCWs during this ongoing pandemic. The healthcare workers should monitor their stress reactions and seek appropriate help both on a personal and professional level. Appropriate workplace interventions including psychological support should be provided to HCWs, to ensure provision of uncompromised quality patient care.\n\n\nData availability\n\nOpen Science Framework: Covid 19 pandemic and mental health outcomes – A study among health care workers in Coastal South India. https://doi.org/10.17605/OSF.IO/J63Z5.33\n\nThis project contains the following extended data:\n\n• Data (Anonymized responses in excel sheet)\n\n• Data key (Codes for responses)\n\nOpen Science Framework: Covid 19 pandemic and mental health outcomes – A study among health care workers in Coastal South India. https://doi.org/10.17605/OSF.IO/J63Z5.33\n\nThis project contains the following extended data:\n\n• Questionnaire (Blank English copy of the questionnaire used in this study).\n\n• Information sheet and consent form.\n\n\nReporting guidelines\n\nOpen Science Framework: STROBE checklist for ‘Covid 19 pandemic and mental health outcomes – A study among health care workers in Coastal South India’. https://doi.org/10.17605/OSF.IO/J63Z5.33\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nWe thank the participants of the study, the Department of Community Medicine, Kasturba Medical College, Mangalore, and the Manipal Academy of Higher Education for their support for this research and its publication.\n\n\nReferences\n\nWorld Health Organization (WHO): WHO Coronavirus (COVID-19) Dashboard. Accessed on 27/02/2022. Reference Source\n\nMinistry of Health and Family Welfare (MoHFW): COVID-19 INDIA (Data Source MoHFW). Accessed on 27/02/2022. Reference Source\n\nKengadaran S, Divvi A, Kengadaran S: Violence among healthcare workers during COVID-19 pandemic in India. J Family Med Prim Care. 2021; 10(2): 1066–1067. PubMed Abstract | Publisher Full Text\n\nPandey V: Coronavirus: Doctors ‘Spat At and Attacked’ India: BBC News; 2020 April; 3. Accessed 25/02/2022. Reference Source\n\nYoung KP, Kolcz DL, O’Sullivan DM, et al.: Health Care Workers’ Mental Health and Quality of Life During COVID-19: Results from a Mid-Pandemic, National Survey. Psychiatr. Serv. 2021; 72(2): 122–128. PubMed Abstract | Publisher Full Text\n\nNumbeo: Health Care in Mangalore, India. Accessed on 26/02/2022. Reference Source\n\nGovernment of Karnataka (GoK): COVID 19 information portal. Accessed on 24/02/2022. Reference Source\n\nCharan J, Biswas T: How to calculate sample size for different study designs in medical research?. Indian J. Psychol. Med. 2013; 35: 121–126. PubMed Abstract | Publisher Full Text\n\nLai J, Ma S, Wang Y, et al.: Factors Associated with Mental Health Outcomes Among Health Care Workers Exposed to Coronavirus Disease 2019. JAMA Netw. Open. 2020; 3(3): e203976. PubMed Abstract | Publisher Full Text\n\nZhang YL, Liang W, Chen ZM, et al.: Validity and reliability of Patient Health Questionnaire-9 and Patient Health Questionnaire-2 to screen for depression among college students in China. Asia Pac. Psychiatry. 2013; 5(4): 268–275. PubMed Abstract | Publisher Full Text\n\nHe XY, Li CB, Qian J, et al.: Reliability and validity of a generalized anxiety scale in general hospital outpatients. Shanghai Arch. Psychiatry. 22(4): 200–203.\n\nYu DS: Insomnia Severity Index: psychometric properties with Chinese community-dwelling older people. J. Adv. Nurs. 2010; 66(10): 2350–2359. PubMed Abstract | Publisher Full Text\n\nWu KK, Chan KS: The development of the Chinese version of Impact of Event Scale–Revised (CIES-R). Soc. Psychiatry Psychiatr. Epidemiol. 2003; 38(2): 94–98. PubMed Abstract | Publisher Full Text\n\nSharma KK, Kaur R, Srinivasan M, et al.: Impact of COVID-19 on mental health of healthcare professionals working in COVID-19 designated clinical areas in India. Int. J. Community Med. Public Health. 2021; 8: 1406–1414. Publisher Full Text\n\nTan BYQ, Chew NWS, Lee GKH, et al.: Psychological Impact of the COVID-19 Pandemic on Health Care Workers in Singapore. Ann. Intern. Med. 2020; 173(4): 317–320. PubMed Abstract | Publisher Full Text\n\nManh Than H, Minh Nong V, Trung Nguyen C, et al.: Mental Health and Health-Related Quality-of-Life Outcomes Among Frontline Health Workers During the Peak of COVID-19 Outbreak in Vietnam: A Cross-Sectional Study. Risk Manag. Healthc. Policy. 2020; 13: 2927–2936. Publisher Full Text\n\nRossi R, Socci V, Pacitti F, et al.: Mental Health Outcomes Among Healthcare Workers and the General Population During the COVID-19 in Italy. Front. Psychol. 2020; 11: 608986. PubMed Abstract | Publisher Full Text\n\nKhanal P, Devkota N, Dahal M, et al.: Mental health impacts among health workers during COVID-19 in a low resource setting: a cross-sectional survey from Nepal. Glob. Health. 2020; 16(1): 89. PubMed Abstract | Publisher Full Text\n\nRobles R, Rodríguez E, Vega-Ramírez H, et al.: Mental health problems among healthcare workers involved with the COVID-19 outbreak. Braz. J. Psychiatry. 2021; 43(5): 494–503. Publisher Full Text\n\nWozniak H, Benzakour L, Moullec G, et al.: Mental health outcomes of ICU and non-ICU healthcare workers during the COVID-19 outbreak: a cross-sectional study. Ann. Intensive Care. 2021; 11(1): 106. PubMed Abstract | Publisher Full Text\n\nLai J, Ma S, Wang Y, et al.: Factors Associated with Mental Health Outcomes Among Health Care Workers Exposed to Coronavirus Disease 2019. JAMA Netw. Open. 2020; 3(3): e203976. PubMed Abstract | Publisher Full Text\n\nZhang C, Yang L, Liu S, et al.: Survey of Insomnia and Related Social Psychological Factors Among Medical Staff Involved in the 2019 Novel Coronavirus Disease Outbreak. Front. Psychiatry. 2020; 11: 306. PubMed Abstract | Publisher Full Text\n\nShah J, Monroe-Wise A, Talib Z, et al.: Mental health disorders among healthcare workers during the COVID-19 pandemic: a cross-sectional survey from three major hospitals in Kenya. BMJ Open. 2021; 11(6): e050316. PubMed Abstract | Publisher Full Text\n\nGhaleb Y, Lami F, Al Nsour M, et al.: Mental health impacts of COVID-19 on healthcare workers in the Eastern Mediterranean Region: a multi-country study. J. Public Health (Oxf.). 2021; 43(3): iii34–iii42. PubMed Abstract | Publisher Full Text\n\nKamberi F, Sinaj E, Jaho J, et al.: Impact of COVID-19 pandemic on mental health, risk perception and coping strategies among health care workers in Albania - evidence that needs attention. Clin. Epidemiol. Glob. Health. 2021; 12: 100824. PubMed Abstract | Publisher Full Text\n\nElkholy H, Tawfik F, Ibrahim I, et al.: Mental health of frontline healthcare workers exposed to COVID-19 in Egypt: A call for action. Int. J. Soc. Psychiatry. 2021; 67(5): 522–531. Publisher Full Text\n\nMattila E, Peltokoski J, Neva MH, et al.: COVID-19: anxiety among hospital staff and associated factors. Ann. Med. 2021; 53(1): 237–246. PubMed Abstract | Publisher Full Text\n\nAlharthy N, Alrajeh OA, Almutairi M, et al.: Assessment of Anxiety Level of Emergency Health-care Workers by Generalized Anxiety Disorder-7 Tool. Int. J. Appl. Basic Med. Res. 2017; 7(3): 150–154. PubMed Abstract | Publisher Full Text\n\nBadahdah A, Khamis F, Al Mahyijari N, et al.: The mental health of health care workers in Oman during the COVID-19 pandemic. Int. J. Soc. Psychiatry. 2021; 67(1): 90–95. PubMed Abstract | Publisher Full Text\n\nAbdullah Elmahdy M, Mahmoud SE: Mental Health Outcomes Among Health Care Workers Exposed to Covid-19 Pandemic, Qalyoubia Governorate: Cross-Sectional Survey. Egypt. J. Hosp. Med. 2021; 84: 1945–1954. Publisher Full Text\n\nTam CW, Pang EP, Lam LC, et al.: Severe acute respiratory syndrome (SARS) in Hong Kong in 2003: stress and psychological impact among frontline healthcare workers. Psychol. Med. 2004; 34(7): 1197–1204. Publisher Full Text\n\nSelikowitz A: 6. Mental health challenges for healthcare workers during the COVID-19 pandemic – psychological impact and management strategies. Accessed on 26/02/2022. Reference Source\n\nKumar N, Thapar R, Hegde K, et al.: COVID-19 Pandemic and Mental Health Outcomes – A study among Health Care Workers in Coastal South India.2022, April 20. Publisher Full Text"
}
|
[
{
"id": "142248",
"date": "19 Jul 2022",
"name": "Sunil Kumar Raina",
"expertise": [
"Reviewer Expertise Epidemiology"
],
"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 relevant in the context of the prevailing COVID 19 pandemic and the taxing effect it has, not only on the physical health of the HCWs, but also their mental health.\nThe manuscript is well written. However, there are few queries I would like the author to address in the manuscript.\nHas the questionnaire used in the study been validated?\n\nWas the questionnaire translated to the local vernacular language for the nurses?\n\nHow was the data collected?\n\nFor how many health care professionals' questionnaires were distributed in order to reach the required sample size? What was the non-response rate?\n\nHow can you attribute the present mental health status to COVID 19? Can it be due to existing mental health condition or health status prior to COVID 19 pandemic ? Did you gather information regarding past mental health status?\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": "8574",
"date": "04 Aug 2022",
"name": "Nithin Kumar",
"role": "Author Response",
"response": "Thank you for your review of our paper titled The COVID-19 pandemic and mental health outcomes – A cross-sectional study among health care workers in Coastal South India\" Kindly find our reply for your queries below: Has the questionnaire used in the study been validated? The Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder (GAD-7) scale, and Insomnia Severity Index (ISI) -all are standard questionnaires which are pre-validated. However, a pilot testing was carried out among 30 HCWs (15 doctors and 15 nurses), to check the usability/feasibility of the questionnaire. Based on the pilot testing, changes were made to Section A (General participant information)-like income of the participants and permanent addresses were removed. No changes were made to Section B (PHQ-9), Section C (GAD-7) and ISI (Section D). Was the questionnaire translated to the local vernacular language for the nurses? The questionnaires were not translated into the local vernacular language. Pre-validated standard questionnaire in English language was sent to all the study participants – doctors and nurses via google form link. All the nurses were proficient in English language. How was the data collected? To limit the personal contact with the study participants due to the prevailing pandemic, the questionnaire was prepared in Google forms and the link was sent to the participants via WhatsApp or email. For how many health care professionals' questionnaires were distributed in order to reach the required sample size? What was the non-response rate? To reach the sample size of 245 (128 doctors and 117 nurses), the link was sent to 280 health care workers, which included 150 doctors and 130 nurses. The response rate for doctors was 85.3% and 90.3% for nurses. How can you attribute the present mental health status to COVID 19? Can it be due to existing mental health condition or health status prior to COVID 19 pandemic? Did you gather information regarding past mental health status? Yes. We did not take into consideration the existing mental health condition of the health care professionals and that is the limitation of our study."
}
]
},
{
"id": "149463",
"date": "03 Oct 2022",
"name": "Devi Wulandari",
"expertise": [
"Reviewer Expertise Health psychology"
],
"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 work was clearly presented however the study cited 72% of current literature. Adding more current literature, especially in the introduction section will suffice.\n\nAppropriateness of study design. There is some information that needs to be completed in the method section, such as criteria for the cutoff score and information regarding the reliability of the measurement.\n\nStatistical analysis. There are some questionable interpretations such as the proportion of participants with depressive symptoms higher among doctors but in fact the result (chi square) was not significant.\n\nConclusion. Since there are several questionable results from the study, thus the conclusion were not adequately supported.\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": [
{
"c_id": "8911",
"date": "01 Nov 2022",
"name": "Nithin Kumar",
"role": "Author Response",
"response": "The work was clearly presented however the study cited 72% of current literature. Adding more current literature, especially in the introduction section will suffice. Response: Thank you sir. We have incorporated current literature in the introduction and discussion as per your suggestion. Appropriateness of study design. There is some information that needs to be completed in the method section, such as criteria for the cut off score and information regarding the reliability of the measurement. Response: Thank you sir. Since the scales used to assess depression, anxiety and insomnia in our study was standard, cut-offs scores mentioned by the scales were used. A note on reliability of the scales have been added in the methods section. The cut-off scores used are also mentioned in the methods section. Statistical analysis. There are some questionable interpretations such as the proportion of participants with depressive symptoms higher among doctors but in fact the result (chi square) was not significant. Response: Thank you sir for pointing out the error. We have modified the statement and added the P value so that the interpretation is clear. Conclusion. Since there are several questionable results from the study, thus the conclusion were not adequately supported. Response: The conclusion has been re-written according to the results."
}
]
}
] | 1
|
https://f1000research.com/articles/11-676
|
https://f1000research.com/articles/12-195/v1
|
20 Feb 23
|
{
"type": "Genome Note",
"title": "The complete mitochondrial genome of the hybrid snow crab Chionoecetes opilio (♀) × C. japonicus (♂) (Crustacea: Decapoda: Majoidea) and its phylogenetic analysis",
"authors": [
"Bong Han Yun",
"Yong Hwi Kim",
"Ho-Seop Han",
"Hye Jin Kim",
"Jong Yeon Park",
"In-Chul Bang",
"Bong Han Yun",
"Yong Hwi Kim",
"Ho-Seop Han",
"Hye Jin Kim",
"Jong Yeon Park"
],
"abstract": "We report the complete mitochondrial genome of a hybrid snow crab between a female Chionoecetes opilio and male C. japonicus. The circular genome was 16,065 bp in length, and consisted of 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and a control region. The composition and arrangement of its complete mitochondrial genome were very similar to that reported for the maternal species, C. opilio. The close genetic relationship is reflected in the phylogenetic tree and supports maternal inheritance patterns.",
"keywords": [
"Chionoecetes opilio",
"Chionoecetes japonicus",
"Chionoecetes",
"hybrid",
"mitogenome"
],
"content": "Introduction\n\nThe snow crab, Chionoecetes opilio Fabricius, 1788 and red snow crab, C. japonicus Rathbun, 1932 are important fishery resources in the Republic of Korea. As their commercial value increases, resource management is very important. Therefore, it is essential to obtain molecular genetic data to support their resource management (Waples et al. 2008).\n\nHybridization is an interesting phenomenon that plays an important evolutionary role in speciation (Barton 2001). Natural hybridization between female C. japonicus and male C. opilio has been reported (Kim et al. 2012; Yamamoto et al. 2018), but the reciprocal cross has not yet been reported. We identified a hybrid between a female C. opilio and male C. japonicus based on the maternally inherited mitochondrial genome and internal transcribed spacer (ITS) gene of the nuclear DNA (Yun 2023), where recombination between parental species occurs (Figure 1). Characterizing the mitochondrial genome of this hybrid snow crab will aid evolutionary and phylogenetic studies of the genus Chionoecetes.\n\nDouble peaks indicate by red arrows.\n\n\nMethods\n\nThe sample used for this study was a snow crab and as per the animal experimental ethics of the Republic of Korea (Standard operating guideline; IACUC - Institutional Animal Care and Use Committee, Book no. 11-1543061-000457-01, effective from December 2020) we did not need any approval from an ethics committee. Also, because the sample is a snow crab, there was no need to obtain permission to collect the sample.\n\nA hybrid between a C. opilio female and C. japonicus male was collected offshore of Ganggu (36°28′52.08″N, 129°59′09.36″E, the East Sea, Republic of Korea) on 1 June 2020, and deposited in the specimen storage facility of Soonchunhyang University (Voucher no. SUC26327; the person in charge of the collection is I.-C. Bang: incbang@gmail.com). Genomic DNA (gDNA) was extracted from walking leg muscle using a HiGene™ Genomic DNA Prep Kit (BIOFACT, Daejeon, Republic of Korea; Cat. No. GD264-060) according to the manufacturer's protocol.\n\nIn order to clearly identify a hybrid snow crab, forward and reverse primers [crabITSw_F (5′- TCGAGCTGACGGAAAGATGT -3′) and crabITSw_R (5′- GCAAGTCTCCCTCTCGTCTT -3′)] were newly designed to amplify the nuclear ITS gene in this study (Yun 2023). A PCR run was conducted with a 20 μL reaction volume using the AccuPower PCR Premix Kit (Bioneer, Daejeon, Republic of Korea; Cat. No. K-2016) containing 0.2 μM of the forward and reverse primers and 1 μL of gDNA (100 ng μL-1). PCR cycling conditions were 94°C/5 min, [94°C/30 s, 60°C/30 s, 72°C/30 s × 35 cycles], 72°C/7 min. PCR product was purified using the AccuPrep PCR Purification Kit (Bioneer, Daejeon, Republic of Korea; Cat. No. K-3038) and directly sequenced on the Applied Biosystems 3730XL DNA Analyzer (Thermo Fisher Scientific Inc., Waltham, USA).\n\nA genomic library for next-generation sequencing (NGS) was constructed from the extracted gDNA using an MGIeasy DNA Library Prep Kit (MGI Tech, Shenzhen, China; Cat. No. 1000006985). After producing NGS raw data using an MGISEQ-2000 (MGI Tech, Shenzhen, China), the entire mitochondrial DNA sequence of the 16,065 bp circular molecule was assembled using Geneious R11 (RRID:SCR_010519) (Kearse et al. 2012), and the final assembled sequence was further annotated using MITOS web server (Bernt et al. 2013), a web-based automatic annotation server.\n\nFor the phylogenetic analysis, 13 protein-coding genes (PCGs) for species in the superfamily Majoidea were obtained from NCBI, and their sequences were aligned with Clustal W2 (RRID:SCR_002909) (Thompson et al. 1994). The aligned sequences were used to reconstruct a maximum-likelihood (ML) tree consisting of 1000 bootstrap replications using raxmlGUI 2.0.9 (RRID:SCR_006086) (Edler et al. 2021) and a Bayesian inference (BI) tree running for 1,000,000 generations using MrBayes 3.2.7 (RRID:SCR_012067) (Ronquist et al. 2012). The substitution model was selected according to the corrected Akaike information criterion (AICc) using jModelTest 2.1.10 (RRID:SCR_015244) (Darriba et al. 2012), and the best model (GTR+I+G) was applied for ML and BI tree reconstructions. Scylla paramamosain in the superfamily Portunoidea was used as the outgroup (Figure 2).\n\nBootstrap values (left) > 60% in the maximum likelihood (ML) tree and posterior probabilities (right) > 0.60 for the Bayesian inference (BI) tree are indicated at each node. GenBank accession numbers for each species are given, along with the scientific name.\n\n\nResults\n\nThe complete mitochondrial genome of the hybrid between a female C. opilio and male C. japonicus (GenBank acc. no. OP787103) was circular, 16,065 bp in length, and contained 13 PCGs, 22 transfer RNA (tRNA) genes, two ribosomal RNA (rRNA) genes, and a control region. Of the 13 PCGs, nine (atp6, atp8, co1, co2, co3, cytb, nd2, nd3, and nd6) were encoded on the H-strand while four (nd1, nd4, nd4L, and nd5) were encoded on the L-strand. All PCGs had ATN start codons (ATG, n = 8; ATT, n = 3; ATA and ATC, both n = 1). There were five incomplete stop codons (co1, co2, co3, cytb, and nd2) and eight complete stop codons (TAA or TAG). The 16S and 12S rRNA genes were 1,312 and 815 bp long, respectively. The 22 tRNA genes ranged in length from 61 bp (tRNA-Arg) to 73 bp (tRNA-Val, Gln). The overall base composition was 34.61% A, 17.40% C, 10.99% G, and 37.00% T, indicating a strong AT bias, as in other Crustacea (Kim et al. 2020; An et al. 2021). In addition, the size, composition, and gene arrangement of the complete mitochondrial genome were very similar to that reported for the maternal species, C. opilio (Jeong et al. 2020).\n\nIn the phylogenetic tree, the hybrid snow crab between a C. opilio female and C. japonicus male was more closely related to the maternal species, C. opilio. In addition, C. opilio and C. japonicus form a sister clade, supporting previous studies (Azuma et al. 2011; Kim et al. 2020). This study provides important basic genetic data for resource management of C. opilio and C. japonicus, and will aid evolutionary and phylogenetic studies of both species.",
"appendix": "Data availability\n\nMendeley Data: Underlying data for ‘The complete mitochondrial genome of the hybrid snow crab Chionoecetes opilio (♀) × C. japonicus (♂) (Crustacea: Decapoda: Majoidea) and its phylogenetic analysis’. http://dx.doi.org/10.17632/cp5x8fbpsw.3 (Yun 2023).\n\nThis project contains the following underlying data:\n\n• Data file 1: Chionoecetes opilio × C. japonicus mitogenome.fasta (Sequence information)\n\n• Data file 2: Chromatogram files and sequence files.zip (Sanger sequencing data)\n\n• Data file 3: PCR gel photograph.jpg (ITS gene, about 1,485 bp)\n\n• Data file 4: PCR and sequencing method.doc (Information relating to primers, reagents and kits, cycling conditions, and sequencing)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)\n\nNCBI Gene: Chionoecetes opilio × Chionoecetes japonicus mitochondrial DNA, complete genome. Accession number OP787103; https://www.ncbi.nlm.nih.gov/nuccore/OP787103\n\nBioProject: Chionoecetes opilio × Chionoecetes japonicus. Accession number PRJNA867912; https://identifiers.org/NCBI/bioproject:PRJNA867912\n\nSRA: Chionoecetes opilio × Chionoecetes japonicus. Accession number SRR20997454; https://identifiers.org/insdc.sra:SRR20997454\n\nBioSample: Invertebrate sample from Chionoecetes opilio × Chionoecetes japonicus. Accession number SAMN30221420; https://identifiers.org/biosample:SAMN30221420\n\nNCBI Gene: Chionoecetes opilio mitochondrion, complete genome. Accession number MT335860; https://www.ncbi.nlm.nih.gov/nuccore/MT335860\n\nNCBI Gene: Chionoecetes japonicus mitochondrion, complete genome. Accession number MT750295; https://www.ncbi.nlm.nih.gov/nuccore/MT750295\n\nNCBI Gene: Chionoecetes japonicus pacificus mitochondrial DNA, complete genome. Accession number AB735678; https://www.ncbi.nlm.nih.gov/nuccore/AB735678\n\nNCBI Gene: Maja squinado mitochondrion, complete genome. Accession number KY650652; https://www.ncbi.nlm.nih.gov/nuccore/KY650652\n\nNCBI Gene: Maja crispata mitochondrion, complete genome. Accession number KY650651; https://www.ncbi.nlm.nih.gov/nuccore/KY650651\n\nNCBI Gene: Damithrax spinosissimus mitochondrion, complete genome. Accession number KM405516.1; https://www.ncbi.nlm.nih.gov/nuccore/KM405516\n\nNCBI Gene: Scyra compressipes mitochondrion, complete genome. Accession number MW451225; https://www.ncbi.nlm.nih.gov/nuccore/MW451225\n\nNCBI Gene: Scylla paramamosain mitochondrion, complete genome. Accession number MG197997; https://www.ncbi.nlm.nih.gov/nuccore/MG197997\n\n\nReferences\n\nAn HE, Choi TJ, Kim CB: The complete mitochondrial genome of Scyra compressipes Stimpson, 1857 (Decapoda: Epialtidae). Mitochondrial DNA B: Resour. 2021; 6(3): 1087–1088. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAzuma N, Grant WS, Templin WD, et al.: Molecular phylogeny of a red-snow-crab species complex using mitochondrial and nuclear DNA markers. Zool. Sci. 2011; 28(4): 286–292. PubMed Abstract | Publisher Full Text\n\nBarton NH: The role of hybridization in evolution. Mol. Ecol. 2001; 10(3): 551–568. PubMed Abstract\n\nBernt M, Donath A, Jühling F, et al.: MITOS: Improved de novo metazoan mitochondrial genome annotation. Mol. Phylogenet. Evol. 2013; 69(2): 313–319. PubMed Abstract | Publisher Full Text\n\nDarriba D, Taboada GL, Doallo R, et al.: jModelTest 2: more models, new heuristics and parallel computing. Nat. Methods. 2012; 9(8): 772. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEdler D, Klein J, Antonelli A, et al.: raxmlGUI 2.0: A graphical interface and toolkit for phylogenetic analyses using RAxML. Methods Ecol. Evol. 2021; 12(2): 373–377. Publisher Full Text\n\nJeong JH, Ryu S, Kim W: The complete mitogenome of the Chionoecetes opilio (Crustacea: Decapoda: Oregoniidae) and its unique characteristics. Mitochondrial DNA B: Resour. 2020; 5(3): 2550–2552. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKearse M, Moir R, Wilson A, et al.: Geneious Basic: An integrated and extendable desktop software platform for the organization and analysis of sequence data. Bioinformatics. 2012; 28(12): 1647–1649. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKim WJ, Jung HT, Chun YY, et al.: Genetic evidence for natural hybridization between red snow crab (Chionoecetes japonicus) and snow crab (Chionoecetes opilio) in Korea. J. Shellfish Res. 2012; 31(1): 49–56. Publisher Full Text\n\nKim YH, Kim KR, Park JY, et al.: The complete mitochondrial genome of Chionoecetes japonicus (Crustacea: Decapoda: Majoidea). Mitochondrial DNA B: Resour. 2020; 5(3): 3524–3526. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRonquist F, Teslenko M, van der Mark P , et al.: MrBayes 3.2: efficient bayesian phylogenetic inference and model choice across a large model space. Syst. Biol. 2012; 61(3): 539–542. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThompson JD, Higgins DG, Gibson TJ: CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic. Acids Res. 1994; 22(22): 4673–4680. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWaples RS, Punt AE, Cope JM: Integrating genetic data into management of marine resources: how can we do it better? Fish Fish (Oxf). 2008; 9(4): 423–449. Publisher Full Text\n\nYamamoto T, Yanagimoto T, Kodama K: A natural hybrid female of Chionoecetes opilio and C. japonicus collected in the coastal water of Fukui Prefecture. Cancer. 2018; 27: 61–66.\n\nYun BH: Complete mitochondrial genome Chionoecetes opilio × C. japonicas. [Data]. Mendeley Data. Version 1. 2023. Publisher Full Text"
}
|
[
{
"id": "165825",
"date": "16 May 2023",
"name": "Jongwoo Jung",
"expertise": [
"Reviewer Expertise Invertebrate taxonomy"
],
"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 paper reports the results of determining the complete mitochondrial genome sequence of a hybrid snow crab found in Korea and analyzing its phylogenetic position. The genetic characteristics of mitochondria of natural hybrid individuals were reported. There is nothing special to point out, and it is a paper suitable for publication.\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? 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? Yes",
"responses": []
},
{
"id": "178195",
"date": "17 Jul 2023",
"name": "Christopher M Austin",
"expertise": [
"Reviewer Expertise Crustacean mitogenomics"
],
"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\nIt is confusing that the authors state from the out set that the individual crab under study is both a hybrid and is the result of a female C. opilio and male C. japonicus mating without any justification.\nA better approach would be to state that a suspected hybrid crab was caught and that the Sanger sequencing of the ITS region and the NGS derived mitogenome indicates that it is from a female C. opilio and male C. japonicus mating.\nNot enough detail is given on how the the mitogenome sequence was obtained from the NGS data. Was it from a denovo - assembly or mapping to a reference and how much data was generated and level of coverage was achieved?\nAlso the authors can use the NGS data to extract the ITS region and confirm their results from the Sanger sequences (and potential other nuclear genes).\n\nAre the rationale for sequencing the genome and the species significance clearly described? Partly\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? 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": []
}
] | 1
|
https://f1000research.com/articles/12-195
|
https://f1000research.com/articles/12-194/v1
|
20 Feb 23
|
{
"type": "Research Article",
"title": "Effect of ACTH4-10Pro8-Gly9-Pro10 on anti-inflammatory cytokine (IL-4, IL-10, IL-13) expression in acute spinal cord injury models (male Sprague Dawley rats)",
"authors": [
"Asadullah Asadullah",
"Abdul Hafid Bajamal",
"Muhammad Arifin Parenrengi",
"Agus Turchan",
"Budi Utomo",
"I Ketut Sudiana",
"Eko Agus Subagio",
"Asadullah Asadullah",
"Abdul Hafid Bajamal",
"Muhammad Arifin Parenrengi",
"Agus Turchan",
"Budi Utomo",
"I Ketut Sudiana"
],
"abstract": "Background: Spinal cord injury (SCI) is a damage to the spinal cord caused mainly by trauma resulting in major motor, sensory and autonomic dysfunctions. Its final neurological outcome is determined by both primary and secondary injury processes. A key component of secondary injury mechanisms after initial trauma is neuroinflammation. A neuroprotective compound, ACTH4-10Pro8-Gly9-Pro10 (ACTH4-10) also known as semax, has shown neuroprotective and anti-inflammatory properties. ACTH4-10 has also been actively used in the treatment of brain ischemia without serious complication reported. Here, we analyzed the effects of ACTH4-10 at regulating the inflammatory cascade in SCI by looking at anti-inflammatory cytokine (IL-4, IL-10 and IL-13) levels after acute SCI. Method: We carried out laminectomies in male Sprague Dawley rats at the second thoracic vertebrae. After laminectomy, we exposed the myelum and created mild SCI models with 20-g, and severe SCI with 35-g aneurysm clips. ACTH4-10 was administered intranasally to the treatment group and 0.9% NaCl to the control group (placebo). Both groups were kept alive and terminated at 3 and 6 hours. The tissue sample preparations were fixed in formalin and examined for immunohistochemistry. Quantitative measurement of the cytokines was done in the posterior horn area with specific associated anti-monoclonal antibodies. Results: Rats with mild SCI that were given ACTH4-10 showed greater anti-inflammatory levels at 3 hours post-compression but only IL-10 and IL-13 were elevated significantly at 6 hours. Rats with severe compression in ACTH4-10 group showed greater levels of IL-10, IL-13 at 3 hours and IL-4, IL-10 at 6 hours compared with the placebo group. Conclusions: Administration of ACTH4-10Pro8-Gly9-Pro10 intranasal can increase anti-inflammatory cytokine expression in Sprague Dawley rat models with mild and severe SCI. Expression of anti-inflammatory cytokines was greater in mild compression and 3-hour termination. Further research is needed to determine the optimal dose and clinical outcome in vivo.",
"keywords": [
"Spinal Cord Injury",
"Anti inflammatory cytokine",
"Neuroprotector",
"Experimental",
"Laminectomy"
],
"content": "Introduction\n\nSpinal cord injury (SCI) is a pathological condition that is known to cause severe neurological deterioration resulting in physical dependency, morbidity, mortality and financial burden for decades.1 Even tough significant research has been conducted to develop effective treatments for SCI, until now none of these treatments has shown any meaningful effect to improve functional outcome after injury.2\n\nDemographic data suggest that SCI mainly affects the male population with over 80% cases occurring in males between 25 to 45 year of age.3 Interestingly, not only do males have a higher incidence rate of SCI, but some studies have also shown males tend to have worse recovery rates compared with females.4 This phenomenon is thought to be caused by female sex hormone such as progesterone and estrogen, that have shown modest neuroprotective behaviour in brain injury.5\n\nIn general, pathophysiology of traumatic SCI comprises primary and secondary injury. The primary injury is caused by the initial traumatic event such as compression, distraction, laceration and transection; this kind of injury causes irreversible damage to the spinal cord. In contrast, secondary injury, including processes such as neuroinflammation, spinal cord ischemia, and cellular excitotoxicity which begin soon after the initial trauma, give a window of opportunity to prevent further damage of the spinal cord. Therefore, managing secondary injuries remains the main target for SCI treatment.6,7\n\nAbove all the potential threats from secondary SCI, neuroinflammation is thought to be the key component causing many local and systemic consequences. It is known that injury to the spinal cord initiates an inflammatory-mediated response that could alter the repair processes within the nervous system and cause more damage to the nerves. Therefore, managing inflammation is thought to be an important factor for optimizing the outcome of SCI.8\n\nInflammation response in the spinal cord begins after macrophages activation and recruitment at the site of injury; activation of these macrophages could work in different pathways promoting, but also inhibiting the inflammation. Macrophages initiate inflammation by releasing pro-inflammatory cytokines (IL-1, IL-6, IL-8, IFN-γ and TNF-α) and other chemical mediators. After three or four days, macrophages that initiate and maintain the inflammation will then be deactivated by anti-inflammatory cytokines (IL-4, IL-10, IL-13 and TGF-β) that are also mainly produced by macrophages. The way that macrophages could regulate the inflammatory process is through the activation and counterbalance of pro- and anti-inflammatory cytokines. This balance determines the net effect of the inflammatory response in SCI.9,10\n\nACTH4-10Pro8-Gly9-Pro10 is an adrenocorticotropic hormone analogue that is known to have an anti-inflammatory effect.11 It has also been used in many conditions such as stroke, traumatic brain injury and Alzheimer disease as a neuroprotective agent with no report of serious complications.12\n\nThis experimental study was intended to show the effect of ACTH4-10 administration on anti-inflammatory cytokine levels in the spinal cord after acute SCI.\n\n\nMethods\n\nIn this study we used 12-week-old male Sprague Dawley rats weighing 250-300 g to reproduce homogenous sample for SCI models and eliminate confounding factor such as sex hormone. This animal study obtained ethical clearance by the Airlangga University animal care and use committee number 2.KE.094.07.2021 to ensure all effort was taken to reduce animal suffering. After randomization, 27 samples were divided into nine groups of three samples each. Laminectomy at the level of second thoracic vertebra was performed on all the samples. We took one group with the spinal cord left uninjured as a baseline control. The other samples became the treatment groups, in which SCI was performed by compressing the spine using an aneurysm clip in one minute with a clamping force of 20 g to reproduce mild SCI (four groups) and 35 g for severe SCI models (four groups).13 The laminectomy site was then closed with sutures and the Sprague Dawley rats were kept alive.\n\nAfter closing the suture, all treatment groups were divided into two subgroups. Placebo control groups were given 0.9 % NaCl intranasally, while the positive treatment groups were given ACTH4-10Pro8-Gly9-Pro10 intranasally at a 300 mg/kg dose. Each group was divided again into two groups to be respectively terminated at 3 hours and 6 hours after compression. Myelum transection was performed at the level of injured myelum after the termination.\n\nSCI myelum samples were fixed in 10% formalin and examined for IHC with specific monoclonal antibodies for each of IL-4, IL-10 and IL-13. Examination was done on the posterior horn of myelum to ensure homogenous sampling area in each group. Then anti-inflammatory cytokines were counted per 100 cells using associated anti-monoclonal antibodies and viewed with a light microscope at 1000× magnification. Cells with a brown colour in the cytoplasm showed positive expression of each anti-inflammatory cytokine.\n\nThe result of cytokine level measurements in each group are shown in a relative expression graph. Normality data analysis was performed using a Shapiro-Wilk test. Normally distributed data were analyzed with ANOVA while the data with non-normal distribution were analyzed using a Kruskal-Wallis test, followed by a non-parametric Mann-Whitney U test.\n\n\nResults\n\nWe carried out an experimental study in 27 male Sprague Dawley rats weighing 250-300 g, we severed the spinal cords in the area of injury, then we fixed the specimen with formalin. The specimen was then cut into 4-6 μm-thick slices with rotatory microtome and mounted on glass slides before further staining as seen in Figure 1.\n\nAfter immunohistochemistry staining with each specific antibody we examined the posterior horn area and counted stained cell number per 100 cells with a light microscope at 1000× magnification. Positive cells appeared brown as seen in Figure 2.\n\nImmunoreacted neutrophil cytoplasm that stained brown after using monoclonal antibodies are shown. White arrows mark positive stained neutrophils for IL-4 (A), IL-10 (B) and IL-13 (C) in mild spinal cord injury (SCI) group.\n\nTable 1 shows higher IL-4 levels in both mild and severe SCI models with ACTH4-10Pro8-Gly9-Pro10 administration that were terminated after three and six hours, compared to the placebo group.\n\n* p < 0.05.\n\nTable 2 shows higher IL-10 levels in both mild and severe SCI models with ACTH4-10Pro8-Gly9-Pro10 administration and who were terminated after three and six hours compared to the placebo group.\n\n* p < 0.05.\n\nTable 3 shows higher IL-13 levels in both mild and severe SCI models with ACTH4-10Pro8-Gly9-Pro10 administration and who were terminates after three and six hours compared to the placebo group.\n\n* p < 0.05.\n\nUsing Shapiro-Wilk test, we found our data had a normal distribution; further statistical analysis was carried out with a post hoc study using the Tukey method (Tables 4-9).\n\n* p < 0.05.\n\n* p < 0.05.\n\n* p < 0.05.\n\n* p < 0.05.\n\n* p < 0.05.\n\n* p < 0.05.\n\nMean levels of IL4, IL-10 and IL-13 were higher in the mild SCI models group that was given ACTH4-10Pro8-Gly9-Pro10 for both three- and six-hour termination groups, compared with placebo. IL-14 levels in models given ACTH4-10Pro8-Gly9-Pro10 at three and six hours were 10.39 and 8.05 respectively, and 6.29 and 5.61 respectively in the placebo group. IL-10 levels in ACTH4-10Pro8-Gly9-Pro10 at three and six hours were 14.64 and 11.46 respectively, while in the placebo group they were 6.86 and 4.71 respectively. IL-13 levels in ACTH4-10Pro8-Gly9-Pro10 at three and six hours were 13.36 and 11.57 respectively, and 7.86 and 6.25 respectively in the placebo group. Post hoc analysis with Tukey test showed significant differences in IL-4, IL-10 and IL-13 at three hours, and in IL-10 and IL-13 at six hours.\n\nThe results from severe SCI models that were given ACTH4-10Pro8-Gly9-Pro10 also showed higher mean IL-4, IL-10 and IL-13 levels compared with placebos in the three-hour and six-hour groups. IL-4 levels in ACTH4-10Pro8-Gly9-Pro10 at three and six hours were 9.36 and 9.21 respectively, and 7.82 and 5.29 respectively in the placebo. IL-10 levels in ACTH4-10Pro8-Gly9-Pro10 at three and six hourswas 13.25 and 9.54 respectively, while in placebos they were 7.07 and 5.71, respectively. IL-13 levels in models administered ACTH4-10Pro8-Gly9-Pro10 at three and six hours were 10.18 and 9.00 respectively, while in placebo they were 5.79 and 5.68 respectively. Post hoc analysis with Tukey test showed significant differences in IL-10 and IL-13 levels at three hours, and in IL-4 and IL-10 at six hours. Overall, level of anti-inflammatory cytokines were higher in each treatment group compared with placebo; the levels were significantly higher in models with mild SCI and terminated three hours after injury.\n\n\nDiscussion\n\nInflammation following the primary spinal cord injury is known to cause further spinal cord damage, resulting in apoptosis of oligodendrocyte, demyelination and degradation of axons, and neuronal cell death. Many attempts were made to reduce this deleterious effect caused by inflammation after initial injury occurrs.14\n\nNeuroinflammation following the primary injury is predominantly regulated by the balance of macrophage activation.15 In order to regulate this inflammation cascade, macrophages play a key role by releasing pro- or anti-inflammatory cytokine. Studies in SCI models have shown that some pro-inflammatory cytokines like TNF-α, IL-1, and IL-6 are found upregulated within an hour after injury, leading to further inflammatory response causing neuronal apoptosis.16 In contrast, anti-inflammatory cytokines that are capable of altering macrophage activity, such as IL-4, IL-1316–19 and IL-10 which can directly inhibiting other pro-inflammatory cytokines, are generally present at low levels after SCI.20,21\n\nWe realize sex hormone like estrogen and progesterone have some immunosuppressive profile in SCI22; to minimize this potentially confounding factor that might bias the outcome we only used male Sprague Dawley rats in this study. Our study found significantly higher IL-4, IL-10 and IL-13 levels in the mild SCI group that was terminated after three hours, and higher IL-10, IL-13 levels in the six-hour termination group that was given ACTH4-10. In the severe SCI group that were given ACTH4-10, we found higher IL-10, IL-13 levels in the group that was terminated after three hours, and higher IL-4 and IL-10 levels after six hours.\n\nCompared with mild SCI, in the severe SCI group inflammation was more pronounced and abundant in pro-inflammatory cytokines. These pro-inflammatory cytokines in turn could suppress the release of anti-inflammatory cytokines. In addition, inflammation that occurs in SCI rat models is known to begin one hour after injury and reach its peak at six hours after injury.23 This may explain our finding that in the group with severe SCI and termination six hours after injury, anti-inflammatory cytokine expression ratio between the ACTH4-10Pro8- Gly9-Pro10 and placebo groups was not as high as in the mild SCI and three-hour group.\n\nACTH4-10Pro8-Gly9-Pro10 is an analogue of adrenocorticotropic hormone and is created from a fragment of ACTH(4–7) combined with C-terminal tripeptide Pro-Gly-Pro, which acts as a neuroprotective compound.24 Similar to its analogue, ACTH4-10Pro8-Gly9-Pro10 is said to bind at the melanocortin receptor promoting anti-inflammatory and neuroprotective effects.25 Activated melanocortin receptors could supress pro-inflammatory cytokine release and promote the anti-inflammatory cytokine release. Together, this condition could supress inflammation.26\n\nMethylprednisolone sodium succinate (MP) became the most discussed treatment in the last three to four decades for reducing the deleterious effect caused by inflammation after initial injury occurs. The first study that was conducted in the early 1980s showed a promising potential neuroprotective effect of MP in reducing inflammation after acute SCI in a preclinical setting. This study has led many clinicians to do more extensive research (NASCIS I and II).27,28 This large-scale randomized control trial showed that there was a statistical improvement in neurological outcomes in the treatment group compared with the placebo if MP was administered within less than eight hours after initial injury.28,29 However, with an average increase of just five points in the American Spinal Injury Association (ASIA) impairment score compared with the placebo, this was said to not be clinically significant in the overall quality of life of the patient. Moreover, along with the limited overall improvement, a high dose of MP came with several complications, such as increased rate of infection along with gastrointestinal haemorrhages.30,31 Considering the limited benefit and potential morbidity or even life-threatening complications, in 2013 the American Association of Neurological Surgeon (AANS) ruled out MP administration from the current recommendations for managing patients with SCI.32,33\n\nOur finding showing increased levels of anti-inflammatory cytokines in the treatment group complements previous studies that revealed ACTH4-10Pro8-Gly9-Pro10 could decrease pro-inflammatory cytokines in SCI rats model.34,35 Those studies might provide a fundamental basis showing ACTH4-10Pro8- Gly9-Pro10 could reduce inflammation and potentially prevent secondary injury in SCI. To date, ACTH4-10Pro8- Gly9-Pro10 has been used as a neuroprotective agent for stroke and Alzheimer patients with no report of serious complications. It has also been given through the intranasal route and has a rapid onset within minute, allowing this drug to be given early on after the initial injury. Finally, we see potential benefits from ACTH4-10Pro8- Gly9-Pro10 to reduce inflammation and its deleterious effect on secondary injury after SCI.\n\n\nConclusions\n\nAdministration of ACTH4-10Pro8-Gly9-Pro10 can increase anti-inflammatory cytokine levels in Sprague Dawley rat models with mild and severe SCI. Rats with mild compression that were terminate after three hours showed an increase in IL-4, IL-10 and IL-13; after six hours, only IL-10 and IL-13 were increased. Rats with severe compression that were terminate after three hours showed an increase in IL-10 and IL-13; after six hours, only IL-4, IL-10 were increased. Further studies are needed to determine the optimal dose and functional outcome in rats with SCI.",
"appendix": "Data availability\n\nDRYAD: Effects of ACTH4-10Pro8-Gly9-Pro10 on anti-inflammatory cytokine (IL-4, IL-10, IL-13) expression in acute spinal cord injury model (Sprague Dawley rats), https://doi.org/10.5281/zenodo.7446188. 36\n\nZenodo: Effects of ACTH4-10Pro8-Gly9-Pro10 on anti-inflammatory cytokine (IL-4, IL-10, IL-13) expression in acute spinal cord injury model (Sprague Dawley rats), https://doi.org/10.5281/zenodo.7568360. 37\n\nZenodo: ARRIVE checklist for “Effect of ACTH4-10Pro8-Gly9-Pro10 on anti-inflammatory cytokine (IL-4, IL-10, IL-13) expression in acute spinal cord injury models (male Sprague Dawley rats)”, https://doi.org/10.5281/zenodo.7568360. 37\n\nData are available under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0).\n\n\nReferences\n\nKhorasanizadeh M, Yousefifard M, Eskian M, et al.: Neurological recovery following traumatic spinal cord injury: a systematic review and meta-analysis. J. Neurosurg. Spine. February 2019; 30: 683–699. PubMed Abstract | Publisher Full Text\n\nHellenbrand DJ, Quinn CM, Piper ZJ, et al.: Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration. J. Neuroinflammation. 2021; 18(1): 284. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen Y, He Y, DeVivo MJ: Changing Demographics and Injury Profile of New Traumatic Spinal Cord Injuries in the United States, 1972-2014. Arch. Phys. Med. Rehabil. 2016; 97(10): 1610–1619. PubMed Abstract | Publisher Full Text\n\nWilson JR, Cadotte DW, Fehlings MG: Clinical predictors of neurological outcome, functional status, and survival after traumatic spinal cord injury: a systematic review. J. Neurosurg. Spine. 2012; 17(1 Suppl): 11–26. PubMed Abstract | Publisher Full Text\n\nStein DG, Hoffman SW: Estrogen and progesterone as neuroprotective agents in the treatment of acute brain injuries. Pediatr. Rehabil. 2003; 6(1): 13–22. Publisher Full Text\n\nEckert MJ, Martin MJ: Trauma: Spinal Cord Injury. Surg. Clin. North Am. 2017; 97(5): 1031–1045. Publisher Full Text\n\nWitiw CD, Fehlings MG: Acute Spinal Cord Injury. J. Spinal Disord. Tech. 2015; 28(6): 202–210. Publisher Full Text\n\nPopovich PG, Stuckman S, Gienapp IE, et al.: Alterations in immune cell phenotype and function after experimental spinal cord injury. J. Neurotrauma. 2001; 18(9): 957–966. PubMed Abstract | Publisher Full Text\n\nMurray PJ, Wynn TA: Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 2011; 11(11): 723–737. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFujiwara N, Kobayashi K: Macrophages in inflammation. Curr. Drug Targets Inflamm. Allergy. 2005; 4(3): 281–286. Publisher Full Text\n\nFaris M, Utomo B, Al Fauzi A , et al.: ACTH4-10PRO8-GLY9-PRO10 improves Neutrophil profile in spinal cord injury of rat models. J Adv Pharm Educ Res. 2021; 11(2): 61–65. Publisher Full Text\n\nKolomin T, Shadrina M, Slominsky P, et al.: A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides. Neurosci Med. 2013; 04: 223–252. Publisher Full Text\n\nPoon PC, Gupta D, Shoichet MS, et al.: Clip compression model is useful for thoracic spinal cord injuries: histologic and functional correlates. Spine (Phila Pa 1976). 2007; 32(25): 2853–2859. PubMed Abstract | Publisher Full Text\n\nFleming JC, Norenberg MD, Ramsay DA, et al.: The cellular inflammatory response in human spinal cords after injury. Brain. 2006; 129(Pt 12): 3249–3269. Publisher Full Text\n\nGensel JC, Zhang B: Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res. 2015; 1619: 1–11. PubMed Abstract | Publisher Full Text\n\nDiSabato DJ, Quan N, Godbout JP: Neuroinflammation: the devil is in the details. J. Neurochem. 2016; 139(Suppl 2): 136–153. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcCormick SM, Heller NM: Commentary: IL-4 and IL-13 receptors and signaling. Cytokine. 2015; 75(1): 38–50. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGordon S, Martinez FO: Alternative activation of macrophages: mechanism and functions. Immunity. 2010; 32(5): 593–604. Publisher Full Text\n\nJunttila IS: Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes. Front. Immunol. 2018; 9: 888. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHellenbrand DJ, Reichl KA, Travis BJ, et al.: Sustained interleukin-10 delivery reduces inflammation and improves motor function after spinal cord injury. J. Neuroinflammation. 2019; 16(1): 93. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThompson CD, Zurko JC, Hanna BF, et al.: The therapeutic role of interleukin-10 after spinal cord injury. J. Neurotrauma. 2013; 30(15): 1311–1324. PubMed Abstract | Publisher Full Text\n\nElkabes S, Nicot AB: Sex steroids and neuroprotection in spinal cord injury: a review of preclinical investigations. Exp. Neurol. 2014; 259: 28–37. PubMed Abstract | Publisher Full Text\n\nTaoka Y, Okajima K, Uchiba M, et al.: Role of neutrophils in spinal cord injury in the rat. Neuroscience. 1997; 79(4): 1177–1182. Publisher Full Text\n\nMedvedeva EV, Dmitrieva VG, Povarova OV, et al.: The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: genome-wide transcriptional analysis. BMC Genomics. 2014; 15: 228. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBertolini A: Drug-induced activation of the nervous control of inflammation: A novel possibility for the treatment of hypoxic damage. Eur. J. Pharmacol. 2012; 679(1): 1–8. PubMed Abstract | Publisher Full Text\n\nWang W, Guo D, Lin Y, et al.: Melanocortin Regulation of Inflammation. Front Endocrinol (Lausanne). Published online. 2019; 10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBracken MB, Shepard MJ, Collins WF, et al.: A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N. Engl. J. Med. 1990; 322(20): 1405–1411. Publisher Full Text\n\nBracken MB, Collins WF, Freeman DF, et al.: Efficacy of methylprednisolone in acute spinal cord injury. JAMA. 1984; 251(1): 45–52. Publisher Full Text\n\nBracken MB, Shepard MJ, Holford TR, et al.: Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA. 1997; 277(20): 1597–1604. PubMed Abstract | Publisher Full Text\n\nHurlbert RJ, Hadley MN, Walters BC, et al.: Pharmacological therapy for acute spinal cord injury. Neurosurgery. 2013; 72: 93–105. Publisher Full Text\n\nEck JC, Nachtigall D, Humphreys SC, et al.: Questionnaire survey of spine surgeons on the use of methylprednisolone for acute spinal cord injury. Spine (Phila Pa 1976). 2006; 31(9): E250–E253. PubMed Abstract | Publisher Full Text\n\nFehlings MG, Wilson JR, Tetreault LA, et al.: A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Use of Methylprednisolone Sodium Succinate. Glob spine J. 2017; 7(3 Suppl): 203S–211S. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFrangen TM, Ruppert S, Muhr G, et al.: The beneficial effects of early stabilization of thoracic spine fractures depend on trauma severity. J. Trauma. 2010; 68(5): 1208–1212. PubMed Abstract | Publisher Full Text\n\nAzzam M, Fahmi A, Utomo B, et al.: The Effect of ACTH(4-10) PRO8-GLY9-PRO10 Administration on the Expression of IL-6 and IL-8 in Sprague Dawley Mice with Spinal Cord Injury. J. Neurosci. Rural. Pract. 2022; 13(3): 370–375. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArdananurdin A, Subagio EA, Utomo B: Spinal Cord’ s IL-1, TNF-α and NF-κB Expression in Sprague-Dawley Rat on Acute Spinal Cord. Injury. 2020; 3(3): 109–114. Publisher Full Text\n\nAsadullah A, et al.: Effects of ACTH4-10Pro8-Gly9-Pro10 on anti-inflammatory cytokine (IL-4, IL-10, IL-13) expression in acute spinal cord injury model (Sprague Dawley rats). Dataset. Dryad. 2023. Publisher Full Text\n\nAsadullah A, Subagio EA, Bajamal AH, et al.: Effects of ACTH4-10Pro8-Gly9-Pro10 on anti-inflammatory cytokine (IL-4, IL-10, IL-13) expression in acute spinal cord injury model (Sprague Dawley rats). Zenodo. 2023. Publisher Full Text"
}
|
[
{
"id": "164062",
"date": "13 Mar 2023",
"name": "Mawaddah Ar Rochmah",
"expertise": [
"Reviewer Expertise Neurology",
"Genetic"
],
"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 explored the use of ACTH4-10Pro8-Gly9-Pro10 in the rat model of spinal cord injury (SCI). The study focused on the role of the above-mentioned agent in ameliorating neuroinflammation within the acute phase of the SCI by measuring the inflammatory cytokines after the treatments. The study is novel and well-written. However, there are some issues that might be addressed to improve the current manuscript.\nThe introduction is quite informative to provide the background of the study. However, in the introduction section, the authors are suggested to elaborate on the introduction of the ACTH4-10Pro8-Gly9-Pro10 in the treatment of SCI.\nThere is information that the authors need to provide in the materials & methods section. In the methods section, it would be clearer if the authors completed the following pieces of information:\nWhy was the ACTH4-10Pro8-Gly9-Pro10 intranasally at a 300 mg/kg dose chosen? Any previous study that suggested the dose? If any, please provide the reference and citation.\n\nHow long was the period between treatment initiation after finishing the laminectomy procedure?\n\nPlease provide the companies which produce the materials (reagents, software, etc) for the purpose of reproducibility.\n\nPlease kindly provide the information if the measurement was performed at least in duple for each sample.\n\nThese are some suggestions for the results section (including figures and tables):\nThe authors are suggested to provide more description of Figure 1, either in Figure Legend of Figure 1 or as a narration in the text. Figure 1 is the evidence to differentiate the spinal cord in healthy, mild SCI, and severe SCI. Please provide the information on whether the histological figure of the spinal cord SCI groups was with or without the administration of ACTH4-10Pro8-Gly9-Pro10 intranasally. The authors need to provide the readers with what to expect in the microscopic changes of the spinal cord after mild and severe SCI.\n\nIn Figure 2, the white arrows are not quite readily visible, the authors are suggested to pick a more contrasting color for the arrow. Why did the authors show only the mild SCI groups here? The authors are suggested to present at least one representative figure for each IHC staining for every group.\n\nTables 1-3 are best presented in bar diagrams between groups in a figure. This will give the readers a better description and impression of the results of the study. In addition, the authors can explain more detailed data in the text. This will avoid the repetition of data explanation in figures/tables in the text.\n\nTables 4-9, in my opinion, can be submitted as supplementary data. In the results section, the authors are suggested to explain the core findings of the posthoc analysis in the text.\n\nThe authors are suggested to make sure that figures and tables are self-explanatory. Any repetition of the data from the figure/tables in the text should be avoided.\nIn the discussion section, the authors have explained and compared the results of the study to other previous studies.\nPlease kindly focus on the difference between the follow up period of 3 hrs and 6 hrs in the study, particularly in the level of the anti-inflammatory cytokines and the SCI severity.\nIn my opinion, I found the fifth paragraph of this section a little odd since the authors did not mention that the study using methylprednisolone was performed in humans. If the authors would like to compare the efficacy of the currently used treatment of SCI, in this case, is methylprednisolone, to the agent used here in the study, I would prefer to use the studies with the same subjects (in this case, the authors should also add any study regarding the use of methylprednisolone treatment in rodents. The study in humans should come as an additional information), the same studied objects/variables (any agents that may increase or decrease anti-inflammatory cytokine in SCI, neurological deficit severity, etc), or other agents that have similar mechanisms of action (in this case, any other agent that binds to melanocortin receptor).\nIn the last sentence of the discussion section, the authors mention “Finally, we see potential benefits from ACTH4-10Pro8- Gly9-Pro10 to reduce inflammation and its deleterious effect on secondary injury after SCI”. Please kindly provide the “deleterious effect of the SCI” that was studied here, since the anti-inflammatory cytokines studied here, in my understanding, are not the deleterious effects of the SCI.\nThe authors are suggested to make the conclusion brief indicating that anti-inflammatory cytokines might be increased after the administration of ACTH4-10Pro8-Gly9-Pro10 intranasally in the acute SCI model.\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": "12562",
"date": "08 Oct 2024",
"name": "Asadullah Asadullah",
"role": "Author Response",
"response": "Why was the ACTH4-10Pro8-Gly9-Pro10 intranasally at a 300 mg/kg dose chosen? Any previous study that suggested the dose? If any, please provide the reference and citation. >This is previous study https://www.scirp.org/journal/paperinformation.aspx?paperid=40560 . Dose is 300 mcg / kg. not mg. thank you. How long was the period between treatment initiation after finishing the laminectomy procedure? > administration of drugs after 1 hour of laminectomy and spinal cord clip with aneurysm clip to reproduce spinal cord injury. Please provide the companies which produce the materials (reagents, software, etc) for the purpose of reproducibility. > The medicine is from PT Axomedica with the trade name Semax"
}
]
}
] | 1
|
https://f1000research.com/articles/12-194
|
https://f1000research.com/articles/11-1327/v1
|
16 Nov 22
|
{
"type": "Research Article",
"title": "Assessment of the synergistic effect of a poly-herbals combination on the antioxidant activity through a statistical approach",
"authors": [
"Ahmad Ainurofiq",
"Nanang Wiyono",
"Rita Warni",
"Syaiful Choiri",
"Ahmad Ainurofiq",
"Nanang Wiyono",
"Rita Warni"
],
"abstract": "Poly-herbals combination was applied to enhance biological activity, particularly antioxidant activity. This present study was purposed to assess the synergistic interaction of a combination of five traditional Indonesian herbal plants through a simultaneous and integrated statistical technique. The plants were extracted using maceration, and purification was conducted before extraction to eliminate the ballast compounds. A simplex lattice design comprising 35 design points was utilized to understand herbal combinations' main effect and interaction through multiple linear regression analysis on the antioxidant activity using DPPH and ABTS assays. The results showed that C. longa, P. niruri, and C. xanthorrhiza had the most potent antioxidant activity than M. oleifera and C. asiatica. The presence of C. longa modulated the synergistic interaction between combinations. Meanwhile, the non-curcuminoid content in C. xanthorrhiza played a fundamental role in reducing the antioxidant activity. The synergistic interaction could enhance the antioxidant activity through poly-herbals combination. In addition, particular consideration should be withdrawn by antagonism interaction in the poly-herbals combination for reducing the biological activity.",
"keywords": [
"synergistic effect",
"poly-herbal combinations",
"Curcuma longa",
"curcumin",
"antioxidant"
],
"content": "Introduction\n\nAntioxidant activity plays a fundamental role in treatments for several diseases, particularly degenerative and metabolic diseases. Therefore, there has been an exponential surge of studies on antioxidant activity in the last decade (Dumore and Mukhopadhyay 2020). The antioxidant compound is beneficial for reducing oxidative stress. It is associated with an imbalance between reactive oxygen species (ROS) and the systems. ROS in our body generates several oxidation mechanisms that promote cell damage and imbalance of the metabolic equilibrium, particularly in the long term. Therefore, it should be minimalized (Amin and Bano 2018). Antioxidant compounds offer a simple step to reduce and inhibit ROS generation in the body. These compounds reduce radical biological generation by stabilizing the unpaired electron in ROS and the distribution in their structure. Furthermore, it reduces cell damage and minimizes the prevalence of chronic degenerative diseases (Amin and Bano 2018; Maya-Cano, Arango-Varela, and Santa-Gonzalez 2021).\n\nGenerally, plants contain several compounds that can serve as antioxidant sources, for example, polyphenols and flavonoids. The multi-compounds contained in plants have better antioxidant activity compared to single compounds. This is due to the interaction between compounds in plants. Herbal therapists administer a concoction of herbal medicines to treat several diseases. However, there is no scientific basis for combining two or more plants in herbal medicine, particularly to achieve higher activity due to their interaction (Salaj et al. 2021). The synergistic effect refers to increasing the activity of combined substances over the additive effect, whereby they interact with compounds through poly-herbal combinations (Du et al. 2021; Zonyane, Van Vuuren, and Makunga 2013). The synergistic effect enhances the antioxidant activity through a combination of several potent herbal plants with high antioxidant activity. The synergistic effect can be assessed using a statistical technique that examines the interaction between two compounds and poly-interaction simultaneously (Liang et al. 2021). The experimental design can offer a statistical evaluation of factors on response in an integrated assessment based on determining factors. The mixture design is a simple technique that can assess the mixture interaction between herbal plants to provide scientific justification for its effects.\n\nIndonesia has diverse herbal plants that are traditionally used to reduce the risk of degenerative diseases and cancer and are applied as immunomodulators (Illian et al. 2021; Liu 2021). Curcuma longa L. and Curcuma xanthorrhiza Roxb have been reported to contain curcumin, which has several known benefits (Azeez and Lunghar 2021; Sultana et al. 2021). It is used for not only preventive treatment but also curative treatment for particular diseases (Catanzaro et al. 2018; Răducanu et al. 2021). Centella asiatica L. has been reported to have neuroprotective effects, whereby it affects antioxidant activity in the brain and surrounding tissues. In addition, traditionally, it has been applied to promote healthy aging (Sabaragamuwa, Perera, and Fedrizzi 2018). Another frequently applied Indonesian herbal medicine, Phyllanthus niruri L., is also known to have potential immunomodulatory and antioxidant properties due to its containing polyphenol and lignin compounds (Colpo et al. 2014; Nhu et al. 2020). Moreover, Moringa oleifera contains high polyphenol compounds, flavonoids (Wang et al. 2020), and peptides (Avilés-Gaxiola et al. 2021). Therefore, it has much potential for promoting antioxidant activity and for use in degenerative disease treatments. The aforementioned plants have been reported and explored extensively. Indonesian herbal therapists widely apply them for their preventive or curative benefits for degenerative diseases. In addition, a study reported that self-medication using herbal medicine is a common practice, particularly in rural areas (Rahayu, Araki, and Rosleine 2020). Therefore, it is worth studying this combination, particularly assessing the synergistic effect between two mixtures and their multi-component poly-interaction. To the best of our knowledge, no studies have assessed the antioxidant activity of these five traditional Indonesian plants using an experimental design. Therefore, the present study aimed to assess the poly-interaction of a multi-component mixture of five traditional Indonesian plants and their synergistic effects on antioxidant activity using a mixture design based on a simplex centroid design model.\n\n\nMethods\n\nDried plant material of Curcuma xanthorrhiza (root), Curcuma longa (root), Centella asiatica (herb), Phyllanthus niruri (herb), and Moringa oleifera (leaves) was obtained from the Center for Research and Development of Medicinal Plants and Traditional Medicine (B2P2TOOT), Department of Health, Republic of Indonesia (Tawangmangu, Indonesia). All plants were cultivated in the Tawangmangu district under controlled monitoring by B2P2TOOT from September to December 2020. Sample plants were authenticated and identified by a plant taxonomist at B2PO2TOOT, and it was deposited as herbarium at B2P2TOOT. The dried plants were processed by following an efficient traditional herbal medicine preparation process, which included sorting, drying, and storing under close monitoring by B2P2TOOT, to ensure the quality of the plants.\n\nEthanol, n-hexane, and potassium persulfate were imported from Merck (Darmstadt, Germany). 1,1-Diphenyl-2-picryl hydrazyl (DPPH) and 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) were purchased from Sigma Aldrich (St. Louis, MO).\n\nThe dried plants were cut into small pieces and grinding and passed through a 250 μm mesh sieve. A maceration process was carried out to extract plant material using a solvent ratio of 1:10 (w/v). Previously, the dried plants were purified using n-hexane to eliminate resin and chlorophyll and plant material to n-hexane ratio of 1:5 (w/v) for 24h. After that, the residue was collected and extracted using ethanol 95%. The macerate was filtered and concentrated using a Stuart RE300P rotary evaporator (Staffordshire, UK) at temperature and vacuum pressure of 50°C and 630 mmHg, respectively. The obtained extract was stored in a refrigerator (4–6°C) for further analyses.\n\nThe total phenolic content (TPC) in each extract was measured using the Folin-Ciocalteu assay, based on Ainsworth and Gillespie (2007), after making minor modifications to the process. An accurate predetermined concentration of each extract dissolved in ethanol was used as the sample. In addition, gallic acid was used as a standard, in a range of 10–160 μg/mL. A 0.30 mL sample was mixed homogeneously with 1.50 mL of 10% Folin-Ciocalteu reagent (diluted 1:10 with deionized water) for 5 min. The mixture was neutralized with 1.20 mL of 7.5% sodium carbonate solution and incubated along with shaking for 30 min. The sample absorbance was recorded spectrophotometrically using Genesis 150 spectrophotometer (Thermo; Waltham, MA) at 764 nm. The TPC of each extract was calculated according to the gallic acid standard calibration curve (y = 0.0116x + 0.2110, where x is gallic acid [μg/mL], and y is absorbance; R2 0.9968) and presented as the percentage of gallic acid equivalent (%w GAE).\n\nA simplex centroid design model was employed to assess the main effects of and poly-interactions among the five traditional Indonesian plant extracts. A 41-run design was applied to assess the variables of antioxidant activity. The design consisted of 31 runs for simplex point, five for augmenting design, and 5 for replication using a quadratic model. A multiple linear regression analysis was performed to construct the model, and the data were fitted to Equation 1. A linear, quadratic, or special cubic was selected according to the best goodness of fit parameters at a 95% confidence level.\n\nWhere a, b, c, d, and e are the coefficient regression of the linear model, known as the main effect. The interaction between two factors was determined by coefficient regression of ab, ac, ad, …, and cd. Meanwhile, the poly-interaction between three factors was assigned by abc, abd, …, and cde. The model was considered significant at p<0.05. In addition, the fitting was straightforward in terms of error, and accordingly, the lack of fit indicated non-significance (p>0.05). A high coefficient determination (R2) was required to obtain an adequate model. It was also followed by a low gap between adjusted R2 and R2. In addition, the model was validated by a leave-one-out technique to achieve the predicted R2. Therefore, the difference between predicted and adjusted R2 was not more than 20%.\n\n\nDetermination of total antioxidant activity\n\nIn-vitro antioxidant activity was assessed by a radical scavenging technique using DPPH and ABTS, given their reproducibility and feasibility.\n\nAll samples and combinations were dissolved and diluted using ethanol concentrations ranging from 0 to 200 μg/mL. A 1.0 mL sample was mixed with 1.0 mL DPPH (0.4 mM in methanol) and diluted with 3.0 mL of methanol. The reaction was incubated under ambient (25±1°C, RH 50±10%) and dark conditions for 30 min. The control solution was a sample concentration of 0 μg/mL. The absorbance of the sample (As) and control solution (Ac) was recorded at 517 nm. The percentage of inhibition was calculated using Equation 2.\n\nAn ABTS assay was performed according to the described method after making minor modifications. The ABTS radical was achieved by reacting 7.0 mM ABTS solution with 2.45 mM potassium persulfate. The mixture was stored in a dark room overnight. A 0.5 mL sample (0-200 μg/mL) was added to 1.0 mL ABTS+ radical and incubated for 15 min in a dark room. The control solution was prepared by mixing the ABTS+ radical 1.0 mL with 0.5 mL double distilled water. The absorbance of the sample (As) and control (Ac) was calculated using Equation 2.\n\nThe antioxidant profile was constructed according to the concentration and inhibition. The IC50 of each run was calculated according to the extrapolation of the inhibition of 50% to the curve by an appropriate statistical method and a 95% confidence level (p=0.05). Linear, log-linear, log non-linear, Weibull, non-linear and logistic models were fitted to the observed inhibition data. The best-fitting model was selected according to the best goodness of fit parameters (Sridhar and Charles 2019).\n\n\nResults\n\nPrior to antioxidant evaluation, an extraction process was carried out. The extracts of the five traditional plants ranged from 2 to 6% of the dried weight. These results present the yield of the extraction process and indicate a relatively low yield due to the purification process to obtain higher antioxidant activity. The TPC of each extract was 10.13, 17.21, 1.03, 5.07, and 3.23 %w GAE for C. xanthorrhiza, C. longa, C. asiatica, P. niruri, and M. oleifera, respectively. In addition, the distribution of TPC in the extract combination is depicted in Figure 1. Due to abundant curcuminoid, C. longa had the highest phenolic content. In addition, C. xanthoriza had a high curcuminoid content. Meanwhile, the C.asiatica had the lowest phenolic content. Therefore, the TPC in the combination (Figure 1) increased gradually with the increment of C. longa or C. xanthorriza. However, C. asiatica and M. oleifera reduced the TPC content in the combination.\n\nEach contour plot consists of three extract combinations and another extract at 0%.\n\nThe radical scavenging profiles of DPPH are presented in Figure 2. A single component of the extract showed a different pattern of antioxidant profiles (Figure 2a). P. niruri had the best antioxidant activity and followed a similar pattern to that of C. xanthorrhiza and C. longa. A sigmoidal antioxidant profile was observed in these antioxidant profiles. However, a linear profile of antioxidants was observed in both M. oleifera and C. asiatica purified extracts. A linear pattern under 50% inhibition showed that both extracts had lower antioxidant activity than the previously mentioned extracts. The combination of two extracts altered all antioxidant profiles to be the linear model except for the interaction between P. niruri and C. xanthorrhiza or C. longa. The combination of three extracts was wholly altered to be the linear model. However, the model had a different IC50 value. The presence of P.niruri extract in the poly-combination had no significant effect on the IC50 value and produced similar patterns (Figure 2f). These results indicate that the presence of an interaction between the components in the extract altered the antioxidant profile and antioxidant capacity.\n\nThe antioxidant activity was expressed by Trolox equivalent (TE) per gram extract. The antioxidant capacity ranged from 0.30 to 1.29 mmol TE/g. To evaluate the main effect of and poly interaction among the five plants and their combination, the antioxidant capacity was fit to the MLRA equation. The antioxidant capacity using the DPPH assay was transformed into an inverse model to achieve a higher goodness of fit. Therefore, the response was also inversed along with the direction of value. The lower the response value, the higher the main effects and interactions. The model was significant (p<0.05), and the lack of fit test was not significant (p>0.05). The model showed that factors ~97% affected antioxidant capacity by the DPPH assay. Therefore, it has adequate power for supporting the main effect and interaction. According to the coefficient regression, P. niruri had the best antioxidant capacity. P. niruri, C. xanthorrhiza, C. longa, M. oleifera, and C. asiatica demonstrated the lowest to most potent antioxidant capacity.\n\nEquation 3 shows the extracted plants' main effect, interaction, and poly-interaction. The main effect was significant (p<0.05), reducing the antioxidant capacity of M. oleifera and C.asiatica extract compared to the others. To quantify the main effect and interaction, their contribution was calculated, and it is presented in Figure 3. It also presents a different perspective regarding the main effect and interaction. The main effect was always positive in increase the antioxidant capacity. However, the lower the main effect, the better the contribution to the antioxidant capacity. Meanwhile, antagonism and synergistic effects showed positive and negative outcomes, respectively. Therefore, the interaction between C. xanthorrhiza and other extracts reduced the antioxidant capacity. In addition, other interactions increased the antioxidant capacity except for the interaction between C. longa and P. niruri. There was only one significant interaction (p<0.05) in improving the antioxidant capacity, i.e., the interaction between C. longa and C. asiatica. Both extracts could enhance the antioxidant capacity if they were combined, indicating a synergistic interaction. However, the other combinations showed no significant effects, altering the antioxidant capacity (p>0.05).\n\n* = p<0.05.\n\nBy evaluating the contour plot (Figure 4), more specific information could be obtained regarding the interaction between the components. The highest antioxidant capacity was shown at a high proportion of P. niruri extract or binary component between C. longa and P. niruri. Meanwhile, the lowest antioxidant capacity was obtained at a high proportion of M. oleifera and C. asiatica. The interaction was depicted in parallel lines between each contour line. The interaction mainly occurred in the ternary mixture of each component. C. longa has the most significant effect on the interaction between the extracts.\n\nEach contour plot consists of three extract combinations and another extract at 0%.\n\nFigure 5 presents the antioxidant profile determined using the ABTS assay. The single-component extract had a similar pattern to the DPPH assay. However, the gap between low and high potential antioxidant profiles was large. The IC50 value of all binary mixtures was 5–10 μg/mL, except for M. oleifera and C. asiatica binary mixture. In addition, the presence of both extracts reduced the antioxidant activity. All ternary extract combinations had similar patterns, and the IC50 was 5–13 μg/mL, except for the combination of M. oleifera, P.niruri, and C.asiatica. However, the quarternary mixtures and multi-component combination had nearly similar antioxidant profiles and activities.\n\nThe antioxidant capacity of five plant extracts and combinations was also expressed using Trolox equivalent per gram extract. The antioxidant capacity of all combinations ranged from 0.18 to 3.71 mmol TE/g, suggesting that the antioxidant capacity using ABTS had more potential than when using the DPPH assay. To understand the effect of a single component and binary mixture of extracts, MLRA was applied to the antioxidant capacity using the ABTS assay. The data were fitted to a quadratic equation (Equation 4). By transforming the data to the square root model, a higher goodness of fit value could be achieved. In addition, the response was in a linear term along with the value. The model showed a significant effect on the response by 95.47% (p<0.05), and the lack of fit test was not significant (p>0.05); there was also a small gap between predicted R2 (0.8601) and adjusted R2 (0.9303).\n\nAccording to Equation 4, C. longa had the highest antioxidant capacity, followed by C. xanthorrhiza, P. niruri, C.asiatica, and M.oleifera. The highest interaction was observed for the combination of C.longa and C.asiatica. The lowest interaction was achieved for the combination of C. longa and P. niruri. Based on the results of the coefficient regression in the model, the contribution of the main effect and interaction was calculated (Figure 6). Only C. xanthorrhiza, C. longa, and P. niruri significantly increased the antioxidant capacity (p<0.05).\n\n* = p<0.05.\n\nMeanwhile, the interaction between C. longa and C. asiatica showed a significant synergistic mechanism (p<0.05). However, it should be considered that the interaction between C. xanthorrhiza and C. longa was antagonistic, which promoted a reduction in the antioxidant capacity. Contour plots are required to provide better insight into the interaction effects of the combination of extracts on antioxidant capacity (Figure 7) by monitoring the color pattern alteration. C. longa and M. oleifera showed the highest and the lowest antioxidant activity, respectively (Figure 7a). The poly-interaction between extracts was dominated by the presence of C. longa, P. niruri, and C. xanthorrhiza (Figure 7b). There was no interaction between the extracts in the presence of P. niruri, C. asiatica, and C. xanthorrhiza due to similar slopes and parallel and no intersection lines (Figure 7c). There was very little interaction between C. longa, C. asiatica, and M. oleifera (Figure 7d). In addition, there was no interaction between P. niruri, C. asiatica, and M. oleifera (Figure 7e).\n\nEach contour plot consists of three extract combinations and another extract at 0%.\n\nThe correlation between TPC and antioxidant activity is presented in Figure 8. The correlation depicts the relationship between phenolic compounds contained in the extract combination and the antioxidant activity. Figure 8a shows the correlation with antioxidant activity, analyzed using the DPPH assay. TPC and antioxidant activity had a medium correlation (r = 0.5502; 30.27%). Weak correlations were due to the non-linear effect, particularly for C. longa and P.niruri in single or high proportions in the extract combination. This suggests that the interaction between radical and phenolic compounds was mediated by the interaction between metabolite compounds in combinations. Meanwhile, the ABTS assay (Figure 8b) showed a strong correlation between phenolic compounds and antioxidant activity (r = 0.9094; 82.7%). However, the outlier data (outside the confidence interval of the regression model) may be attributed to a single or dominant proportion of C. longa and P. niruri extract. Both antioxidant assays proved a similar pattern in that the combination of extract had adequate correlation with antioxidant, but ABTS assays revealed a stronger correlation.\n\nTPC vs. AA using DPPH assay (a) and TPC vs. AA using ABTS assay (b).\n\n\nDiscussion\n\nThe purification process in this study was intended to obtain better antioxidant activity by eliminating ballast compounds. Better antioxidant activity was reported in low chlorophyll (Rajan et al. 2020) and resin (Wan et al. 2014) levels. Therefore, low yield of extraction was due to the absence of both ballast compounds. Moreover, it enhanced metabolic contents and antioxidant activity considerably.\n\nRadical scavenging assays, DPPH and ABTS, were used to assess the antioxidant capacity of a combination of five traditional Indonesian plants. The reliability and stability of assay method mainly guided the selection of this assay and simple methods to assess the antioxidant activity (Mareček et al. 2017; Zhang, Yang, and Zhou 2018). Moreover, they are also applied extensively for more variation in plant sources (Sridhar and Charles 2019). The bioactive compound primarily determined the antioxidant activity in the extract. P. niruri contains a bioactive marker compound, phyllanthin, a lignin compound with potent antioxidant and immunomodulatory activities (Colpo et al. 2014; Naidu et al. 2004). Meanwhile, both C. longa and C. xanthorrhiza contain curcuminoid. It is also reported to have antioxidant and other pharmacological activities (Yang et al. 2020). The most potent antioxidant activity showed a sigmoidal curve. Thus, it assumed that the antioxidant profiles were covered from initial, inflection, and steady concentrations. It is a native characteristic of the interaction between radical and antioxidant molecules that involves radical stabilization. However, the linear pattern of antioxidants was observed in M. oleifera and C.asiatica due to the linear correlation between active compounds and radical scavenging activity. Both extracts contain major constituents, that is, flavonoid compounds, which governed the antioxidant activity (Zhang, Yang, and Zhou 2018). However, C. asiatica contains a specific biological marker, namely asiaticoside (Loc and Nhat 2013). The antioxidant profiles of binary, ternary, and poly-mixture were altered due to the contribution and interaction of the active compounds. Several studies have shown that the interaction of herbal mixture or poly-herbal mixture enhances antioxidant activity (Bhargavi and Madhan Shankar 2021; Salaj et al. 2021; Senol Deniz, Orhan, and Duman 2021). Therefore, the quantification of the interaction can be assessed by an experimental design model. Moreover, the requirement for model prediction should follow the best goodness of fit parameters (Choiri, Sulaiman, and Rohman 2020). Both antioxidant models had an adequate equation for predicting the response of the antioxidant activity. There was an antagonist interaction between C. xanthorrhiza and other plants due to the non-curcuminoid compound in C. xanthorrhiza. In addition, the antioxidant activity of C. xanthorrhiza was not a linear function, along with phenolics and flavonoids (Akter et al. 2019). Due to its containing sesquiterpene (e.g., xanthorrhizole and curcumene), the curcumin content was lower than C. longa (Losso et al. 2022; Awin et al. 2019). Therefore, it reduced the antioxidant activity when combined with other plants. However, another curcuminoid-contained plant, C. longa, had synergistic interaction. These data indicate that the non-curcuminoid compound in plants played a fundamental role in reducing the antioxidant effect. Curcumin in C. longa and C. xanthorrhiza has a scavenging ability, mainly through hydrogen atom transfer reactivity with •OH and •OOH radicals (Purushothaman et al. 2021). The synergistic interaction was affected by an interaction between specific components in both extracts. Future studies may explain this phenomenon more comprehensively.\n\nThe ABTS assay was also applied to assess the antioxidant activity of the five plants and their combination using the HET approach, which is similar to the DPPH assay. However, it differs from the DPPH assay. It uses a water-based solution for evaluating the antioxidant activity. The results indicated a different pattern of antioxidant activity, particularly at the gap between the low and high potential antioxidant profiles. As discussed above, the antioxidant properties of single-component and poly-combination were affected by the biological activity and interaction of components in the extract (Abbas et al. 2021). The interaction between C. longa and C. asiatica showed the synergistic effect through interaction between primary marker compounds—curcumin and asiaticoside. According to the results, C. longa made the most outstanding contribution to the antioxidant capacity. The use of a contour plot can be applied for a visual evaluation of the effect of each combination and interaction between two extracts simultaneously.\n\nThe correlation between the TPC and antioxidant activity involved the main responsibility of the antioxidant activity, particularly phenolic compounds (Cirak et al. 2022; Maya-Cano, Arango-Varela, and Santa-Gonzalez 2021). The major mechanism of radical scavenging involves the hydrogen electron transfer between radical ion and OH groups in phenolic compounds, followed by stabilization (Mareček et al. 2017; Schaich, Tian, and Xie 2015). Therefore, the higher the phenolic compound, the greater antioxidant activity, and thus, it had a linear correlation. However, a unique correlation between single extract and the poly-herbal combinations was observed. The outlier results (against the regression model) were observed particularly at single extract components or the dominant proportion of a particular extract. Meanwhile, the poly-combination showed a linear model and higher antioxidant activity. Hence, it was affected by a synergistic interaction between polyphenolic compounds or polyphenols with another compound in the extract (Cianciosi et al. 2022).\n\n\nConclusions\n\nA combination of five traditional Indonesian plants was assessed using the simplex lattice design model. C. longa, P. niruri, and C. xanthorrhiza demonstrated more potent antioxidant activities than M. oleifera and C. asiatica. In addition, the phyto-components contained in C. longa governed the synergistic interaction during poly-herbal interaction. Meanwhile, non-curcuminoids in C. xanthorrhiza modulated the reduction of antioxidant activity during poly-herbal interaction. The polyphenol contents demonstrated a synergistic effect on the antioxidant activity. The synergistic interaction could be helpful to enhance antioxidant activity through multi-component interaction in the herbal combination.\n\n\nAuthor contributions\n\nConceptualisation, S. Choiri, and A. Ainurofiq; methodology, N. Wiyono.; software, S.Choiri.; validation, All authors.; formal analysis, S. Choiri; investigation, R. Warni, N. Wiyono.; resources, N. Wiyono.; data curation, R. Warni; writing—original draft preparation, A. Ainurofiq.; writing—review and editing, S. Choiri; visualization, R. Warni; supervision, S. Choiri.; project administration, A. Ainurofiq.; funding acquisition, A. Ainurofiq.",
"appendix": "Data availability\n\nOSF. Assessment of the synergistic effect of a poly-herbals combination on the antioxidant activity through a statistical approach. DOI: https://doi.org/10.17605/OSF.IO/2GFMN (Choiri, 2022).\n\nThis project contains the underlying data:\n\n- Data Set (Data Set.docx)\n\n\nAcknowledgments\n\nThe authors would like to thank the Ministry of Education, Culture, Research, and Technology, Republic of Indonesia & Universitas Sebelas Maret for funding and supporting this research.\n\n\nReferences\n\nAbbas Z, Manoharan AL, Jagadeesan G, et al.: Evaluation of an Edible Polyherbal Formulation against Urinary Tract Infection Pathogens, Its Antioxidant and Anti-Inflammatory Potential. Biocatal. Agric. Biotechnol. 2021; 35(August): 102104. Publisher Full Text\n\nAinsworth EA, Gillespie KM: Estimation of Total Phenolic Content and Other Oxidation Substrates in Plant Tissues Using Folin–Ciocalteu Reagent. Nat. Protoc. 2007; 2(4): 875–877. PubMed Abstract | Publisher Full Text\n\nAkter J, Amzad Hossain M, Kensaku Takara M, et al.: Antioxidant Activity of Different Species and Varieties of Turmeric (Curcuma Spp): Isolation of Active Compounds. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology. 2019; 215(January): 9–17. Publisher Full Text\n\nAmin F, Bano B: Damage of Cystatin Due to ROS-Generation and Radical-Scavenging Activity of Antioxidants and Associated Compounds. Int. J. Biol. Macromol. 2018; 119(November): 369–379. PubMed Abstract | Publisher Full Text\n\nAvilés-Gaxiola S, León-Félix J, Jiménez-Nevárez YB, et al.: Antioxidant and Anti-Inflammatory Properties of Novel Peptides from Moringa Oleifera Lam. Leaves. S. Afr. J. Bot. 2021; 141(September): 466–473. Publisher Full Text\n\nAwin T, Buzgaia N, Ghafar SZA, et al.: Identification of Nitric Oxide Inhibitory Compounds from the Rhizome of Curcuma Xanthorrhiza. Food Biosci. 2019; 29(June): 126–134. Publisher Full Text\n\nAzeez TB, Lunghar J: 6 - Antiinflammatory Effects of Turmeric (Curcuma Longa) and Ginger (Zingiber Officinale). Inflammation and Natural Products. Gopi S, Amalraj A, Kunnumakkara A, et al., editors.Academic Press;2021; 127–46. Publisher Full Text\n\nBhargavi S, Madhan Shankar SR: Dual Herbal Combination of Withania Somnifera and Five Rasayana Herbs: A Phytochemical, Antioxidant, and Chemometric Profiling. J. Ayurveda Integr. Med. 2021; 12(2): 283–293. PubMed Abstract | Publisher Full Text\n\nCatanzaro M, Corsini E, Rosini M, et al.: Immunomodulators Inspired by Nature: A Review on Curcumin and Echinacea. Molecules (Basel, Switzerland). 2018; 23(11): E2778.\n\nChoiri S, Sulaiman TNS, Rohman A: Assessment of the Effect of Polymers Combination and Effervescent Component on the Drug Release of Swellable Gastro-Floating Tablet Formulation through Compartmental Modeling-Based Approach. Drug Dev. Ind. Pharm. 2020; 46(1): 146–158. PubMed Abstract | Publisher Full Text\n\nCianciosi D, Forbes-Hernández TY, Regolo L, et al.: The Reciprocal Interaction between Polyphenols and Other Dietary Compounds: Impact on Bioavailability, Antioxidant Capacity and Other Physico-Chemical and Nutritional Parameters. Food Chem. 2022; 375(May): 131904. PubMed Abstract | Publisher Full Text\n\nCirak C, Radusiene J, Raudone L, et al.: Phenolic Compounds and Antioxidant Activity of Achillea Arabica Populations. S. Afr. J. Bot. 2022; 147(July): 425–433. Publisher Full Text\n\nChoiri S: Assessment of the synergistic effect of a poly-herbals combination on the antioxidant activity through a statistical approach.2022, September 20. Publisher Full Text\n\nColpo E, Vilanova CDDA, Pereira RP, et al.: Antioxidant Effects of Phyllanthus Niruri Tea on Healthy Subjects. Asian Pac. J. Trop. Med. 2014; 7(2): 113–118. PubMed Abstract | Publisher Full Text\n\nDu Z, Yingyuan L, Sun J, et al.: Pharmacokinetics/Pharmacometabolomics-Pharmacodynamics Reveals the Synergistic Mechanism of a Multicomponent Herbal Formula, Baoyuan Decoction against Cardiac Hypertrophy. Biomed. Pharmacother. 2021; 139(July): 111665. PubMed Abstract | Publisher Full Text\n\nDumore NS, Mukhopadhyay M: Antioxidant Properties of Aqueous Selenium Nanoparticles (ASeNPs) and Its Catalysts Activity for 1, 1-Diphenyl-2-Picrylhydrazyl (DPPH) Reduction. J. Mol. Struct. 2020; 1205(April): 127637. Publisher Full Text\n\nIllian DN, Siregar ES, Sumaiyah S, et al.: Potential Compounds from Several Indonesian Plants to Prevent SARS-CoV-2 Infection: A Mini-Review of SARS-CoV-2 Therapeutic Targets. Heliyon. 2021; 7(1): e06001. PubMed Abstract | Publisher Full Text\n\nLiang Z, Han D, Han F, et al.: Novel Strategy of Natural Antioxidant Nutrition Quality Evaluation in Food: Oxidation Resistance Mechanism and Synergistic Effects Investigation. Food Chem. 2021; 359(October): 129768. Publisher Full Text\n\nLiu C-x: Overview on Development of ASEAN Traditional and Herbal Medicines. Chinese Herb. Med. 2021; 13: 441–450. September. PubMed Abstract | Publisher Full Text\n\nLoc NH, Nhat NTD: Production of Asiaticoside from Centella (Centella Asiatica L. Urban) Cells in Bioreactor. Asian Pac. J. Trop. Biomed. 2013; 3(10): 806–810. Publisher Full Text\n\nLosso K, Bec KB, Mayr S, et al.: Rapid Discrimination of Curcuma Longa and Curcuma Xanthorrhiza Using Direct Analysis in Real Time Mass Spectrometry and Near Infrared Spectroscopy. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2022; 265(January): 120347. Publisher Full Text\n\nMareček V, Mikyška A, Hampel D, et al.: ABTS and DPPH Methods as a Tool for Studying Antioxidant Capacity of Spring Barley and Malt. J. Cereal Sci. 2017; 73(January): 40–45. Publisher Full Text\n\nMaya-Cano DA, Arango-Varela S, Santa-Gonzalez GA: Phenolic Compounds of Blueberries (Vaccinium Spp) as a Protective Strategy against Skin Cell Damage Induced by ROS: A Review of Antioxidant Potential and Antiproliferative Capacity. Heliyon. 2021; 7(2): e06297. PubMed Abstract | Publisher Full Text\n\nNaidu N, Buchi KPR, Chowdary KVR, et al.: Physicochemical Characterization and Dissolution Properties of Meloxicam–Cyclodextrin Binary Systems. J. Pharm. Biomed. Anal. 2004; 35(1): 75–86. PubMed Abstract | Publisher Full Text\n\nNhu TQ, Dam NP, Hang BTB, et al.: Immunomodulatory Potential of Extracts, Fractions and Pure Compounds from Phyllanthus Amarus and Psidium Guajava on Striped Catfish (Pangasianodon Hypophthalmus) Head Kidney Leukocytes. Fish Shellfish Immunol. 2020; 104(September): 289–303. Publisher Full Text\n\nPurushothaman A, Rose KST, Jacob JM, et al.: Curcumin Analogues with Improved Antioxidant Properties: A Theoretical Exploration. Food Chem. 2021; 373: 131499. October. PubMed Abstract | Publisher Full Text\n\nRăducanu AE, Tihăuan B-M, Marinaș IC, et al.: The Biological Effects of Novel Nutraceuticals with Curcuminoids and Other Plant-Derived Immunomodulators and Pre-Probiotics. Pharmaceutics. 2021; 13(5): 666. PubMed Abstract | Publisher Full Text\n\nRahayu YY, Sally TA, Rosleine D: Factors Affecting the Use of Herbal Medicines in the Universal Health Coverage System in Indonesia. J. Ethnopharmacol. 2020; 260(October): 112974. PubMed Abstract | Publisher Full Text\n\nRajan M, Rajkumar G, Guedes TJFL, et al.: Performance of Different Solvents on Extraction of Bioactive Compounds, Antioxidant and Cytotoxic Activities in Phoenix Loureiroi Kunth Leaves. J. Appl. Res. Med. Aromat. Plants. 2020; 17(May): 100247. Publisher Full Text\n\nSabaragamuwa R, Perera CO, Fedrizzi B: Centella Asiatica (Gotu Kola) as a Neuroprotectant and Its Potential Role in Healthy Ageing. Trends Food Sci. Technol. 2018; 79(September): 88–97. Publisher Full Text\n\nSalaj N, Kladar N, Čonić BS, et al.: Traditional Multi-Herbal Formula in Diabetes Therapy – Antihyperglycemic and Antioxidant Potential. Arab. J. Chem. 2021; 14(10): 103347. Publisher Full Text\n\nSchaich KM, Tian X, Xie J: Hurdles and Pitfalls in Measuring Antioxidant Efficacy: A Critical Evaluation of ABTS, DPPH, and ORAC Assays. J. Funct. Foods. 2015; 14(April): 111–125. Publisher Full Text\n\nDeniz S, Sezer F, Orhan IE, et al.: Profiling Cosmeceutical Effects of Various Herbal Extracts through Elastase, Collagenase, Tyrosinase Inhibitory and Antioxidant Assays. Phytochem. Lett. 2021; 45(October): 171–183. Publisher Full Text\n\nSridhar K, Charles AL: In vitro Antioxidant Activity of Kyoho Grape Extracts in DPPH and ABTS Assays: Estimation Methods for EC50 Using Advanced Statistical Programs. Food Chem. 2019; 275(March): 41–49. PubMed Abstract | Publisher Full Text\n\nSultana S, Munir N, Mahmood Z, et al.: Molecular Targets for the Management of Cancer Using Curcuma Longa Linn. Phytoconstituents: A Review. Biomed. Pharmacother. 2021; 135(March): 111078. PubMed Abstract | Publisher Full Text\n\nWan P, Sheng Z, Han Q, et al.: Enrichment and Purification of Total Flavonoids from Flos Populi Extracts with Macroporous Resins and Evaluation of Antioxidant Activities in vitro. J. Chromatogr. B. 2014; 945-946(January): 68–74. PubMed Abstract | Publisher Full Text\n\nWang F, Long S, Zhang J, et al.: Antioxidant Activities and Anti-Proliferative Effects of Moringa Oleifera L. Extracts with Head and Neck Cancer. Food Biosci. 2020; 37(October): 100691. Publisher Full Text\n\nYang Q-Q, Cheng L-Z, Zhang T, et al.: Phenolic Profiles, Antioxidant, and Antiproliferative Activities of Turmeric (Curcuma Longa). Ind. Crop. Prod. 2020; 152(September): 112561. Publisher Full Text\n\nZhang H, Yang Y-f, Zhou Z-q: Phenolic and Flavonoid Contents of Mandarin (Citrus Reticulata Blanco) Fruit Tissues and Their Antioxidant Capacity as Evaluated by DPPH and ABTS Methods. J. Integr. Agric. 2018; 17(1): 256–263. Publisher Full Text\n\nZonyane S, Van Vuuren SF, Makunga NP: Antimicrobial Interactions of Khoi-San Poly-Herbal Remedies with Emphasis on the Combination; Agathosma Crenulata, Dodonaea Viscosa and Eucalyptus Globulus. J. Ethnopharmacol. 2013; 148(1): 144–151. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "155972",
"date": "12 Dec 2022",
"name": "Andrzej L. Dawidowicz",
"expertise": [
"Reviewer Expertise Analytical chemistry (chromatography)",
"antioxidant properties of plant extracts"
],
"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 entitled “Assessment of the synergistic effect of a poly-herbals combination on the antioxidant activity through a statistical approach” by Ainurofiq et al. refers to five traditional Indonesian herbal plant.\nThe presented results seem to be interesting and valuable. However, the manuscript, in my opinion, requires major revision. The following comments should be taken into account in the revised version of manuscript:\nDifferent reaction times were used to estimate the antioxidant properties of extracts by the applied methods. To compare the results/methods, the measurements should be performed in the same time.\n\nIncorrect location of the figures in the manuscript text makes it difficult to read. Figures showing the results obtained by DPPH method should be presented in the manuscript text fragment where the results from this method are described, etc.\n\nHow were multi-component mixtures of plant extracts for testing their antioxidant properties prepared - how were the ingredients mixed, in what ratio? This should be described.\n\nThe authors should clarify the calculation way of the contributions which were used to express the interactions between the extracts (it concerns data in Figures 3 and 6).\n\nCaptions to Figures 3 and 6 should be changed. The expression \"five combinations\" is misleading. The figures show the interactions for five single extracts and for ten their binary mixtures. Authors probably intended to express that five plants were examined.\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": [
{
"c_id": "9335",
"date": "15 Feb 2023",
"name": "Syaiful Choiri",
"role": "Author Response",
"response": "Reviewer Comment 1: Different reaction times were used to estimate the antioxidant properties of extracts by the applied methods. To compare the results/methods, the measurements should be performed in the same time. Responses: Thank you for pointing this out and I agree with the reviewer statement. Before performing the tests, we have conducted operating time evaluation. This step determines the time which the kinetic reaction is relatively stable. It means, the time of reaction has negligible effect on the alteration of the response. In addition, the selected time for reaction is chosen based on the most efficient way (the shorter, the better along with stable response). Reviewer Comment 2: Incorrect location of the figures in the manuscript text makes it difficult to read. Figures showing the results obtained by DPPH method should be presented in the manuscript text fragment where the results from this method are described, etc. Response: Thank you for pointing this out and we have revised the figure location according to the proper location and discussion. Reviewer Comments 3: How were multi-component mixtures of plant extracts for testing their antioxidant properties prepared - how were the ingredients mixed, in what ratio? This should be described. Response: Thank you for pointing this out, we have added a sub-caption “Sample preparation” for describing the preparation of sample for those assays. Reviewer Comment 4: The authors should clarify the calculation way of the contributions which were used to express the interactions between the extracts (it concerns data in Figures 3 and 6). Response: The interaction contribution was calculated according to the percentage between regression coefficients of the interaction and the total the main effect and interaction regression coefficient. It was also calculated automatically using Design Expert Software. Reviewer Comment 5: Captions to Figures 3 and 6 should be changed. The expression \"five combinations\" is misleading. The figures show the interactions for five single extracts and for ten their binary mixtures. Authors probably intended to express that five plants were examined. Response: The figure captions revised. The data showed that the main effect, it means the single extracts effect on the response. In addition, the interaction appears according to the presence of two or more components."
}
]
}
] | 1
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https://f1000research.com/articles/11-1327
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https://f1000research.com/articles/12-192/v1
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20 Feb 23
|
{
"type": "Review",
"title": "A review of recent advances in the diagnosis of cardiac amyloidosis, treatment of its cardiac complications, and disease-modifying therapies",
"authors": [
"Maharshi Raval",
"Sajid Siddiq",
"Kamal Sharma",
"Labdhi Sanghvi",
"Akhil Jain",
"Sagar Patel",
"Jaahnavee Trivedi",
"Kanishka Uttam Chandani",
"Dhriti Patel",
"Rupak Desai",
"Sajid Siddiq",
"Kamal Sharma",
"Labdhi Sanghvi",
"Akhil Jain",
"Sagar Patel",
"Jaahnavee Trivedi",
"Kanishka Uttam Chandani",
"Dhriti Patel",
"Rupak Desai"
],
"abstract": "Cardiac amyloidosis (CA), a significant condition resulting in infiltrative cardiomyopathy and heart failure with preserved ejection fraction (HFpEF), is caused by extracellular deposition of amyloid fibrils in the heart. Even though this has been known for an extended period, its prevalence in elderly patients with heart failure is increasingly being recognized. Recent advances in diagnosis with non-invasive methods like technetium pyrophosphate-labeled cardiac scintigraphy (i.e., Tc-PYP scan) and treatment options with tafamidis have played a pivotal role in awareness of the burden of this disease. Management of cardiac complications like heart failure, atrial arrhythmias, conduction block, ventricular arrhythmias, coronary artery disease, and aortic stenosis is now more critical than ever. We aim to review and outline the recent advances in diagnoses of CA. We also review management strategies for cardiac complications of CA with a brief summary of disease-modifying therapies.",
"keywords": [
"cardiac amyloidosis",
"heart failure",
"bone scintigraphy",
"ATTR amyloidosis",
"AL amyloidosis",
"tafamidis"
],
"content": "Introduction\n\nCardiac amyloidosis (CA) is primarily classified as either transthyretin (ATTR) or light chain (AL) amyloidosis. ATTR amyloidosis may result from a genetic mutation in the TTR gene, which is inherited (ATTRv), or may result from age-related deposition from wild-type ATTR (ATTRwt).1,2\n\nCA should be suspected in elderly patients with heart failure symptoms such as dyspnea or fatigue. Deposition of amyloid fibrils in the atrium and the conduction system, including the atrioventricular (AV) node, may result in various rhythm abnormalities. These range from atrial tachycardias such as atrial fibrillation to AV conduction delays to heart blocks. In recent studies on the autopsied heart, amyloid deposition in the ventricles is found frequently; however, sustained ventricular tachycardias are not frequently reported.3–5\n\nPlasma cells produce monoclonal immunoglobulin light chains, which result in amyloid fibrils responsible for AL amyloidosis. Cardiac involvement in AL amyloidosis is attributed to two mechanisms. One is the extracellular deposition of amyloid fibril in the myocardium, and another involves direct cardiotoxicity from the fibril aggregates.3 Although many organ systems are typically involved, cardiac involvement is the leading cause of mortality and morbidity in 50-70% of cases.6 Diagnosis is achieved by detecting free light chains or monoclonal immunoglobulins in blood and urine. Treatment is through specifically directed chemotherapy.3\n\nPreviously, ATTRv amyloidosis was considered to be of neurological importance and ATTRwt to be of systemic importance. This was because of the predominance of neurological symptoms, including neuropathies reported with ATTRv amyloidosis. ATTRwt amyloidosis was always known to be a culprit for cardiomyopathy.7 However, with the recent recognition of the disease and the development of noninvasive diagnostic modalities, ATTRv amyloidosis has also been implicated in causing cardiomyopathy.7 Despite these advances, there remains a vast number of undiagnosed cases of ATTR amyloidosis. Studies on valves replaced/removed by either transcutaneous or surgical approach have shown a 16-25% prevalence of ATTRwt deposits.8 This has led to an increased focus on CA in pre-operative evaluation for transcatheter aortic valve replacement (TAVR).9\n\nIn the absence of effective therapies for cardiac amyloidosis previously, diagnosis of AL and ATTR amyloidosis was not an area of focus. However, with the advent and availability of specific chemotherapy, early diagnosis and initiation of therapy are crucial.10\n\n\nDiagnosis\n\nClinical clues are essential in leading clinicians toward thinking of amyloidosis. AL amyloidosis is associated with multisystem involvement. Thus, signs of nausea, vomiting, diarrhea, gastrointestinal bleeding for GI involvement, renal failure with albuminuria, and systemic symptoms of macroglossia are typical red flag symptoms. ATTRv amyloidosis may present with early neurological symptoms of neuropathies which may be diffuse or axonal.7 ATTRwt amyloidosis may concern patients with bilateral carpal tunnel syndrome and lumbar stenosis, as such manifestations may predate cardiomyopathy by decades.9\n\nElectrocardiography is typically the first diagnostic study to be performed due to its easy availability. Low voltage QRS complexes have been known to be associated with cardiac amyloidosis, although recent data suggests it may be over-implicated. Almost 70% of patients with proven cardiac amyloidosis may not have low voltage and may have a standard or even high voltage meeting the criteria for left ventricular hypertrophy.11 Atrial deposits can result in arrhythmias, and deposits in the conduction system resulting in heart block may represent other findings on the electrocardiogram. Pseuodoinfaction identified by pathological Q waves or QS waves on two consecutive leads is seen in patients with AL amyloidosis. If present, the study demonstrates worse outcomes of AL amyloidosis.12\n\nEchocardiography has been an essential tool for the evaluation of patients with symptoms of heart failure. Unexplained LV thickness >12 mm, along with grade 2 or worse diastolic dysfunction and reduced tissue doppler velocity, can meet echocardiographic criteria; however, these need to be coupled with biopsy or nuclear imaging.13 LVEF has been previously used to diagnose and monitor patients with decline associated with disease progression. It is noted that LVEF declines later, and thus, it does not accurately predict the worsening of the disease.14 Global longitudinal strain (GLS) has developed as an emerging tool to predict diagnosis and outcome accurately. Relative apical sparing of GLS resulting in a bull’s eye pattern of apical sparing is strongly suggestive of CA, differentiating from other causes of cardiomyopathy.14 GLS has proved to be superior to LVEF in diagnosis, risk stratification, and decision-making amongst patients with AL amyloidosis.15\n\nCardiac magnetic resonance (CMR) utilizes its intrinsic property to differentiate normal myocardium from pathologic through T1 and T2 signals. This, when coupled with late gadolinium enhancement (LGE) and extracellular volume (ECV) measurement, vastly improves the diagnostic ability for CA.16 Recent studies challenge the typical LGE pattern in CA of global subendocardial enhancement. Progression of LGE pattern from subendocardial to transmural has been recently reported.16 CMR was also studied for its ability to differentiate between AL and ATTR amyloidosis; however, it was not found to be sensitive or specific.10\n\nNuclear imaging with bone scintigraphy and single photon emission computed tomography (SPECT) is widely available. 99m Technetium-pyrophosphate (PYP) is increasingly used to diagnose ATTR amyloidosis in the United States. It is also now recognized as confirmatory in the absence of cardiac biopsy.1 99mTc-hydroxydiphosphonate (HMDP) and 99mTc-DPD are other radiotracers used in Europe, depending on availability. Heart to contralateral lung ratio (H/CL) evaluated 1 hour after uptake quantifies cardiac uptake. Visual uptake is reported by the Perugini grading system, with grade 0 reported with no cardiac uptake, grade 1 reported with mild cardiac uptake compared to rib, grade 2 with equal uptake, and grade 3 with higher cardiac uptake compared to rib.16 While studies have shown that grade 2 and 3 uptake and H/CL ratio >1.5 are sensitive for ATTR amyloidosis, mild uptakes are also noted in about 40% of cases with AL amyloidosis.17 Recently, the H/CL ratio has been challenged. Mitral annular and aortic valve calcifications can cause increased uptake while myocardial scars can cause decreased uptake.18 Blood-blood imaging (PYP in blood pool in RV and LV cavity) can cause false positives. Therefore SPECT evidence for PYP uptake is considered a diagnostic cornerstone.19\n\nGiven AL amyloidosis's different management and prognosis, it is important to rule it out with the help of urine and blood immunoglobulin light chains. Once AL amyloidosis is ruled out, grades 2 and 3 uptake become more than 90% sensitive and 98% specific for ATTR CA when coupled with positive SPECT images.20 With the availability of such a test, obtaining a PYP scan in patients with LV thickness ≥12 mm on echocardiogram and any one red flag sign is recommended.13 We utilize the algorithm as noted in Figure 1 for the diagnosis of CA.\n\nLV-left ventricle, Tc-99m PYP-Technetium-99m pyrophosphate, CA-cardiac amyloidosis, CMR-cardiac magnetic resonance, ATTR- transthyretin amyloidosis, AL-amyloid with light chain\n\n*Red flags - heart failure ≥65 years, aortic stenosis ≥65 years, hypotension or normotensive if previously hypertensive, sensory involvement, autonomic dysfunction, peripheral polyneuropathy, proteinuria, skin bruising, bilateral carpal tunnel syndrome, ruptured biceps tendon, subendocardial/transmural late gadolinium enhancement or increased extracellular volume fraction, reduced longitudinal strain with apical sparing, decreased QRS voltage to mass ratio, pseudo Q waves on ECG, atrioventricular conduction disease, possible family history.\n\nPosition emission tomography (PET) has been studied and suggested to have a role in diagnosis and therapeutic monitoring.21 However, studies with a direct comparison between SPECT and PET have demonstrated the superiority of SPECT over PET in terms of sensitivity and specificity for the diagnosis of ATTR CA.22\n\n\nTreatment of cardiac complications\n\nTreatment of cardiac amyloidosis focuses on managing cardiac complications and preventing the worsening of underlying organ failure. The most common complication encountered clinically is heart failure. Typically, it presents as HFpEF. Management strategies with usual heart failure medications may prove harmful in CA. ACE inhibitors/ARBs may aggravate orthostatic hypotension secondary to activation of the renin-angiotensin-aldosterone system due to autonomic dysfunction.23 Beta-blockers can also precipitate hypotension by decreasing heart rate and contractility; however, a recent study from Italy has demonstrated that beta-blockers may be tolerated for the management of co-morbidities even in the presence of CA.23,24 Calcium channel blockers are implicated in binding to amyloid fibrils which may result in cytotoxicity. If treated with digoxin, CA is already prone to arrhythmias due to amyloid deposition in the atrium, which can increase fatal arrhythmias.23 Treatment should be diuretics which help relieve congestion as needed. Loop diuretics have been used for an extended period in CA; however, recent data suggest vasopressin receptor antagonists may be more suitable for achieving balanced euvolemia and avoiding the risk of hypotension with loop diuretics.25 In addition, recent emperor preserved and deliver trials have shown the benefit of sodium-glucose cotransporter 2 inhibitors in patients with HFpEF in decreasing hospitalizations and are now incorporated in HFpEF management with 2a evidence. Although specific studies on patients with CA are lacking, data from these trials can be extrapolated in this specific circumstance.26,27\n\nAtrial fibrillation is a known complication of CA; however, its management has been of interest recently. Rate control medications such as beta-blockers and calcium channel blockers are relatively contraindicated, as noted above. Rhythm control strategies may be appropriate, and amiodarone is the antiarrhythmic drug of choice. Electrical cardioversion is also attempted; however, it is essential to rule out LA thrombus, and the recurrence rate of atrial fibrillation is high at 51%, as noted in a recent study.28 A similar value holds for catheter ablations, with a recent study demonstrating an 80% recurrence rate at two years.29 Anticoagulation with NOACs is indicated irrespective of the CHA2DS2-VASc score because of the risk of thrombus formation in CA due to its inherent risk of thrombogenicity beyond known risk factors.30\n\nCoronary artery disease (CAD) in patients with CA presents various issues regarding management. It is possible that in a person with CAD, it may mask the symptoms of CA. Ischemic cardiomyopathy resulting in heart failure symptoms may prolong the diagnosis of cardiac amyloidosis. An issue arises when medical therapy with beta-blockers and ACEI/ARBs are indicated for ischemic cardiomyopathy but avoided in CA. Patients with triple vessel CAD with known CA need to be considered for percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG). The benefits of CABG over PCI in triple vessel disease with diabetes are typically seen in the long run.31 ATTR CA has a better prognosis than AL amyloidosis; however, that as well is about 3-5 years.3 A decision that will need to be addressed in this scenario is whether the short-term risk of CABG outweighs its long-term benefits, given prognosis is not prolonged to reap the benefits of CABG. Heart block is a known complication of CABG, and the risk may be very high in patients with CA. Case reports have shown increased morbidity in patients with CA undergoing CABG.32 Further studies looking specifically at the question of PCI versus CABG in patients with CA and triple vessel CAD are needed.33\n\nAortic stenosis (AS) and its association with CA are well known now, with studies showing the incidence of CA in AS patients undergoing valve replacement as high as 29%.34 It is still unclear precisely if CA contributes to AS or if they are independent and association is merely age-related. Deposition of amyloid fibrils on the valve resulting in AS argues for CA contributing to AS. Recent data suggest that combined AS-CA is associated with worse 1-year-mortality compared to lone AS.35,36 Previously, ATTR amyloidosis therapies were not vastly available and approved. Now with TTR stabilizer and silencer therapy available, various new areas to explore are available. Two questions are critical to avoid such an increased risk of heart block; 1) Whether patients with severe AS undergoing TAVR should be routinely tested for CA? 2) If they are tested and found to have ATTR CA, should they receive a trial of TTR stabilizer/silencer medication prior to valve intervention? Data regarding this is lacking at this point.\n\nPacemaker implantation is seen frequently in patients with CA who develop conduction disorders. These are the patients who develop symptomatic bradycardia or high-degree atrioventricular block. The question that arises with this is, can pacemaker implantation be considered in high-risk individuals for primary prevention? There has been sparse data regarding the role of permanent pacemaker implantation (PPM) for primary prevention and the optimal time to pursue such a step. A recent study by Milner et al. on patients referred for liver transplants tried to answer this question. Data did not suggest improved mortality or morbidity in patients who received a PPM before liver transplantation for prophylaxis.37 A recent study by Porcari et al. noted that 8.9% of patients with the diagnosis of CA needed PPM implantation within 3 years of diagnosis.38 Thus, until further data is available, it is reasonable to reserve pacemaker placement for secondary prevention.\n\nCardiac resynchronization therapy (CRT) has been previously suggested to be used for patients in whom a high-paced burden is expected who are undergoing pacemaker placement.13 Traditionally indicated for patients with LVEF <35% with left bundle branch block and QRS >150 ms; theoretically, it also plays a role in CA. Infiltrative cardiomyopathies in which RV pacing leads to LV systolic dysfunction, and when AV conduction block is associated with LV dysfunction, CRT may be indicated. Detailed data on CRT in patients with CA is lacking. A recent study on major cardiovascular events and outcomes after CRT implantation in CA patients has not shown any benefit and has suggested that it may be associated with worsened HF symptoms and hospitalization. Compared to dilated cardiomyopathy, CRT had much lower response rates in patients with CA.39\n\nAn implantable cardiac defibrillator (ICD) has a role in the primary prevention of sudden cardiac death in patients with LVEF <35%. Electromechanical dissociation is likely the cause behind SCD in CA. ICD placement is recommended in CA for secondary prevention after the patient has developed sustained ventricular tachycardia.40 However, its role in the primary prevention of SCD in patients with CA is not established.41 Nonetheless, recent case reports have opened a new discussion area in this matter. Patients with cardiac amyloidosis who develop non-sustained ventricular tachycardia may not qualify for ICD placement just yet but do qualify for an electrophysiological study (EPS) to identify a potential area of the arrhythmogenic substrate for ventricular tachycardia.42 Further studies are needed for risk stratification and establishing guidelines regarding primary ICD in such patients.\n\nCardiac transplantation has been performed for decades in patients with cardiac amyloidosis, particularly AL amyloidosis. However, outcomes were not favorable previously. This was secondary to extracardiac involvement and limitations of chemotherapy options. With the advent of advanced chemotherapy given even after cardiac transplantation and better diagnostic techniques allowing extracardiac detection, proper candidates are being chosen for cardiac transplantation associated with improved outcomes.43\n\nMechanical circulatory support (MCS) has not been studied adequately in CA. Being restrictive cardiomyopathy, to implant assist devices in CA with small cardiac cavities is technically challenging. If selective left ventricular assist devices are placed, it increases the risk of right-sided heart failure. Also, considering patients with CA being on active immunosuppressive therapy, the risk of infection needs to be considered. Despite these factors, there has been recent data to suggest a role of MCS in patients with left ventricular end-diastolic diameter >46 mm. Even if performed as a bridge to transplantation, MCS is associated with increased survival.44\n\n\nDisease-modifying treatment\n\nAL amyloidosis is managed with various chemotherapy agents. Oral melphalan with steroids has been used for treatment for an extended period. Autologous stem cell transplant and melphalan became the mainstay of treatment in the 1990s and remained robust treatment options. However, the introduction of proteasome inhibitors revolutionized the treatment of AL amyloidosis with the enteral agent of bortezomib.45 In a recent study, bortezomib is shown to have a significant hematological response and improved survival.46 Various regimens have been studied, but no regimen is found to be superior to others.47 Newer therapies with anti-CD38 human IgG monoclonal antibody agents daratumumab and isatuximab are currently under investigation, with preliminary data showing better short-term outcomes.48\n\nATTR amyloidosis therapies are aimed at two mechanisms. One is to silence the TTR gene, and the other is to stabilize the TTR tetramers preventing them from forming monomers and thus constituting amyloid fibrils. TTR stabilizer includes Tafamidis and Diflunisal, showing promising data with substantially improved long-term outcomes in recent studies.49 Patients with ATTR CA treated with Tafamidis have had reduced CV-related hospitalizations and length of stay in the hospital.50 The most significant barrier to tafamidis being widely used is its cost-effectiveness. Even with insurance, it is estimated that the cost of production of tafamidis may need to be reduced by >90% for it to be cost-effective.51,52\n\nGene silencer therapy with Patisiran has been studied in ATTRv and has shown significant improvement in neurological symptoms in patients with ATTRv amyloidosis after liver transplantation.53 Another gene silencer medication Inotersen has shown similar improvement.54 Many patients with ATTRv amyloidosis may have a mixed phenotype of cardiomyopathy and polyneuropathy. These patients can be considered for either TTR stabilizer or gene silencer therapies. Current practice and guidelines recommend selecting medication based on the predominance of cardiac or neurological phenotype. However, data to support this approach is not conclusive. Given their mechanism of action, gene silencer medications may be even more effective than TTR stabilizer medications in managing ATTR CA.\n\nMost recently, targeted delivery of gene-editing therapy with the Cas9 endonuclease (CRISPR-Cas9) system to the hepatocytes is being studied. This is a single infusion and reduces the production of transthyretin by the hepatocytes.55 Clinical trials are ongoing, focusing on new therapies such as vutrisiran, AG10, doxycycline, green tea, and monoclonal antibody NNC6019-0001 for their role in managing ATTR CA.56\n\n\nConclusion\n\nMany recent advances have been made in diagnosing and managing cardiac complications of amyloidosis and disease-modifying treatment. Bone scintigraphy has played a pivotal role in early, non-invasive diagnosis coupled with disease-modifying therapy with medications such as Tafamidis and Bortezomib have changed the perception of CA. With better diagnostic capabilities, cardiac complications need to associate with CA and be managed based on specific guidelines obtained from data of CA patients. This opens new doors for research questions. Management of triple vessel CAD with co-existent CA with PCI versus CABG, routine PYP scan prior to TAVR, a trial of Tafamidis prior to valve intervention, ICD for primary prevention of SCD in CA after EP study, MCS in patients with adequately sized cardiac chambers are few of such questions which we have raised and hypothesized in this article.\n\n\nAuthor contributions\n\nMR prepared the manuscript with the help of LS, AJ, SP, JT, KUC, DP, and RD. SS and KS are the senior authors who helped revise the manuscript and reviewed it for intellectual content.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nHanna M, Ruberg FL, Maurer MS, et al.: Cardiac Scintigraphy With Technetium-99m-Labeled Bone-Seeking Tracers for Suspected Amyloidosis. J. Am. Coll. Cardiol. 2020; 75(22): 2851–2862. PubMed Abstract | Publisher Full Text\n\nMacedo AVS, Schwartzmann PV, de Gusmão BM , et al.: Advances in the Treatment of Cardiac Amyloidosis. Curr. Treat. Options in Oncol. 2020; 21(5): 36. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMartinez-Naharro A, Hawkins PN, Fontana M: Cardiac amyloidosis. Clin. Med. 2018; 18(Suppl 2): s30–s35. Publisher Full Text\n\nPorcari A, Bussani R, Merlo M, et al.: Incidence and Characterization of Concealed Cardiac Amyloidosis Among Unselected Elderly Patients Undergoing Post-mortem Examination. Front. Cardiovasc. Med. 2021; 8: 8. 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}
|
[
{
"id": "164947",
"date": "06 Mar 2023",
"name": "Apoorva Kondapally",
"expertise": [
"Reviewer Expertise Areas of interest and research are endocrinology",
"immunology",
"neurology."
],
"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\nAn excellent report in reviewing the key aspects of cardiac amyloidosis focusing on recent advances and current literature. All statements appear to be factual, and the language is appropriate.\nIt has detailed recommendations of recent advances in management with adequate and appropriate citations and the conclusions are made in accordance with the current literature.\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": "164944",
"date": "08 Mar 2023",
"name": "Bhavi Trivedi",
"expertise": [
"Reviewer Expertise Internal Medicine"
],
"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 comprehensive review of cardiac amyloidosis. Figure 1 was a good overview. A good number of resources were cited. The authors provided a detailed oriented review of cardiac amyloidosis and advances in the field. The information provided is thorough and has efficiently summarized the management strategies and disease modifying therapies. I did not answer \"no\" or \"partly\" to any questions.\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
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https://f1000research.com/articles/12-192
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https://f1000research.com/articles/11-1321/v1
|
15 Nov 22
|
{
"type": "Review",
"title": "Avian influenza (H5N1) virus, epidemiology and its effects on backyard poultry in Indonesia: a review",
"authors": [
"Saifur Rehman",
"Mustofa Helmi Effendi",
"Adiana Mutamsari Witaningruma",
"Ugbo Emmanuel Nnabuikeb",
"Muhammad Bilal",
"Asghar Abbas",
"Rao Zahid Abbas",
"Kashif Hussain",
"Saifur Rehman",
"Adiana Mutamsari Witaningruma",
"Ugbo Emmanuel Nnabuikeb",
"Muhammad Bilal",
"Asghar Abbas",
"Rao Zahid Abbas",
"Kashif Hussain"
],
"abstract": "Avian influenza (AI) is a zoonotic viral endemic disease that affects poultry, swine, and mammals, including humans. Highly pathogenic avian influenza (HPAI) is caused by influenza type A virus subtypes H5, and H7 which are naturally carried by a wild bird and often affect domestic poultry. Avian influenza (AI) is a major problem worldwide that causes significant economic losses in the poultry sector. Since 2003, the widespread H5N1 HPAI in poultry has led to high mortalities resulting in huge economic losses in the poultry sector in Indonesia. Domestic poultry is a key source of income that contributes to economic growth, both directly and indirectly, by reducing poverty among the people living in rural communities. Furthermore, in many developing countries, including Indonesia, rural people meet a portion of their food needs through backyard poultry. Nevertheless, this sector is strongly affected by biosecurity hazards, particularly in Indonesia by HPAI infections. Avian influenza (AI), subtype H5N1 has zoonotic significance, posing major risks to public health and poultry. Due to close interaction between wild migratory birds and ducks, the domestic poultry sector in Indonesia is directly affected by this virus. This virus continues to be ubiquitous in Indonesia as a result of the unpredictable mutations produced by antigenic drift and shift, which can persist from a few days to several years. In this review, the epidemiology and impact, of highly pathogenic avian influenza H5N1 subtype virus infection on backyard poultry in Indonesia were discussed.",
"keywords": [
"Avian influenza",
"backyard poultry",
"Public health",
"H5N1",
"Indonesia"
],
"content": "Introduction\n\nHighly pathogenic avian influenza (HPAI) virus subtype H5N1 had caused multiple outbreaks in poultry worldwide and hundreds of (mostly fatal) human cases since their discovery in Hong Kong in the late 1990s.1–4 Avian influenza virus (AIV) affects a variety of animals, including birds, horses, dogs, cats, whales, and pigs, and have zoonotic potential that causes death in humans. AI A virus subtypes (including H5N1 and H9N2) have caused significant economic losses in the poultry sector, especially in the backyard and commercial poultry farming around the world. Massive vaccinations have been used to reduce the number of avian influenza infections, but still, no appropriate precautionary measures were adopted in the domestic poultry industry. Highly pathogenic avian influenza (HPAI) strain H5N1 has been found in domestic poultry or wild birds from 61 countries since the isolation of HPAIV subtype H5N1 from a domestic goose in Guangdong Province, China (A/goose/Guangdong/1/96).5 HPAIV outbreaks were reported in seven of the eleven Southeast Asian countries between 2003 and 2008. In December 2003, Vietnam was the first country to report poultry death caused by H5N1 HPAIV infection.6 Although the disease was first reported in Indonesia in January 2004, a retrospective investigation suggests that outbreaks in backyard poultry in Indonesia began in August 2003.7 Similarly, the infection could have existed in Vietnam before December 2003. In several Southeast Asian countries, high poultry mortalities due to other illnesses, such as Newcastle disease, are widespread, which may have contributed to HPAI detection and diagnosis delays.6 Domestic bird losses in the area were estimated to be 140 million in 2005, at a cost of almost US$10 billion.8 The backyard and commercial poultry farming play an important role in many Asian countries in providing a suitable percentage of protein in the form of meat and eggs. The increasing population will immediately increase the food requirement percentage items all over the world. As a result, this source has evolved into a strong source of energy between the supply and demand for animal protein. Rural poultry has made a substantial contribution to poverty alleviation in many industrialized and developing countries.9 The highly pathogenic avian influenza virus subtype H5N1 affects all segments of the chicken population, including commercial and domestic poultry, and the risk of infection spread increases with wild migratory birds, which have no restrictions on crossing international boundaries.9 However, farmers' ignorance and lack of knowledge of the systematic source of this virus play a key part in the spread of infection.10 Women play a key role in the development of the backyard poultry production system in many regions of the world, allowing them to meet their economic demands regularly by growing birds at home.11 HPAI H5N1 has been endemic in Indonesian poultry since 2003, resulting in severe economic losses for both the poultry industry and backyard farms. In high-incidence areas, the disease has been detected in 32/34 provinces,12,13 resulting in the deaths of millions of birds and the closure of numerous farms.14 According to the universal naming scheme for the HA gene of the HPAI H5N1 virus, the hemagglutinin (HA) genes evolved from clade 2.1 into several subclades while HPAI H5N1 viruses were continually distributed among poultry in Indonesia from 2003 to 2010.15 Vaccination programs have been used to control the spread of HPAI H5N1, however, due to low vaccination coverage and the use of unlicensed vaccines, they have not proven successful.16\n\nIn this review, epidemiology and impact of highly pathogenic avian influenza H5N1 subtype virus infection on backyard poultry in Indonesia was discussed. The epidemiology, evolutionary history, detection method, and threat level of avian influenza A virus subtype H5N1 in backyard poultry of Indonesia is discussed in detail. Recommendations for future initiatives and policies to reduce the risk of avian influenza (HPAI and LPAI) in Indonesian backyard poultry.\n\n\nEpidemiology and life cycle\n\nAvian influenza is a contagious viral infection that affects poultry, animals, and humans worldwide. The majority of human infections were caused by type A and B influenza viruses, while poultry was only infected by type A influenza. A number of strains of the avian influenza virus (LPAI and HPAI) have been detected in poultry farms around the world.17 In 1996, the H5N1 virus, which is a type of HPAI, was found in geese in China. In 1997, during a poultry outbreak in Hong Kong, Asian H5N1 was discovered in humans for the first time. Since then, it has been found in humans, poultry, and wild birds in over 50 countries throughout Africa, Asia, Europe, and the Middle East.18–21 The presence of living cells is necessary for the spread of viruses.\n\nInitial surveillance of avian influenza viruses in Indonesia found a significantly higher prevalence of HPAI H5N1 at LBMs than in poultry-producing areas, implying that the HPAI virus must move widely during the trade process. Moreover, the value chain of backyard poultry (e.g., Kampung or indigenous chickens) and commercial poultry (e.g., broilers and layers) marketed in Indonesian urban live bird markets (LBMs) differs significantly. Backyard poultry is typically bought by middle-class or small-scale poultry dealers who go by motorbike to several villages to trade with farmers or purchase birds from small village markets (Food and Agriculture Organization, unpublished data). To provide greater insight into the epidemiology of HPAI in Indonesia, genetic and antigenic data are significant. Epidemiological research on duck scavenging in smallholder farms in central Java, Indonesia, highlighted that these birds could be an important source of the H5 virus for indigenous chickens.22 In 2004 there were 7 pandemics in Indonesia involving 4 types of the H5N1 virus, but nothing was seen to be transmitted to the Sumatera region.23 In 2004, the phylogenetic analysis of the H5N1 pandemic in Bangka Belitung was genotypically different from the other 6 regions outside Sumatra. Meanwhile, two new H5N1 virus clades were introduced in Sumatra in 2005 and distributed through Riau, Jambi, Palembang, and Lampung in 2005.24 They have a mutation that is very similar to the variant of H5N1 found at almost the same time in West and East Java, Bali, and Nusa Tenggara Barat (NTB). The possibility of transmission between these areas is therefore very high.24 In 2004, FAO identified four poultry production sectors globally: village or backyard production with birds or products consumed locally include in sector four.25 The first phase of the PDSR project from January 2006 to April 2008 emphasized the detection and control of HPAI by separate PDS and participatory disease response (PDR) teams primarily in sector 4 poultry at the household level. Through the participatory disease surveillance response (PDSR) program, outbreak control, and prevention capacity in village-based poultry have been developed across endemic areas of Indonesia.25\n\nThe influenza virus has a multistep process for reproduction and infection. Haemagglutinin (HA or H) plays a role in host cell virus attachment and subsequent fusion with cell membranes, while neuraminidase (NA or N) promotes the release of viruses from the surface of the host cell by hydrolyzing glycoprotein sialic acid, which helps to release particles of the progeny virus particles from host cells.26 Non-structural protein 1 (NS1) plays a major role in inhibiting host immune response through interferon (IFN) production limitation.27 NS2 referred to as a nuclear export protein or NEP plays a role in the export of RNPs during viral replication from the nucleus to the cytoplasm, and also regulates the transcription and replication processes of viruses.28 The dominant structural protein is matrix protein 1 (M1), the major structural protein that also plays an important role in the assembly and budding of viruses in determining virus morphology.29 Matrix protein 2 (M2) is the pH-regulating ion channel and is responsible for virus uncoating, the phase following the entry of the virus into the host cell.30 In addition, in the last stage of the viral life cycle (Figure 1), this protein also plays an important role in membrane splitting.31 Matrix protein 42 (M42) can replace M2 functionally and promote effective replication in null M2 influenza viruses.32 The incubation period of the disease in chickens is one to seven (1–7) days. The most prevalent sialic acid links with which influenza viruses have a strong affinity are 2,3 and 2,6 linkages. One aspect of host specificity could be the various sialic acid connections. Both types of receptors are widely expressed in chickens, ducks, cats, and pigs, with SA 2,6Gal being the most abundant in human respiratory tissues, including epithelial cells in the nasal mucosa, paranasal sinuses, pharynx, trachea, bronchi, and bronchioles33–36 while SA 2,3Gal is occasionally found in the nasal mucosa and non–ciliated cuboidal bronchiolar cells at the junction of the respiratory bronchiole and alveolus, SA 2,3Gal is rarely found in the pulmonary bronchiole and alveolus.37\n\nAll influenza A virus subtypes are naturally found in wild aquatic birds. Viruses of avian influenza A are often transmitted from wild birds to domestic poultry and from domestic poultry to pigs. The influenza A virus can reassort in pigs from avian, swine, and human sources, and pigs are frequently exposed to human and domestic poultry virus strains. Humans might be affected by influenza A viruses from pigs act as mixing vessels for the transmission of these viruses38 (Figure 2).\n\n\nVirus identification\n\nClade 2.1 viruses have been enzootic in Indonesia since 2003. However, during poultry outbreaks since 2012, a new HPAI H5N1 clade 2.3 virus has been found. To date, a new H5N1 subclade (2.3.2.1) has evolved, and a novel vaccine based on isolate A/duck/Sukoharjo/BBVW-1428-9/2012 has been produced.39\n\nThere are numerous diagnostic techniques available for detecting avian influenza viruses in respiratory tissues, and notably molecular assays (PCR). Haemagglutination inhibition and ELISA are serological teststhat are frequently used to identify antibodies of influenza A and B viruses. As a consequence, proper influenza serological testing involves the collection of matched acute and convalescent samples 2-3 weeks apart in order to identify a 2 or 4-fold or more elevation in influenza virus strain-specific antibodies.40 Rapid influenza diagnostic tests (RIDTs) are immunoassays that can detect influenza A and B viral nucleoprotein antigens in respiratory samples and display the results in a qualitative manner.41\n\n\nEffects of HPAI A virus subtype H5N1 on backyard poultry\n\nBackyard poultry farming is a conventional method of maintaining chickens that are mostly used in rural areas. It is a low-input enterprise that involves raising small flocks of poultry birds in backyards using a free-range system in which the birds forage for food.42 In developing countries, small-scale poultry is raised by family members utilizing available locally mixed feed resources. Backyard chickens typically wander around more inside and outside the house, scavenge for food, and share it with other wild birds.43 Mostly every rural and urban family owns 5-20 adult chickens in a small flock, which are primarily cared for by children and women. Profits are often modest, and products are consumed for their usepresented as religious offerings, or given as gifts.44,45 In most Asian countries, AI has an impact on all aspects of the poultry industry, but it appears to be most widespread in industrial ducks, rural chickens, live bird markets, and fighting cocks.46 The majority of infections spread across backyards and other commercial and wild migratory birds contribute to the global spread of the high pathogenic subtype H5N1 virus. Wild migratory birds act as a reservoir host for AI viruses that become a formidable source of AIV infection all over the world. Indonesia's poultry-producing industry is extremely diversified. Village or backyard production with birds or products consumed locally include in sector four.47 AIV subtype H5N1 was introduced to Indonesia on multiple occasions.48 The virus was likely propagated by wild migratory birds, as well as through trade and transportation of poultry and poultry products between different places.49,50 A higher level of backyard poultry contact is likely linked to the nature and purpose of visits, which disclose additional farm-to-farm and farm-to-live bird market tours aimed at observing birds or acquiring live birds and items. This shows that Indonesia's Sector 4-(backyard farms) has the highest risk of being infected with HPAIV from other poultry sectors and of being a possible infection source, particularly for the small-scale commercial poultry farms.51,52\n\nIn Indonesia, Sector 4-(backyard farms) was shown to have a higher incidence of HPAIV infection and a higher proportion of disease outbreaks, suggesting that they may play a role in maintaining the HPAIV infection cycle in poultry.51,53 In most years, HPAI H5N1 poultry epidemics in backyard poultry in Indonesia peak in January or February (USAID Indonesia, unpublished data). Backyard poultry production accounts for around 50% of Indonesia's total chicken population.54 Backyard chicken raising in Indonesia is connected with poor sanitation and biosecurity, which appears to pose a considerably higher risk of HPAI virus transmission.55 According to Loth et al., participatory disease surveillance (PDS) study in backyard chickens found that “human population density” and “rice cultivation” had a significant association with HPAI cases in Indonesia. Reassortment of HPAIV has largely occurred in backyard chickens in Indonesia. Reassortment may have occurred in West Java due to high poultry density, the existence of many poultry kinds, and frequent contact between poultry farms and domestic poultry and wild birds.56 Domestic poultry is described as free-ranging birds living in a limited space alongside humans and other animals. These backyard birds can also scavenge other types of food from wild migrating birds, which can spread HPAI infection.57 In both developed and developing countries, this industry is one of the most important contributions to poverty alleviation. Children and women raise poultry in a relatively constrained area of the home due to the cheap adjustable cost and rapid changeover of productive output. In general, backyard poultry serves as a source of income and savings in Indonesia, where chickens/ducks can be sold to pay for children's school fees and other household emergency needs such as medical care.58 Around 300 million chickens, ducks, and quails are believed to be kept in the backyards of 30 million Indonesian homes, or 60% of the country's total population.59\n\nAccording to PDRS findings, the village attack rate in Bali (number of villages reporting H5N1 in S4 poultry/total number of villages) was 12.74% (92/722) in 2009 and 28.26% (204/722) in 2007 (PDSR, unpublished data, 2010). To estimate the frequency of H5N1 in backyard poultry, a survey was done in Bali. 14 of 1714 collected faecal samples from afflicted villages were positive for H5N1 after viral isolation.60 Due to higher H5N1 frequency in these places than in Bali, inferring surveillance data for semi-intensive poultry farms in other Indonesian provinces, such as Java, is particularly difficult.61,62 Desniwaty Karo-karo et al. conducted a study among different bird species to determine the prevalence of HPAI H5N1 in the Indramayu and Subang regencies of West Java Province. The findings of their research stated that the biggest peak AI occurred in February 2016 (average 41.3%, 95% confidence interval: 25.6–56.5%), with the majority of positive samples coming from backyard poultry (average 69.23%, 95% confidence interval: 54.74 –83.71%).13 E. Basuno et al. reported that smallholders and backyard farmers in Indonesia suffered enormous financial losses as a result of the HPAI outbreak. These losses were due to high mortality, decreased production, less demand for poultry products, and a decrease in price specifically in backyard poultry.14\n\nAnother study conducted in West Java among backyard chickens, ducks and other birds observed backyard chickens have (average 59%, 95% confidence interval: 49–69%) with the highest death rate, followed by ducks (average 32%, 95% confidence interval: 19–45%) and others (average 28%, 95% confidence interval: 16–40%). Backyard poultry had the highest observed morbidity, at 44% (95% confidence interval: 32–54%), whereas ducks had 28% (95% confidence interval: 17–38%).63 Although the role of wild bird migrations in the spread of H5N1 across the Indonesian archipelago cannot be ruled out, migrating ducks may have carried the virus to Java. Agricultural techniques and the chicken trade, on the other hand, are believed to have kept the virus alive in Indonesia.64 In Bangladesh, the seroprevalence of AI virus was reported to be 20% in chickens and 23% in flocks, whereas in Vietnam, the seroprevalence of H5 was found to be 17.5% at the bird level in backyard poultry and smallholder commercial duck farms.65,66 Avian influenza was also reported in backyard poultry to be (1.5% out of 100 birds in Thailand67 and a high prevalence (62.5%) in Pakistan.68 As a result of the free-range nature of these birds, backyard poultry is primary source of AI infection in this poultry farming system. Food is readily available, which attracts wild migrating birds to backyard poultry enterprises.\n\n\nConclusion\n\nThe epidemiology, molecular mechanisms used by highly pathogenic avian influenza H5N1 to cause pathogenicity, and risk scale of avian influenza in Indonesian backyard poultry were reviewed. Research articles reviewed from different areas of Indonesia indicated that H5N1 infection is endemic in backyard poultry. It was observed that backyard poultry is an important source of transmission of H5N1 disease to other sectors of poultry farms in Indonesia because of the poor sanitation, lack of biosecurity system, and easy mixing of free-range birds with the wild long-distance migrating birds. The primary goal of this review is to determine the impact of highly pathogenic avian influenza subtype H5N1 in backyard poultry in Indonesia, as well as identify high-risk locations or villages for ongoing monitoring and effective control of AI viruses in hotspot areas, as well as define the backyard production system. The existence of the HPAI virus subtype H5N1 in many parts of Indonesia revealed the AIV exposure among backyard chickens. A broad vaccination strategy at the route levelis required for the control of H5N1 infection in backyard chickens to prevent the early phase of infection and limit the danger of avian influenza transmission. Regular surveillance of backyard poultry is required because these birds are at a higher risk of contracting the infection. Washing hands after handling birds, especially backyard and other fancy birds, is vital for human infection control, and this will likely reduce the occurrence of infection among them. Mass surveillance will help to determine the optimal time for avian influenza viruses to infect backyard poultry and lower the percentage of cases.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgements\n\nThis article was supported in part by the Penelitian Hibah Mandat funding from Universitas Airlangga, Indonesia in the fiscal year 2022, with grant number: 220/UN3.15/PT/2022.\n\n\nReferences\n\nBridges CB, Lim W, Hu-Primmer J, et al.: Risk of influenza A (H5N1) infection among poultry workers, Hong Kong, 1997–1998. J. Infect. Dis. 2002; 185(8): 1005–1010. Publisher Full Text\n\nMackenzie JS, Jeggo M, Daszak P, et al.: One Health: The human-animal-environment interfaces in emerging infectious diseases. Springer;2013.\n\nCox NJ, Trock SC, Uyeki TM: Public health implications of animal influenza viruses. JAi. 2016; 92–132.\n\nWHO: Cumulative Number of Confirmed Human Cases for Avian Influenza A(H5N1) Reported to WHO, 2003-2017.2017. (accessed on 5 September 2019).Reference Source\n\nWHO: Avian influenza facts & figures website, updated 4 January 2008.2008. 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Publisher Full Text\n\nLoth L, Gilbert M, Wu J, et al.: Identifying risk factors of highly pathogenic avian influenza (H5N1 subtype) in Indonesia. Prev. Vet. Med. 2011; 102(1): 50–58. Publisher Full Text\n\nPermin A, Pedersen G: The need for a holistic view on disease problems in free-range chickens. J. Netw. Smallhold Poult. Dev. R. Vet. Agric. Univ. Frederiksb Den. 2002.\n\nRahma SM: The role of NGOs in combating avian influenza in Indonesia: a Muhammadiyah case study. JN-Arp. 2010; (2).\n\nNormile D: Indonesia taps village wisdom to fight bird flu. American Association for the Advancement of Science;2007.\n\nChua TH: Studies on the diagnosis, epidemiology and control of highly pathogenic H5N1 avian influenza. Murdoch University;2009.\n\nIndriani R, Samaan G, Gultom A, et al.: Environmental sampling for avian influenza virus A (H5N1) in live-bird markets, Indonesia. Emerg. Infect. Dis. 2010; 16(12): 1889–1895. Publisher Full Text\n\nFAO: H5N1 Highly Pathogenic Avian Influenza, Monthly Global Update. Issue No. 26 – November–December.2010. (accessed 12.12.11).Reference Source\n\nKaro-Karo D, Pribadi ES, Sudirman FX, et al.: Highly pathogenic avian influenza a (H5N1) outbreaks in West Java Indonesia 2015–2016: Clinical manifestation and associated risk factors. Microorganisms. 2019; 7(9): 327. Publisher Full Text\n\nStoops AC, Barbara KA, Indrawan M, et al.: H5N1 surveillance in migratory birds in Java, Indonesia. Vector Borne Zoonotic Dis. 2009; 9(6): 695–702. PubMed Abstract | Publisher Full Text\n\nBiswas P, Barua H, Uddin G, et al.: Serosurvey of five viruses in chickens on smallholdings in Bangladesh. Prev. Vet. Med. 2009; 88(1): 67–71. PubMed Abstract | Publisher Full Text\n\nHenning J, Henning KA, Morton JM, et al.: Highly pathogenic avian influenza (H5N1) in ducks and in-contact chickens in backyard and smallholder commercial duck farms in Viet Nam. Prev. Vet. Med. 2011; 101(3-4): 229–240. PubMed Abstract | Publisher Full Text\n\nChantong W: Epidemiological Study of Avian Influenza in Backyard Chickens and Open Field-reared Ducks in Northern Thailand: Michigan State University. Large Animal Clinical Sciences. 2011.\n\nRehman S, Khan M, Rantam F, et al.: Seroprevalence and associated risk factors of avian influenza virus subtype H9N2 in backyard poultry of Peshawar Pakistan. J. Indonesian Trop. Anim. Agric. 2021; 46(3): 209–218. Publisher Full Text"
}
|
[
{
"id": "155892",
"date": "21 Nov 2022",
"name": "Sahibzada Waheed Abdullah",
"expertise": [
"Reviewer Expertise Virus-host interaction"
],
"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\nAn interesting review by Rehman et al. However, there are some issues the authors need to address before it could be considered for publication.\nSection introduction lines 1 and 2, Has instead of Had, its instead of their\n\nLine 6, Remove “Still,”\n\nPlease modify the following sentence, Recommendations for future initiatives and policies to reduce the risk of avian influenza (HPAI and LPAI) in Indonesian backyard poultry.\n\nPlease define LBMs at the first mention.\n\nThe mutation was very similar to the variant of H5N1 found at almost the same time in West and East Java, Bali, and Nusa Tenggara Barat (NTB). Instead of “They have a mutation that is very similar to the variant of H5N1 found at almost the same time in West and East Java, Bali, and Nusa Tenggara Barat (NTB).”\n\nIn the epidemiology and life cycle section, in 2nd paragraph, the authors mentioned, “FAO identified four poultry production sectors globally,” but the authors failed to describe the other three poultry production sectors.\n\nDefine DPSR at first mention in the text.\n\nDefine PDS at first mention in the text.\n\nThe authors said that the Influenza virus has a multistep process for reproduction. I suggest that the authors first define all the viral proteins and then describe their roles in the virus life cycle. In fact, the virus life cycle paragraph is a disaster by mixing various viral proteins involved in the replication cycle. Authors are suggested to write this paragraph in an order from virus entry to release.\n\nThe last paragraph of the epidemiology and life cycle should be moved to the start of this section.\n\nPlease revise figure 1 by making some changes as follows; authors mentioned uncoating, but it was not shown in the figure. The receptor was still attached to the virus after the entry into the cytoplasm. The transcription stage occurs in the nucleus, but it was not shown, and the packaging step was also not shown. Provide a little detail of the figure in legend.\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? Partly\n\nAre the conclusions drawn appropriate in the context of the current research literature? Partly",
"responses": [
{
"c_id": "9274",
"date": "17 Feb 2023",
"name": "Saifur Rehman",
"role": "Author Response",
"response": "Dear Reviewer, Thanks for your valuable comments and suggestions on the manuscript entitled: “Avian influenza virus, epidemiology and its effect on backyard poultry in Indonesia: a review” We welcome feedback. We have made modifications to the study on the following points: Section introduction lines 1 and 2, Has instead of Had, its instead of their Response: We have replaced had with has accordingly Line 6, Remove “Still Response: We have removed Please modify the following sentence, Recommendations for future initiatives and policies to reduce the risk of avian influenza (HPAI and LPAI) in Indonesian backyard poultry. Response: We have revised this sentence accordingly Please define LBMs at the first mention Response: We have mentioned the full name of LBMS The mutation was very similar to the variant of H5N1 found at almost the same time in West and East Java, Bali, and Nusa Tenggara Barat (NTB). Instead of “They have a mutation that is very similar to the variant of H5N1 found at almost the same time in West and East Java, Bali, and Nusa Tenggara Barat (NTB).” Response: We have revised according to valuable suggestions In the epidemiology and life cycle section, in 2nd paragraph, the authors mentioned, “FAO identified four poultry production sectors globally,” but the authors failed to describe the other three poultry production sectors. Response: We have mentioned all four sectors according to your suggestions Define DPSR at first mention in the text Response: we have defined accordingly The authors said that the Influenza virus has a multistep process for reproduction. I suggest that the authors first define all the viral proteins and then describe their roles in the virus life cycle. In fact, the virus life cycle paragraph is a disaster by mixing various viral proteins involved in the replication cycle. Authors are suggested to write this paragraph in an order from virus entry to release. Response: All the viral proteins and then describe their roles in the virus life cycle according to your suggestions The last paragraph of the epidemiology and life cycle should be moved to the start of this section. Response: We have moved the last paragraph as you mentioned Please revise figure 1 by making some changes as follows; authors mentioned uncoating, but it was not shown in the figure. The receptor was still attached to the virus after the entry into the cytoplasm. The transcription stage occurs in the nucleus, but it was not shown, and the packaging step was also not shown. Provide a little detail of the figure in legend. Response: We have revised figure 1 by making new figures with your recommended changes"
}
]
},
{
"id": "159652",
"date": "26 Jan 2023",
"name": "Gangil Rakhi",
"expertise": [
"Reviewer Expertise Virus isolation and Development of diagnostics for identification of virus"
],
"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 review on \"Avian influenza virus, epidemiology and its effect on backyard poultry in Indonesia: a review\" is interesting and gives much more information about status of Avian influenza outbreaks in Indonesia. This review can be considered for indexing with some corrections.\n\nLine no. 4: Avian influenza type A virus should be written instead of AI A virus (because first time strain should be clearly mentioned)\n\nSecond paragraph of Introduction:\n\nLine 2...it should be were discussed instead of was discussed. Line 3....it should be are discussed in details instead of is discussed in detail. rewrite the last sentence of this paragraph (Recommendations for future.........backyard poultry).\n\nSecond paragraph of Epidemiology and life cycle: full form of LBM should be write first time then abbreviation can be used.\n\nIn this paragraph phylogenetic analysis and different clades of AIV strains were discussed. So it is suggested that phylogenetic tree should be included in this paper which is discussed.\nIn this paragraph according to author FAO identified four poultry sectors globally whereas other three sectors are not discussed.\nPDSR describe first\nThe last paragraph of Epidemiology and lifecycle should comes first.\n\nFirst paragraph Viral identification: this paragraph included (clad 2.1 virus....has been produced) discussion about clad of phylogenetic tree. So this paragraph should be included in above paragraph of epidemiology where phylogenetic analysis discussed.\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? Partly\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": [
{
"c_id": "9275",
"date": "17 Feb 2023",
"name": "Saifur Rehman",
"role": "Author Response",
"response": "Dear Reviewer, Thanks for your valuable comments and suggestions on the manuscript entitled: “Avian influenza virus, epidemiology and its effect on backyard poultry in Indonesia: a review Line no. 4: Avian influenza type A virus should be written instead of AI A virus (because first-time strain should be clearly mentioned) Response: We have corrected by following your valuable suggestions Second paragraph of Introduction: Line 2...it should be were discussed instead of was discussed. Line 3....it should be are discussed in details instead of is discussed in detail. rewrite the last sentence of this paragraph (Recommendations for future.........backyard poultry). Response: We have corrected these mistakes in the mentioned paragraphs Second paragraph of Epidemiology and life cycle: full form of LBM should be written first time then abbreviation can be used. Response: We have mentioned full form of LBM In this paragraph phylogenetic analysis and different clades of AIV strains were discussed. So it is suggested that phylogenetic tree should be included in this paper which is discussed. Response: Dear reviewer thanks for your valuable suggestions we have not found any phylogenetic tree like that we have found only paragraph which we have mentioned already in manuscript In this paragraph according to author FAO identified four poultry sectors globally whereas other three sectors are not discussed. Response: We have mentioned all the four sectors PDSR describe first Response: We have corrected accordingly The last paragraph of Epidemiology and lifecycle should comes first. Response: We have corrected this paragraph by following both reviewer suggestions First paragraph Viral identification: this paragraph included (clad 2.1 virus....has been produced) discussion about clad of phylogenetic tree. So this paragraph should be included in above paragraph of epidemiology where phylogenetic analysis discussed. Response: We have moved this paragraph accordingly"
}
]
}
] | 1
|
https://f1000research.com/articles/11-1321
|
https://f1000research.com/articles/11-1038/v1
|
12 Sep 22
|
{
"type": "Research Article",
"title": "Students' Digital Competence and Perceived Learning: The mediating role of Learner Agility",
"authors": [
"Vidya Patwardhan",
"Jyothi Mallya",
"Rahul Shedbalkar",
"Sandeep Srivastava",
"Kartikeya Bolar",
"Vidya Patwardhan",
"Rahul Shedbalkar",
"Sandeep Srivastava",
"Kartikeya Bolar"
],
"abstract": "Background: The ravages of COVID-19 escalated the penetration of online education and usage of digital technologies. While educational institutions across the globe adopted different forms of computer-mediated communication, the institutes in India have gradually attuned to the new normal, notwithstanding the initial glitches of adopting new technology and shifting to blended. It became increasingly significant to gain a better understanding of students’ perspectives of newly emerged learning environment. This motivated the researchers to study the digital competencies (DC) and their impact on students’ learning agility (LA) and perceived learning (PL) in professional/technical education.\nMethods: In this cross-sectional study, a DigiComp 2.1 framework was attempted to investigate the relationship between DC and PL among higher education students in India. The data from 359 graduate and post-graduate students were analyzed using Structural equation modelling and Process Macro 4.0.\nResults: The findings of this study revealed that DC has a significant positive impact on PL (b = 0.33; p < 0.001), indicating that higher learners’ DC leads to higher learning outcomes. Similarly, DC also had a significant positive impact on LA (b = 0.59; p < 0.001), suggesting that the higher DC of learners leads to higher learning agility. Further, a positive significant relationship was also found between LA and PL (b = 0.21; p < 0.001). This significant positive path reveals that higher learners’ agility leads to higher student learning outcomes.\nDiscussion: Post-COVID, DC, a technology-related skill set is linked to the academic performance of teachers and students. Our findings reveal that DC significantly positively impacts PL and LA. Therefore, we recommend that the higher educational institutes in India consider the inclusion of DC in their curriculum as a fundamental competence for a better learning outcome for learners.",
"keywords": [
"Digital competence",
"learners' agility",
"perceived learning"
],
"content": "Introduction\n\nWith the unprecedented entry of COVID-19 into our lives, digital technologies are re-evolving and emerging as one of the most potent tools even in the most non-volatile ecosystem of education. Today, education is broken, and we are trying to fix it with technology (technologization) (Teräs et al., 2020). This profound change toward democratization of education expects high levels of digital competence (DC) from teachers and students. Though it started as a stopgap solution due to the COVID crisis, the technology dependence spearheaded the abrupt shift toward full-fledged online education (OECD, 2020). This shift necessitates proficiency in a series of DC for learning and performance in digital formal and informal learning environments (Elstad & Christophersen, 2017; Heidari et al., 2021; Mehrvarz et al., 2021). Critical to the success of the transition to online education is the inevitability of attaining the requisite knowledge, skills, and attitudes to embrace digital technologies constructively (Coman et al., 2020; OECD, 2020). It is a tectonic shift (Govindarajan & Srivastava, 2020) featuring hybrid or blended classrooms, collaboration, equity, experimentation, and innovation that may continue to be an effective learning ecosystem (Miroshnikov, 2021). Numerous online resources facilitated students to access, create, and share digital content for collaborative education. The role of DC has become more critical due to its holistic emphasis on the ethical, safety, and social dimension and the inclusion of diverse knowledge, abilities, and desires of individuals (Falloon, 2020; Foulger et al., 2017). Parallel direction is apparent within the education domain, where the focus should be on enhancing the learner’s capabilities for better participation in digital society (Martzoukou et al., 2020).\n\nThe development of digitally competent, able, and skilled professionals within the ever-changing technological and online environment expect learners to be agile in their ability to learn, adapt, unlearn, and relearn to keep up with the frequently changing learning environment (Fulton & McGuinness, 2016; Martzoukou et al., 2020). The digitally literate generation must remember the three vital components of learning agility (LA): 1. Potential to learn, 2. Motivation to learn, and 3. Adaptability to learn (Amato & Molokhia, 2016). Agile learners are willing to learn continuously and apply the knowledge in new situations (De Meuse et al., 2010; Kim et al., 2018). In a post-COVID academic environment, it is extremely important to be agile in the adoption of technologies that allow for flexible and personalized learning (OECD, 2020). Today, governments, institutions, educators, and students have experienced the need for digital literacy and generic digital skills. However, past research shows that undergraduate students need intense training in digital technologies as they do not effectively attempt to integrate them into their educational experiences (Piotrowski, 2015; Strømsø et al., 2013).\n\nThe key terms used to explain digital technologies in digital parlance include information and communication technology (ICT) literacy, Internet skills, Information literacy, media literacy, digital literacy, and DC (Chetty et al., 2018). Among these, DC, an emerging concept that describes technology-related knowledge and skills, has been acknowledged as a critical competence vital for enduring learning (Falloon, 2020; Iordache et al., 2017). In the higher education research context, it is defined as “the ability to explore and face new technological situations flexibly, to analyze, select and critically evaluate data and information, to exploit technological potentials to represent and solve problems and build shared and collaborative knowledge, while fostering awareness of one’s responsibilities and respect of reciprocal rights/obligations” (Scuotto & Morellato, 2013; Spante et al., 2018). Due to the advent of continued online learning, DC has become a buzz term that resonates explosion of digital information, communication, and interaction among people, especially the academic fraternity. According to the European DC framework for citizens (DigComp 2.1), the five key components of DC are; 1. Information and data literacy, 2. Communication and collaboration, 3. Digital content creation, 4. Safety, and 5. Problem-solving (Ferrari et al., 2013a). Experts opine that the key components of DC are fundamental to supporting an individual’s lifelong learning and employability (Guitert et al., 2021; Zhao, et al., 2021). Therefore, the student perspectives of cognitive, emotional and social aspects of the learning process in a digital environment require special attention.\n\nIn India, Ministry of Human Resource Development (MHRD) launched various digital initiatives to address the challenge of remote learning to build the future of 25 crore students (MHRD, 2020). It is time to develop systematic approaches to map the DCs of students in higher educational institutions as a coherent learning continuum. Despite its importance, many higher education institutions in India have not yet developed an organized method to map the DCs of students as a priority. Today, the development of digital skills from the point of view of employability is a baseline requirement. Universities have to design resources to support students to develop digital skills. Using the DigComp 2.1 framework, this study tries to report students’ current DC profile and learning agility that might help bridge the digital divide in institutions of higher learning in India. It is presumed that the extent to which students benefit from digital learning depends on students’ competence in utilizing these environments. As propagated by the developers of DigComp, we need a tool to enhance learners’ DC as a pointer for policymakers to formulate guidelines to improve the DC of specific target groups (Vuorikari et al., 2016).\n\nAlongside, understanding self-perceived DC levels by the students would facilitate learning as students have diverse digital experiences based on their background characteristics. Hence, the LA of students is taken as a mediator to investigate the effect of DC on students’ PL. It is assumed that LA stimulates the student’s motives to enhance digital skills. This quantitative study aims to test the conceptual framework highlighting the positive relationship between DC, LA, and PL using structural equation modelling and mediation analysis. To the authors’ knowledge, this is an under-researched domain and could be an addendum to continue efforts towards creating a digital society by developing novel DC frameworks specific to the needs of Indian higher education students. Throughout this paper, the term ‘DC’ will be used as an umbrella term for various key terms related to digital skills.\n\n\nLiterature review\n\nDC is a multi-faceted concept (Sánchez-Caballé et al., 2020) that evolved from diverse backgrounds (Gallardo-Echenique et al., 2015; Lucas, 2019). The UK higher education context proposed Digital Capabilities Framework having six elements (Biggins et al., 2017) that can be used to enhance students’ ability to steer self-learning for continuous development. Likewise, the European Commission developed the DC framework (DigComp2.1) to respond to the ever-increasing need to operate effectively in a knowledge-intensive society (Sillat, Tammets, & Laanpere, 2021). With five dimensions and 21 elementary competencies, this framework was first published for European citizens in 2013 and renewed in 2017. This framework highlights the significance of digital creation, innovation, communication, collaboration, engagement, and digital identity (Lucas, 2019; Sillat et al., 2021). Later it was adopted within the education sector to create a standard for evaluating the DC of educators and students (Lucas, 2019). Experts predict that acceleration in edutech growth will sustain, and DC training in higher education (MHRD, 2020) will profoundly shift the focus towards using digital technologies to enhance students’ learning experiences and facilitate the development of their DC.\n\nRegrettably, in a traditional learning environment, similar instruction styles are followed regardless of the individual learning abilities of students. The digital resources are designed at baseline, ignoring individual learners’ present DC levels (Martzoukou et al., 2020). As students belong to different demographics, the requirement of levels of support for DC may vary (Martzoukou, et al., 2020). The diversity in socio-demographic characteristics may widen the digital divide (Moore et al., 2018). Hence, it cannot be presumed that all students arrive at university with the same levels of DC. Some studies suggest that students develop DC spontaneously in digital learning environments through active engagement and self-motivation (Heidari et al., 2021; Lucas, 2019; McGuinness & Fulton, 2019). At the same time, few others emphasize the close linkage between well-founded pedagogy, didactics, and DC (Sung et al., 2016; Tamim et al., 2011). In the digital learning environment, it is argued that meaningful learning occurs when students are active, constructive, intentional, authentic, and cooperative (Howland et al., 2012). The above standpoints deliberated by researchers with diverse backgrounds invite the inquiry of learning processes from students’ perspectives (Blau et al., 2020).\n\nTheoretically PL consists of cognitive, emotional, and social aspects that deal with understanding new insights, feelings and experiences during learning and inter-personal interactions through the learning sessions (Blau et al., 2020; Rockinson-Szapkiw et al., 2016). It primarily relates to two predominant aspects of learning: knowledge acquisition and knowledge transfer (Barbera et al., 2013) which are projected to be essential to acquire DCs. However, the prediction of DC having a significant relationship with PL has largely remained unexplored. There is no evidence thus far investigating this relationship in the extant literature related to online education. Hence, we propose the following research hypothesis:\n\nH1: There is a significant positive relationship between students’ Digital competence and perceived learning in an online learning environment.\n\nThe researchers in the field of digital literacy and competence feel that mere usage of digital tools will not automatically make students digitally competent (González & Martín, 2017; Sánchez-Caballé et al., 2020). There is a gap between formal (e.g. educational software, technology theory) and informal (e.g. multimedia tools) digital skills and abilities of university students (Flores & Roig, 2016; Parvathamma & Pattar, 2013; Prieto et al., 2020; Purushothaman, 2011). In the formal setup, students lack experience in e-learning skills and abilities (Poulová et al., 2011). Research studies have revealed that undergraduate students need extensive training in digital technologies (Kim et al., 2018). This training is essential when students enter a blended learning environment, primarily pointing to the post-COVID education scenario. To moderate the gap, in institutions of higher learning, both learners and educators need to develop technology-related knowledge, skills, and attitudes through ongoing learning programmes (Kim et al., 2018). Only agile (\"agile\" as used in the domain of technology) methodology and development referring to iterative processes and continuous improvement by building a culture of constant growth (Himmelsbach et al., 2019) seems to be the viable solution. Students must embrace an agile mindset to meet the demands of digital innovations.\n\nLA is an essential factor that integrates digital technologies into student learning and engagement in academic life. The theory of Learning Agility emphasizes that “individuals who have performed well in the past will not necessarily perform well in the future in a new job” (Connolly, 2001). It is believed to significantly influence learners’ ability to progress to more complex and challenging learning assignments (Almeida, 2019). Similarly, it can be presumed that students living in an era of transition may find it challenging to adapt to new learning situations with the present DC levels. Therefore, they are anticipated to be flexible and fast learners amid a high level of knowledge uncertainty posed by COVID-19 and evolving digitalization as prerequisites to seize new opportunities. The construct LA is more appropriate for consideration in this research context as its basis is rooted in adult learning and self-regulated learning (Allen, 2016). Students perceive that agile practices have a great potential to enhance their learning experiences (Melnik & Maurer, 2002). The definition of perceived learning, i.e. \"changes in the learner’s perceptions of skill and knowledge levels before and after the learning experience\", as given by Alavi et al. (2002), is appropriate in this context to ensure the quality of learning and improvement in the learning experience. Hence, as a predictor of students’ enriched learning experience, we hypothesize that LA mediates the relationship between DC and PL.\n\nH2: There is a significant positive relationship between students’ Digital competence and learning agility in an online learning environment.\n\nH3: There is a significant positive relationship between students’ learning agility and perceived learning in an online learning environment.\n\nH4: The learning agility of students mediate the relationship between students’ Digital competence perceived learning in an online learning environment.\n\nBased on the above literature, the following model (Figure 1) is proposed.\n\n\nMethods\n\nEthical approval was obtained from the Institutional Research and Ethical Committee of Welcomgroup Graduate School of Hotel administration (WGSHA), Manipal Academy of Higher Education via Reference No. WGSHA–IRC-2021-02 dated 14-08-2021. The committee waived the written consent since there was no risk involved for the participants, and most participants were above 18 years of age. Parental consent was also waived for a few participants of 17 years because of the no-risk nature of the study, and these underage participants were in the same cohort as the other participants, i.e., university students. Additionally, one of the authors visited the classrooms to explain the objectives and informed the participants that participation in the survey is voluntary. Thus, verbal consent was obtained before distributing the online survey form.\n\nData was collected from 359 full-time students across professional disciplines of a well-known private university in India. This university offers higher education in Medical, Paramedical, Allied Health, Health Science, Pure Science, Technology, Management, Hospitality Management, Commerce, Media, Humanities, Geopolitics, and few other disciplines. The diversity in the background was considered adequate to represent the different proficiency levels in DC among the student community. The questionnaire was developed in Microsoft Forms, and the web link of the online questionnaire was emailed to 1,200 students with an explanation on the constructs as well as study objectives. A week after this, a follow-up email was sent as a reminder to expedite the data collection process. The data was collected in the month of May 2021 and August 2021.\n\nIn this cross-sectional research, the respondents were selected based on purposive sampling. The respondents have attended a minimum of 12 months of online classes. In total, 359 valid responses were received yielding a response rate of 30%. The sample included among the respondents, 224 (62.4 %) male and 135 (37.6%) female students. Among the respondents, 315 (87.7%) were undergraduates, and 44 (12.3%) were postgraduates.\n\nThe measuring instrument was developed after an in-depth literature review. The DC survey instrument was borrowed from (Ferrari et al., 2013b). The 21 items were measured on a 5-point Likert scale where 1 represents “very low”, and 5 represents “very high”. A higher value would indicate a higher level of DC. The LA (five items) was measured based on the scale of Kim et al. (2018). Respondents were requested to rate their agreement or disagreement with the statements on a 5-point Likert scale where 1 representing strongly disagree and 5 representing strongly agree. The outcome variable’s PL scale (six items) was adopted from the study by Narayan et al. (2021). These variables were operationalized using a 5-point Likert scale ranging from 1 (strongly disagree) and 5 (strongly agree). The respondents’ demographic details such as age, gender, and education were also included in the survey instrument. The full questionnaire can be found in the Extended data (Mallya & Patwardhan, 2022b).\n\nThe Kaiser-Meyer-Olkin (KMO) test was used to test the sample adequacy. The KMO value is above the recommended value of 0.6 (0.93), and Bartlett’s test of sphericity is significant (χ2 (210) = 4478, p < .001), thus confirming the suitability of data for factor analysis (Kline, 1994).\n\nBefore assessing the structural model, the first-order factor’s measurement model’s psychometric properties were assessed using the confirmatory factor approach. The model displayed good model fit indices (CFI = 0.95; TLI = 0.94; RMSEA = 0.05; SRMR = 0.05; x2/df = 2.64). The model was further tested for its reliability and convergent validity (Table 1). Reliability was assessed based on the composite reliability (CR), and convergent validity was assessed based on the average variance extracted (AVE) values. According to Hair et al. (2014), the value of CR and AVE should be more than 0.70 and 0.50, respectively. All these values were above the recommended value (Table 1), suggesting the constructs’ reliability and convergent validity. Further, except for the factor “Communication”, the model achieved discriminant validity (Table 2). However, this is common due to the high correlation between the manifest indicators (Koufteros et al., 2009; Marsh & Hocevar, 1985).\n\n*** Significant at 0.001 level.\n\nAfter achieving reliability and validity for the first-order factors model, the performance of the second-order factor model of DC was tested. The development of four models using a hierarchical approach was adopted to validate the second-order factor model (Rindskopf & Rose, 1988). First, the single first-factor model with 21 items of DC was loaded (Model 1). The second model hypothesized that all the five dimensions of DC were separate and unrelated (Model 2). The third model (Model 3) hypothesized that all the five dimensions of DC were distinct but correlated. The fourth model (Model 4) was the second-order factor model of DC.\n\nThe hypotheses were tested using confirmatory factor analysis. The results are presented in Table 3. Table 3 shows that Model 1 and Model 2 did not have acceptable model fit indices. Further, Model 3 had marginally better model fit indices than model 4. Though model 3 had better fit indices, model 4, which hypothesizes a second-order factor model, was considered since it also had an acceptable fit.\n\n\nResults\n\nThe overall measurement model was tested using CFA after achieving desired model fit for the second-order factor. The model indices values as per the recommended values (CFI = 0.94; TLI = 0.94; RMSEA = 0.04; SRMR = 0.05; x2/df = 2.37). The second-order factor model of DC was further tested for convergent and discriminant validity. The CR and AVE values were above 0.7 and 0.5, respectively (Hair et al., 2014) (Table 4). The discriminant validity of the constructs was tested by comparing the square root of AVE to bivariate correlation values between the constructs (Table 5). According to (Fornell & Larcker, 1981) square root of all measuring constructs should be greater than the bivariate correlation values between the constructs. The overall measurement model achieved discriminant validity.\n\nAfter establishing the reliability and validity of the measurement model, the model fit indices of the structural model were tested (Table 6). The fit indices were within acceptable range (CFI = 0.928; TLI = 0.922; RMSEA = 0.0544; SRMR = 0.0604; x2/df = 2.04).\n\nThe structural model assessment was used to test the hypothesized relationship as conceptualized in the proposed model. This included the relationship between DC, LA, and PL. The R2 values (the coefficient of determination) and beta values (path coefficients) were the parameters used to determine the strength and magnitude of the relationship between the constructs. All path relationships were statistically significant (Figure 2).\n\nHypothesis 1 (H1), proposing a significant positive relationship between DC and PL, was accepted (b = 0.33; p < 0.001), indicating that higher learners’ DC leads to higher learning outcomes. Similarly, hypothesis 2 (H2), which postulated the significant positive relationship between DC and learners’ agility also found support (b = 0.59; p < 0.001), suggesting that the higher DC of learners’ leads to a higher level of learning agility. The third hypothesis (H3) that proposed the positive relationship between the learners’ agility and PL also found support (b = 0.21; p < 0.001). This significant positive path reveals that higher learners’ agility leads to higher student learning outcomes.\n\nThe mediating effect of learning agility between DC and PL was analyzed using PROCESS macro model 4 (Hayes, 2018). We have used the bootstrap method with 5000 re-samples to test the indirect effect as the sample size was adequate (Zhao, et al., 2010). It is found that LA has a mediating effect between their DC and PL (H4MFE-SAT-SWL: β= 0.1238, 95%, CI [0.0381, 0.216]).\n\n\nDiscussion\n\nToday higher education is becoming learner centric. The teacher assumes the role of a facilitator and catalyst to engage students in active learning with the support of innovative online teaching-learning tools and high-tech, content-rich instructional resources. Blended learning has emerged as a viable solution to manage the rapid shift to online education. In such an environment, DC plays a crucial role in students’ academic life (Alexander et al., 2016; Olszewski & Crompton, 2020). In this environment, LA (the ability to learn from the experience and adapt to new circumstances) becomes essential for integrating digital technologies into student learning and engagement in academic life.\n\nThe overarching aim of this study was to investigate the postulated association between students’ DC, LA, and PL in institutions of higher learning. To do this, we proposed four hypotheses, and the findings supported the proposed hypotheses. First, DC of students positively impacts their PL (H1). In other words, the greater the DC higher the self-perceived learning among students. E.g. the greater the self-perceived DC of students while dealing with daily digital tasks, the more likely they are to develop high self-perceived DC in areas related to their education (Martzoukou et al., 2020). However, thus far, no empirical studies in the literature have established the direct relationship between DC and PL. Second, DC significantly influences LA (H2), and the LA positively impacts students’ PL. Per the preceding statement, Kim et al. (2018) argued that their agility mediates the college student’s perception of DC (ability to learn and readiness to apply the acquired knowledge). The additive results revealed that LA mediated the relation between DC and PL (H4), primarily an unexplored relationship predicted in this study. In all, the findings of our study is in line with few of the past research findings (Blau et al., 2020; Heidari et al., 2021; Himmelsbach et al., 2019; Kim et al., 2018; Mehrvarz et al., 2021).\n\nAs the introduction and literature review mentioned, DC is a complex and multi-faced concept that spans several social, motivational, personal, cultural, and technical understandings. First, in the remote learning environment, students must be strongly encouraged toward self-directed learning. Researchers have a consensus that students are reflective of their learning (Miller & Mushfiq Mobarak, 2015; Plaza-De-La-Hoz et al., 2015). Their efforts in developing DC by becoming agile learners are a value addition (Kim et al., 2018). Second, in higher educational settings, educators’ technology-related knowledge, skills, and attitudes become important to improve students’ DC (García-Vandewalle García et al., 2021; Mishra & Warr, 2021). The importance of DC in students is also mirrored in the educator’s attitudes, beliefs, and professional development (Spante et al., 2018). When an educator assigns a low value to DC, students do not appreciate or acquire the soft competencies. Educators must develop a positive attitude toward imparting the digital knowledge to students (Miller & Mushfiq Mobarak, 2015; Plaza-De-La-Hoz, et al., 2015) at different levels to promote a culture of information-seeking. Third, students must be encouraged to develop self-efficacy in a safe atmosphere through the trial and error method. While researchers are investigating to develop an efficient method for improving DC among students, for a student, educators must open up for the adoption of new technologies and pedagogies. Lastly, the inclusion of course/s on DC in the higher education curriculum of all professional programs can become a ‘best practice’ of education. The dimensions of DC and their respective elements are undoubtedly applicable to a multitude of subject-specific areas (Karsenti et al., 2020), which is essentially to be adopted in present day higher education. DC can become an empowering agent to transform students into digitally literate by increasing awareness, safety behavior, digital tools, resources, and interfaces (Alt & Raichel, 2020). As students advance through the different levels of education, DC will support students to become more autonomous in using digital technologies in academic, professional, and daily lives.\n\n\nConclusion\n\nCritical to the success of the transition to online education is the inevitability of having the requisite knowledge, skills, and attitudes to embrace digital technologies in a most productive manner (Coman et al., 2020; OECD, 2020). Numerous online resources facilitated students’ access, creation, and digital content sharing for collaborative education. However, every student may not possess the digital skills and competence for a seamless changeover. Though today’s learners are digitally enriched, it is evident that they are not entirely competent and agile in using the digital resources offered by the institutions. The convergence of technology, pedagogy, and an inclusive online or hybrid learning environment will push students to develop critical DC that fosters active learning and participation. Students’ prior experience with DC, where they can use a full range of digital technologies for information, communication, creation, safety, and problem-solving, will take centre stage in learning in this environment. It is documented that DC development should be initiated at an early age. Introducing a DC-based curriculum at the secondary-school level education would be ideal. However, to address the immediate needs in the post-COVID world, the integration of components of digital technologies within the higher education curriculum would support the transformation of students as “digitally literate natives”. In India, with the ‘youth bulge’ (UNFPA India, 2021), to advocate the livelihood skill education of youth, digital enablement is vital in creating a digitally inclusive society. Towards this end, our study throws light on the necessity of developing a DC framework as a policy document that can be used in various disciplines within the landscape of higher education. This framework’s orientation should be towards using digital technology in professionally purposeful ways for lifelong learning.\n\n\nLimitations and further research\n\nThough this study attempted to comprehend how DC and learning agility relate to and predict perceived online learning, some limitations must be noted. First, a quantitative survey is a self-report of perception of DC and learning agility. Other methods such as focus group interviews and different experimental designs can be utilized for future research. Second, a broad-based teacher DC framework must be introduced as educators have an indispensable role in implementing digital initiatives. Therefore, further studies could investigate the teaching fraternity’s DC levels and learning agility. Third, this research focused on the students in only one large private university; hence, the results may not be generalizable. Inclusion of students in diverse learning settings may be undertaken to compare the perceptions. Fourth, the demographic variables should be considered to compare the results in future investigations. Finally, this article argues the need to expand students’ understanding of the variety of DC necessary to function productively, safely and uprightly in diverse and progressively digitally mediated learning environments.\n\n\nData availability\n\nFigshare: Students’ Digital Competence and Perceived Learning: The mediating role of Learner Agility, https://doi.org/10.6084/m9.figshare.20423496.v3 (Mallya & Patwardhan, 2022a).\n\nThis project contains the following underlying data:\n\n• Data.xlsx (the data set consists of four constructs: digital competence, perceived learning, learners’ agility, and self-efficacy).\n\nFigshare: Digital competency_questionnaire.docx, https://doi.org/10.6084/m9.figshare.20423364.v2 (Mallya & Patwardhan, 2022b).\n\nThis project contains the following extended data:\n\n• Digital competency_questionnaire.docx.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
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}
|
[
{
"id": "153846",
"date": "02 Nov 2022",
"name": "Ramachandran Sivakumar",
"expertise": [
"Reviewer Expertise Physiotherapy",
"Education 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 authors have taken a very relevant topic on digital competency for research. In the current development and use of digital tools and platforms, it is critical for the user to have an understanding of a few basic elements to explore the content, use it ethically, and explore without major limitations.\nThe authors could have expanded PL in the content of the article, though it is expanded in the abstract.\n\nThe authors have developed a measuring instrument for DC using the Digicomp manual. The manual itself does not use a Likert scale to measure the attributes of DC but used a three-level rubric with an operational definition. The attributes and Likert scale have been used in the survey for students to respond. Some of the attributes like 'Engaging in citizenship through digital technologies'', 'Netiquette', 'Managing digital identity', and 'Protecting health and well-being' needs an operational definition for the respondent/student to respond appropriately.\n\nThe authors have mentioned that oral informed consent has been obtained, but not detailed about any measures taken to orient the responders to the terminologies used in the survey and grading used. This step is likely to cause bias or median responses like moderate. However, the survey items for PL and LA were clear to read.\n\nAs the statistical methods used were not common, a brief outline for using them in the analysis could help the reader to understand the data analysis better.\n\nThe discussion has been to give a way forward to introduce DC in the learning environment.\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?\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": "9309",
"date": "17 Feb 2023",
"name": "Jyothi Mallya",
"role": "Author Response",
"response": "The authors have taken a very relevant topic on digital competency for research. In the current development and use of digital tools and platforms, it is critical for the user to have an understanding of a few basic elements to explore the content, use it ethically, and explore without major limitations. The authors could have expanded PL in the content of the article, though it is expanded in the abstract. Our reply: Thank you for this advice; we have now added more content on the PL at the end of the introduction, as recommended by you. The authors have developed a measuring instrument for DC using the Digicomp manual. The manual itself does not use a Likert scale to measure the attributes of DC but used a three-level rubric with an operational definition. The attributes and Likert scale have been used in the survey for students to respond. Some of the attributes like 'Engaging in citizenship through digital technologies'', 'Netiquette', 'Managing digital identity', and 'Protecting health and well-being' needs an operational definition for the respondent/student to respond appropriately. Our reply: Since other constructs were on a 5-point Likert scale, we measured the DC on a 5-point Likert scale. The DC was measured on five levels instead of three: 1 being a low level and 5 being a high level of competence. The authors have mentioned that oral informed consent has been obtained, but not detailed about any measures taken to orient the responders to the terminologies used in the survey and grading used. This step is likely to cause bias or median responses like moderate. However, the survey items for PL and LA were clear to read. Our reply: Though online, the researchers circulated the questionnaire to the students in the classroom. The research team members were present to explain the constructs of the study variables. As the statistical methods used were not common, a brief outline for using them in the analysis could help the reader to understand the data analysis better. Our reply: We have added the purpose of using these statistical analyses. The discussion has been to give a way forward to introduce DC in the learning environment. Our reply: We have addressed this observation. Please refer to last paragraph of the conclusion section of the manuscript."
}
]
},
{
"id": "154642",
"date": "17 Nov 2022",
"name": "Heliona Bellani (Miço)",
"expertise": [
"Reviewer Expertise The right to education",
"educational policy",
"teacher education",
"social inclusion"
],
"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 addressed a very current topic, digital competence in education, which has been very sensitive in recent years, especially during the COVID-19 pandemic. Considering the need for digital competence in education, the article focuses on the connection between digital competence, perceived learning, and students' learning agility.\nThe authors are recommended to expand the concept of online education, which is touched on in the Introduction part.\n\nThe authors are recommended to dwell more on the concept of perceived learning presented in the literature review, as well as on the concept of students' learning agility as a skill inside the digital area.\n\nIn the framework of the analysis, there should be taken into consideration reasons that the students' DC is different. This can be related to the knowledge gained in pre-university education, which is addressed in the conclusions of the article but not during its analysis. Since the conclusions have affected the need for DC to be included in the curriculum of pre-university education, it is necessary to touch on how students have acquired these competencies. On the other hand, in the analysis, it is recommended to highlight the connection between digital competence and the study program followed by students, for example, the IT study program who may have higher DC than students from other fields.\n\nThe article used the DigComp 2.1 framework to evaluate the DC profile for students and learning agility. DigComp 2.1 provides the areas of digital competence and proficiency levels. Since the article referred to the DigComp 2.1 framework, it is suggested that this should be better evidenced in the methodology used.\n\nIt is necessary that the methodology used in the article be analyzed by psychometric experts.\n\nThe topic addressed in the article is current since society nowadays requires a set of competencies related to technology, which should start from school.\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?\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": "9308",
"date": "17 Feb 2023",
"name": "Jyothi Mallya",
"role": "Author Response",
"response": "The authors have addressed a very current topic, digital competence in education, which has been very sensitive in recent years, especially during the COVID-19 pandemic. Considering the need for digital competence in education, the article focuses on the connection between digital competence, perceived learning, and students' learning agility. The authors are recommended to expand the concept of online education, which is touched on in the Introduction part. Our reply: We have added more online educational content in the introduction. The authors are recommended to dwell more on the concept of perceived learning presented in the literature review, as well as on the concept of students' learning agility as a skill inside the digital area. Our reply: We have added this now. In the framework of the analysis, there should be taken into consideration reasons that the students' DC is different. This can be related to the knowledge gained in pre-university education, which is addressed in the conclusions of the article but not during its analysis. Since the conclusions have affected the need for DC to be included in the curriculum of pre-university education, it is necessary to touch on how students have acquired these competencies. On the other hand, in the analysis, it is recommended to highlight the connection between digital competence and the study program followed by students, for example, the IT study program who may have higher DC than students from other fields. Our reply: Thank you for this suggestion; since we did not measure the knowledge gained by the students during pre-university education, we can not perform this analysis now. However, we will keep this in mind and include it in future studies. The article used the DigComp 2.1 framework to evaluate the DC profile for students and learning agility. DigComp 2.1 provides the areas of digital competence and proficiency levels. Since the article referred to the DigComp 2.1 framework, it is suggested that this should be better evidenced in the methodology used. Our reply: We have briefly explained the proficiency levels of DC in the methodology section. It is necessary that the methodology used in the article be analyzed by psychometric experts. Our reply: We have consulted statistical experts about the methodology involved in the study. Further, we have also reported the psychometric properties of the constructs used in the study. The topic addressed in the article is current since society nowadays requires a set of competencies related to technology, which should start from school."
}
]
}
] | 1
|
https://f1000research.com/articles/11-1038
|
https://f1000research.com/articles/12-189/v1
|
16 Feb 23
|
{
"type": "Research Article",
"title": "Electronic invoicing: a cross sectional study of its implementation in micro and small businesses in Lima, Peru",
"authors": [
"Rosario Violeta Grijalva Salazar",
"Víctor Hugo Fernández-Bedoya",
"Walter Gregorio Ibarra Fretell",
"Ena Elizabeth Cuba Mayuri",
"Marco Antonio Yzaguirre Ruiz",
"Víctor Hugo Fernández-Bedoya",
"Walter Gregorio Ibarra Fretell",
"Ena Elizabeth Cuba Mayuri",
"Marco Antonio Yzaguirre Ruiz"
],
"abstract": "Background: The implementation of electronic taxation systems helps every company to be able to control, verify and simplify its tax operations. It allows them to manage all their obligations in a faster and more efficient way. In this study, we aim to deduce from the accountants' perspective, what attitudes, practices and compliance with tax obligations are being carried out as a result of the implementation of electronic invoicing. Likewise, to note the benefits it has brought to Micro and Small Enterprises during COVID-19 in Peru. Methods: We used methods of applied research with a quantitative and non-experimental approach. The sample consisted of 384 accountants who manage taxation in their respective companies in Metropolitan Lima, to whom a questionnaire was applied as a data collection instrument. Results: The study sample believes that the use of an electronic issuance system can help combat tax evasion (9.6%), cumbersome tax audits (38.8%), informality (9.4%), falsification of payment vouchers (8.9%), loss and deterioration of payment vouchers (9.1%) and informality (8.3%). They also consider, in their opinion, that the use of the electronic tax system has greatly facilitated the taxation processes (96.6%), generated a reduction in costs (96.4%), reduced the use or consumption of paper (96.9%) and streamlined the administrative and accounting operations (97.4%) of the MSEs Conclusions: It is evident that the sample is in favour of the implementation with an electronic tax system in their business. This new system would be a promising means to help businesses voluntarily comply with their tax obligations. In turn, it generates a positive effect on tax collection and compliance levels.",
"keywords": [
"Electronic system",
"tax obligations",
"electronic vouchers",
"electronic invoicing",
"taxes."
],
"content": "Introduction\n\nIn the globalised world in which we live, changes are increasingly frequent, and companies are no strangers to this, year after year they adopt new ways of doing business. In previous years, it was thought that the use of computer systems at all levels and modalities would be difficult, however, the growth of technology and social distancing, originated as the main measure against COVID-19, has caused technology and computer systems to be of support to continue with the different activities that must be carried out and to help with the development of automation within the business world.\n\nAccording to Velazco (2016) the new “Information and Communication Technologies (ICTs)” have enabled and managed to change the processes that were traditionally carried out in companies, which is evidenced by seeing how they have incorporated activities from the implementation of websites to the integrated interaction of business operations with suppliers and customers. As part of these implementations are also those originated by the “Superintendencia Nacional de Aduanas y de Administración Tributaria (SUNAT)”.\n\nSUNAT oversees providing taxpayers with services that facilitate compliance with their tax obligations, as well as providing services to citizens in general within the scope of its competence. One of its functions is to document operations related to purchases or sales of goods and services, for which it has implemented new forms of digitalisation to provide a better service to the population, as well as to simplify operations applied by different organizations (Superintendencia Nacional de Aduanas y de Administración Tributaria, 2016).\n\nAccording to Nina (2019), one of the important factors of the implementation of electronic taxation is to be able to control and verify the correct operations since tax evasion is a recurrent issue (Santillán & Barbaran, 2021), another advantage also includes the simplification of operations, time, cost reduction (Becerra & Ojeda, 2022); so, the implementation of these new forms of digitalization undoubtedly helps to improve tax collection.\n\nGlobally, Latin America hosts a number of leading countries in the implementation of electronic payment vouchers, specifically in countries such as Brazil, Mexico, and Chile according to Koch (2022). In Peru, starting in 2015 with the upgrade of computerized accounting software, processes became much faster and data entry became quicker, more reports completed, and the software consumed fewer resources. However, the most significant factor contributing to this was due to the COVID-19 pandemic, in particular making electronic invoicing in most cases a necessity because it avoided the displacement of workers and taxpayers from one place to another (Gómez, 2021), as well as enhancing payment options and the delivery of documents (bills, invoices) to avoid contact (Sierra et al, 2022). In view of the above, as of June 2022, the Peruvian tax administration implemented controls and obligations to reinforce collection and fiscalization by means of Resolution No. 000128-2021-SUNAT of 27 August 2021, requiring all companies to issue electronic invoices and receipts (Resolución de Superintendencia N° 000128-2021/SUNAT, 2021)\n\nFor this reason, the purpose of this research work is to find out, from the accountants' perspective, what attitudes, practices and measures of compliance with tax obligations are being carried out due to the implementation of electronic invoicing, as well as the benefits it has brought to Micro and Small Enterprises (MSEs) during the COVID-19 process in Peru.\n\n\nMethods\n\nThe study's research methodology was non-experimental (Baena, 2017), applied and quantitative (Ñaupas, et al., 2018).\n\nThe sample population is comprised of active accountants, who are working in MSEs (Micro and Small Enterprises) around Metropolitan Lima, Peru.\n\nIt is reported that in Peru there are close to three million (approx. 2,838,494) incorporated companies (Instituto Nacional de Estadística e Informática, 2021), of which 95% are MSEs (ComexPerú, 2020)\n\nPeru has a high rate of incorporation and creation of MSEs; nationally, it is reported that around 730 companies are incorporated every day, 95% of which are MSEs (PQS, 2015). It is reported that 34% (965,087 MSEs) of all of them are located in Lima and that metropolitan Lima is home to 98.93% (95,476 MSEs) of that total (Instituto Nacional de Estadística e Informática, 2014).\n\nOne of them is the accounting sector, which deals with all accounting, finance and taxation issues of the company and is managed by a professional accountant.\n\nThe list of MSE's constituted within the area of Lima Metropolitana was obtained from the Municipality of Lima, which was only used for the purposes of the study.\n\nAccording to Aguilar (2005), an infinite population is taken as “when the total number of observation units is unknown or the population is greater than 10,000”, since the total number of accountants currently working in MSEs is not known, the formula for infinite populations will be used to determine the sample size. Where it will be used at a confidence level of 95% equivalent to a Z value of 1.96, with a margin of error (e) of 5%, with a probability of success of 50% and a probability of failure of 50% (Hernández-Sampieri & Mendoza, 2018), presented in the following way:\n\nThe sample consisted of a total of 384 accountants who perform tax management functions in their respective MSEs in Metropolitan Lima, taking only one accountant per company selected.\n\nThe type of sampling was non-probabilistic by convenience, because the researchers chose the members of the sample by convenience, according to the proximity and ease of access to the companies and accountants (Hernández-Sampieri & Mendoza, 2018).\n\nThey were subjected to an inclusion and exclusion criterion\n\nInclusion Criteria:\n\n• Companies with a maximum of 10 employees.\n\n• Employees in the accounting area.\n\n• Active accountants working in a MSEs\n\n• Accountants of both sexes (male and female).\n\nExclusion Criteria:\n\n• Accounts workers who are not professionally qualified.\n\n• Accountants who do not wish to participate in the study.\n\nThe technique used was a survey and the data collection instrument was a questionnaire divided into three sections:\n\n- Section 1. Information and opinion on electronic invoicing: This section analysed whether the companies have encountered difficulties in implementing the electronic invoicing system, the time taken to implement it, which receipts they issue, and whether they consider that it has contributed both socially and to business.\n\nThis section has 6 questions, the first is a closed question with a “Yes” and “No” alternative answer, and the other 5 are multiple-choice questions.\n\n- Section 2. Attitudes and practices on electronic invoicing: In this section, the attitudes, and practices of businesses regarding electronic receipts were studied.\n\nThis section has 11 questions with an alternative answer of “Yes” and “No”.\n\n- Section 3. Fulfilment of tax obligations: This section assessed whether companies are complying with their tax obligations.\n\nThis section has 7 questions with an alternative answer of “Yes” and “No”.\n\nThe full questionnaire can be found in the extended data (Grijalva, et al. 2022). For the development of the questionnaire, we used the works of: Suárez (2019), Atachagua & Ortega (2019) and Pérez (2019) which served as sources of support for the elaboration of the instrument.\n\nThe collection and application of the instrument was carried out between September 1 and November 15, 2021, and this was done physically (paper copies), then data processing took place between December 1, 2021, and January 30, 2022. Finally, the presentation and interpretation of results was carried out until March 30, 2022. The researchers went directly to the management of each MSEs, and the instrument was physically delivered to each accountant in charge of the accounting area of the MSEs visited. It should be noted that it was the accountants themselves who completed the questionnaire freely and without the intervention of the interviewers.\n\nThe questionnaire was sent to the entire sample, after which all the information was processed and compiled in an Excel 2019 spreadsheet, and then exported to the SPSS Vr. 25 statistical program, where all the data processing was carried out. The results obtained were presented in the form of a table of frequencies, which were used to respond to the stated objective, the discussion of results and conclusions of the research.\n\nIt should be noted that the questionnaire was validated by experts, and after obtaining these validations, the Kuder-Richardson test was carried out, where the instrument was subjected to a reliability test, which was carried out by means of a pilot test with the participation of 40 accountants. The result obtained was a Kuder-Richardson of 0.863, according to Durán & Lara (2021), which indicates that “it is considered acceptable when it is between 0.75 and 0.90”, so the result obtained is considered acceptable.\n\nThe questionnaire did not undergo any changes after the pilot test and the accountants who were in the pilot test were not included in the final sample.\n\nThe project was presented to the research board, being approved on 01 July 2021 by the “Vicerrectorado de Investigación” of the “Universidad César Vallejo” by means of the document called “Resolución de vicerrectorado de investigación N°190-2021-VI-UCV”.\n\nEach accountant was respectively notified about the intention of the study by means of an informed consent document in which all information related to the research was presented, informing them about the objective of the study, costs, whether they were going to be exposed to any risk, among other sections. Each person read the document and those who agreed to participate had to sign the document, which was then returned to the researcher. In addition, they were informed that all personal data would be handled anonymously, which means that no information about the participants such as names, identity documents, place of work or other information that could violate the confidentiality of data would be exposed within the work and that this information would be respected in accordance with the “Personal Data Protection Act” (Ley No. 29733, July 3, 2011).\n\n\nResults\n\nNone of the 384 respondents declined to participate in the study. There were also no blank questionnaires, so it is recorded that all 384 accountants participated and filled in each questionnaire to the best of their knowledge and belief. There was also no loss of data in the processing.\n\nTable 1 shows that all the accountants indicate that the company where they work in is an electronic issuer of payment vouchers by designation of SUNAT (26.05%), as well as by their own will (73.95%). At the same time, they indicate that the MSEs took between 1 and 2 months (33.6%) and between 4 and 6 months (16.9%) to implement the electronic issuance system, and finally, the sample's opinion on the use of an electronic issuance system and what it helps to counteract in the tax and social spheres: tax evasion (9.6%), cumbersome audits (38.8%), informality (9.4%), falsification of payment vouchers (8.9%), loss and deterioration of payment vouchers (9.1%), informality (8.3%) and none of the above (15.9%).\n\nTable 2 shows the difficulties encountered by the MSEs in implementing an e-issuance system, being the lack of economic resources (47.7%), the main difficulty encountered by the companies, followed by the lack of electronic service providers (PSE) in the city (49.9%) and finally the lack of access to technology (45.1%) that some MSEs had, together with the lack of information (44%) about this type of system.\n\nIt also shows which are the electronic payment vouchers and electronic issuance documents, being the bills (100%) and electronic invoice (89.8%) the most used in the companies, followed by electronic receipts (44.5%), followed by electronic purchase invoices (45.3%) and lastly, electronic waybills (60.9%).\n\nLastly, we analyzed the benefits most noted by respondents from the implementation of electronic receipts within companies, the most important being that it facilitates tax declarations and payment (54.2%), followed by having real-time information (46.4%), saving time (43.5%), that this type of system reduces the costs of issuing and storing documents (42.4%) and, lastly, that it helps to conserve the environment (38.1%).\n\nTable 3 shows that 81% indicated that it was convenient for the company to have adopted an electronic invoicing system, while 80.5% indicated that their respective companies had the necessary equipment to carry out this type of management; 32% indicated that they do not attend the training sessions held by the supervisory body that views this type of document; this last result means that 23.7% of those surveyed still have difficulties in issuing electronic payment receipts. It is also evident that 96.6% consider that the use of this type of system has facilitated processes, as well as reducing costs (96.4%), reducing paper (96.9%) and that administrative and accounting operations have become much more agile (97.4%). Finally, it is evident that respondents indicate that they have physical receipts (97.9%), as a contingency plan, and that they also comply with reporting to SUNAT on the physical receipts issued (94%).\n\nTable 4 shows that companies make their tax payments within the established deadlines (97.7%), that the use of electronic payment vouchers greatly facilitates the payment of tax debts (97.9%), that since they have been electronic issuers of payment vouchers, companies have faithfully complied with the issuance and delivery of such vouchers to the requesting agents (97.1%), but it is evident that 3.1% at some point in the management of this type of process committed at least one infraction related to compliance with issuing and/or delivering electronic payment vouchers. Finally, it is shown that most of them comply with submitting their electronic books and records within the established deadline (97.7%), as well as their sworn statements and within the deadlines established by law (95.8%).\n\n\nDiscussion and conclusion\n\nAccording to the results shown, the accountants interviewed indicate that the companies where they work are electronic issuers of payment receipts by designation of SUNAT in a lower proportion (26,05%) than those that do so of their own free will (73.95%). A trend that has continued over the years, since according to the Inter-American Development Bank in its 2018 publication, only 11% of the total number of taxpayers that issued electronic invoices up to that time did so by SUNAT designation, which means that 89% were voluntary electronic issuers (Banco Interamericano de Desarrollo y Centro Interamericano de Administraciones Tributarias, 2018).\n\nThe implementation of electronic invoicing has been incorporated for some time, as the tax administration of the different Latin American countries has advanced with modernization. This has enabled taxpayers to use different virtual services in order to make the functioning of the economy viable and to comply with the various tax and fiscal obligations, which is why many taxpayers have seen digitalization as an option for change.\n\nThe virtualisation of tax services implies a change of paradigm and although this change was possible thanks to the laws and rules that have been in place over the years, as well as the improvement of platforms to produce documents in electronic format, the health crisis that began in 2020 prompted a 360-degree change.\n\nIt should be stressed that the road to incorporating electronic invoicing has not been an easy one, according to what was stated by the MSEs, with problems of access to technology being one of the main problems faced by the companies. It was also found that one of the problems was the scarcity of electronic service providers (PES) in the city (49.9%), poor access to technology (45.1%) and lack of information (44%) about this type of system. As can be seen, despite the progress that has been made in digital infrastructure in recent decades, access to technology is a major problem that we face every day. According to Comisión Económica para América Latina (CEPAL, 2020), telecommunications infrastructure and digital connectivity is still a problem facing the entire region, together with the challenge for operators to preserve adequate levels of quality in internet services. To this end, it is important that the country should provide improvements in the quality of these services (internet) as they are important and necessary to maintain active supply chains and distribution of goods.\n\nThe results of the survey showed that among the main milestones regarding the importance and benefits of e-invoicing, it is highlighted that it facilitates tax declarations and payments, followed by having information in real time, time savings, that this type of system reduces the costs of issuing and storing documents, and finally that it is an environmentally sustainable means. In addition, García et al. (2021) indicate that it has been confirmed that the electronic invoicing process is more beneficial for the company and has various benefits such as cost savings and a strong impact related to the protection and care of the environment, which allows the company to be more competitive and profitable.\n\nRegarding the attitudes and practices carried out, we can see that the necessary precautions have been taken when implementing electronic invoicing systems, and that it has also brought benefits for the company, such as the reduction of paperwork, simplification and streamlining of processes and, lastly, facilitates the issuing and delivery of payment receipts.\n\nFinally, compliance with tax obligations is also an important part of the implementation of electronic invoicing, since tax collection depends on generating greater conditions that benefit the country. Sierra et al. (2022) indicate that electronic invoicing can be used to make tax collection and tax liability (fines, penalties, coercive collections, etc.) more evident, because electronic invoicing facilitates the monitoring of transactions, regardless of their number, as it is systematised, facilitating monitoring by the organisation in charge of administering taxes.\n\n\nConclusions\n\nAs can be seen, during the development of this research, that due to the COVID-19 pandemic, the incorporation of electronic invoicing in companies has been of great help in complying with tax obligations.\n\nThe implementation of electronic invoicing in the different tax regimes is a promising means that will help companies to voluntarily comply with their tax obligations. This is of particular importance, as it allows for an increase in tax collection and compliance levels, especially when compared to more developed countries.\n\nThe incorporation of electronic invoicing has an impact on all the country's companies, as it is a total change from traditional issuance, involving interaction with new technologies, terminology, and new processes, which means that investment, time and staff training must be taken into account.",
"appendix": "Data availability\n\nZenodo. Electronic invoicing: an analysis of its implementation in micro and small businesses in Lima, Peru. https://doi.org/10.5281/zenodo.7378956 (Grijalva, et al. 2022)\n\nThis project contains the following underlying data:\n\n• SPSS - ELECTRONIC INVOICING AN ANALYSIS.csv\n\n• SPSS - ELECTRONIC INVOICING AN ANALYSIS.sav\n\nZenodo. Electronic invoicing: an analysis of its implementation in micro and small businesses in Lima, Peru. https://doi.org/10.5281/zenodo.7301948 (Grijalva, et al. 2022)\n\nThis project contains the following extended data:\n\n• ELECTRONIC INVOICING OPINION QUESTIONNAIRE.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAguilar A: Fórmulas para el cálculo de la muestra en investigaciones de salud. Salud en Tabasco. 2005; 11(1-2): 333–338.Reference Source\n\nAtachagua R, Ortega A: Análisis comparativo de los sistemas de emisión electrónica de comprobante de pago en el estudio contable Ríos, Santa Anita 2019. [To opt for the professional title of Public Accountant]. Perú:Universidad Cesar Vallejo;2019.Reference Source\n\nBaena G: Metodología de la investigación. México:Grupo Editorial Patria;3era edición. ed2017.\n\nBanco Interamericano de Desarrollo y Centro Interamericano de Administraciones Tributarias: La facturación electrónica en América Latina. [Archive PDF].2018.Reference Source\n\nBecerra E, Ojeda R: Beneficios de la facturación electrónica en las pequeñas y medianas empresas del Ecuador. Visionario Digital. 2022; 6(4): 76–97. Publisher Full Text\n\nComexPerú: Las micro y pequeñas empresas en el Perú: Resultados en 2019. [Archive PDF].2020.Reference Source\n\nComisión Económica para América Latina: Las oportunidades de la digitalización en américa latina frente al COVID-19. [Archive PDF]. 2020.Reference Source\n\nDurán F, Lara A: Aplicación del coeficiente de confiabilidad de Kuder Richardson en una escala para la revisión y prevención de los efectos de las rutinas formadas durante el periodo de confinamiento a partir de la identificación del seguimiento de medidas de seguridad, de comida y de descanso. Boletín Científico de la Escuela Superior Atotonilco de Tula. 2021; 8(5): 51–55.Reference Source\n\nGarcía J, Saavedra A, Salazar S, et al.: Costo beneficio del uso de la factura electrónica en los principales contribuyentes de la Región San Martín. Revista Amazónica De Ciencias Económicas. 2021; 1(1): e285. Publisher Full Text\n\nGómez Duque E: Ventajas de la Facturación Electrónica Durante la Pandemia del Covid-19. Revista Reflexiones y Saberes. julio –diciembre, 2021; (15): 55–61.Reference Source\n\nGrijalva R, Fernández V, Ibarra W, et al.: Electronic invoicing: an analysis of its implementation in micro and small businesses in Lima, Peru.2022. Publisher Full Text\n\nHernández-Sampieri R, Mendoza C: Metodología de la investigación. Las rutas cuantitativa, cualitativa y mixta. México:Grupo editorial Mc Graw Hill Education;2018.\n\nInstituto Nacional de Estadística e Informática: En el Perú existen más de 2 millones 838 mil empresas.2021.Reference Source\n\nInstituto Nacional de Estadística e Informática: Análisis de la estructura empresarial de Lima Metropolitana. [Archive PDF].2014.Reference Source\n\nKoch B: E-Invoicing/E-Billing: International Market Overview & Forecast. [Archive PDF].2022.Reference Source\n\nLey 29733 of 2011: Ley de protección de datos personales. July 3, 2011. Diario El Peruano.\n\nNina J: La Facturación Electrónica y los factores que influyen en su aplicación [Bachelor's Thesis, Universidad Católica San Pablo]. 2019.Reference Source\n\nÑaupas H, Valdivia M, Palacios J, et al.: Metodología de la investigación cuantitativa – cualitativa y redacción de tesis. 5ta ed.Colombia:Ediciones de la U;2018.\n\nPérez J: Implementación de la factura electrónica y sus beneficios en el consorcio de frutas Lambayeque SAC – 2017. [To opt for the professional title of Public Accountant]. Perú:Universidad Señor de Sipan;2019.Reference Source\n\nPQS: En el Perú se crean más de setecientas empresas al día.2015.Reference Source\n\nResolución de Superintendencia N° 000128-2021/SUNAT: [Superintendencia Nacional de Aduanas y de Administración Tributaria]. Modifican la resolución de superintendencia N° 279-2019/SUNAT que designa emisores electrónicos del sistema de emisión electrónica.August 27, 2021.\n\nSantillán I, Barbaran P: La figura de la evasión tributaria y sus implicancias en el desarrollo socioeconómico del estado. Ciencia Latina Revista Científica Multidisciplinar. 2021; 5(4): 5097–5111. Publisher Full Text\n\nSierra J, Caro J, Suarez R, et al.: [Comercio electrónico y las tendencias tributarias del sector gastronómico en Colombia durante la COVID-19].2022.Reference Source\n\nSuperintendencia Nacional de Aduanas y de Administración Tributaria: Finalidad. May 20, 2016.Reference Source\n\nSuárez C: La emisión electrónica de comprobantes de pago en el cumplimiento de obligaciones tributarias de las personas jurídicas del sector comercio del distrito de Cajamarca, periodo 2018. [To opt for the professional title of Public Accountant]. Perú:Universidad Nacional de Cajamarca;2019.Reference Source\n\nVelazco J: La facturación electrónica en el Perú. Revista Lidera. 2016; 11: 4–10.Reference Source"
}
|
[
{
"id": "172245",
"date": "02 Jun 2023",
"name": "Matthieu Bellon",
"expertise": [
"Reviewer Expertise 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\nThis article surveys accountants in micro and small enterprises (MSEs) in Peru to examine the use of electronic invoicing systems as well as the challenges, risks and benefits associated with their adoption for MSEs. The study finds that limited access to technology and electronic service providers and lack of information have been the main sources of difficulties for implementation, while facilitated tax filing and payments, access to real-time information, and savings (processing time and storage) are most frequently perceived as benefits.\nThis article makes a nice contribution to the literature by documenting perceived costs and benefits of e-invoicing systems for MSEs, a category of firms for which information is typically less frequently available.\n\nBroadly speaking, the work is clearly presented, and the methods and the interpretation of findings are sound. However, there are some points that remain unclear and should be discussed in more detail. The article could improve on the following dimensions.\nThe paper in general, and the introduction (3rd paragraph from last) in particular, are somewhat unbalanced as they focus more on the benefits than on the costs of adopting e-invoicing. The paper would benefit from a more upfront and candid discussion of potential costs, like transition costs (costs corresponding to the time and investments in the equipment that are necessary to switch to the new system and to make it work) and the costs associated with less fraud (some firms may commit fraud less, that is reduce tax avoidance, which is a cost for them). Such a discussion could benefit from references to Bellon et al. (2022) and the references therein. Fortunately, question 16 seems to suggest that some costs were reduced but a broader discussion of all costs would be welcome.\n\nRelatedly, the answers to question 12 and 13 suggest that the majority of firms still have paper invoices. Does it mean that firms operate two systems (paper and digital) at the same time? If that is the case, how can costs decrease? Could this be better explained?\n\nThe accountants who filled the survey may not have been truthful. This problem is likely more acute for the questions that relate to their performance and their legal/tax compliance, because of fear of consequences. The paper should discuss the possibility of lying, the resulting biases, and try to assess the size of these biases (if any).\n\nThe paper could be improved by explaining better the inclusion and exclusion criteria and their consequences for interpreting results. Specifically, is it the case that the survey was only applied to accounting firms? If that is the case, can the paper discuss if the results can be generalized to firms in other sectors? In addition, can the authors confirm that they excluded firms that decided not to adopt e-invoicing (including informal firms)? That is probably the case because such firms are not complying to SUNAT’s requirements and are possibly informal, but the paper would benefit from discussing this in more detail. The costs of adopting e-invoicing may have pushed some firms into informality. Relatedly, can the authors clarify question 2? How can a company say no since all firms are designated to adopt e-invoicing?\n\nAdditional minor comments. There are a few grammatical errors and typos in the paper (for example, the last sentence in abstract background section, the first sentence in the introduction, etc.) and the article could be improved by being copyedited. Also, I would recommend providing more explanation about the differences between payment documents (as in Table 2) because the reader may not know what these mean.\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": "177605",
"date": "22 Jun 2023",
"name": "Idrissa Kayijuka",
"expertise": [
"Reviewer Expertise Applied Statistics."
],
"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 aims to investigate the attitudes, practices, and compliance measures regarding tax obligations from accountants' perspectives in light of the implementation of electronic invoicing. It also examines the benefits experienced by Micro and Small Enterprises (MSEs) during the COVID-19 process in Peru.\nBelow are some comments:\nThere are some grammatical errors that need to be corrected.\n\nThe abstract's results paragraph needs to be rephrased for better clarity.\n\nIn your statement, \"The questionnaire did not undergo any changes after the pilot test,\" does that mean you did not identify any issues or areas for improvement in the questionnaire during the pilot test?\n\nYou mentioned that all respondents agreed to respond. Did they answer all the questions? Were there any missing responses or errors in their answers? Did you perform any data cleaning? If so, what steps did you take?\n\nYou mentioned that the accountants completed the questionnaire without intervention from interviewers. What happened when respondents needed clarification on the questions?\n\nThe discussion section needs to clearly indicate whether the results found in one sector can be generalized to other sectors. Have you identified any reasons for low compliance with SUNAT? How did you select the accounting sector for your study?\n\nWhat are the future perspectives of this research? It might be beneficial to consider obtaining data from the tax administration to validate or support the results on compliance behaviors of companies where the accountants work.\n\nDid you encounter any limitations during the research process?\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?\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? No",
"responses": []
},
{
"id": "165292",
"date": "13 Sep 2024",
"name": "Larissa Batrancea",
"expertise": [
"Reviewer Expertise Tax behavior",
"financial analysis",
"family businesses",
"cognitive 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\nRecommendations for Manuscript F1000 Research „Electronic invoicing: a cross sectional study of its implementation in micro and small businesses in Lima, Peru” for the F1000 Research Journal.\nGeneral Comments From my point of view, it is a very interesting topic, which presents from the accountants' perspective, what attitudes, practices and compliance with tax obligations are being carried out as a result of the implementation of electronic invoicing. Likewise, it notes the benefits it has brought to Micro and Small Enterprises during COVID-19 in Peru. The paper contains the following sections: Introduction, Methods, Results, Discussion and Conclusion and Conclusions.\nPlease find below some recommendations:\nThe Discussion section appears twice. In my view, the Discussion and Conclusion section should be called only Discussion and the Conclusion section should be called Conclusions and Policy Implications. Furthermore, this last section of the paper needs to be developed.\n\nThe abstract must contain the main purpose of the paper, the research method used in the research and the main contributions.\n\nIt would be very useful to add in the \"Introduction\" section the purpose, objectives and hypothesis of the research. The authors did not show the novelty of the paper as compared to other works. Hence, the introduction should specify the novelty of the paper.\n\nThe research is well based on science and the results are in agreement with the theoretical part. From my point of view, the paper is original and the topic addressed brings added value to the specialized literature. The paper is well written and easy to read.\n\nAt the same time, the authors are required to work on the results sections as the analyses are rather simplistic. These only contain frequency and percentage. Authors could present Descriptive Statistics, Correlation matrix, reliability analyses, maybe try some regressions. At the same time, I consider that the conclusions part of the work should be expanded with policy implications.\n\nThe literature review part needs to be improved with other works, as the following: Refer: 1,2,3,4,5,6,7\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?\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": []
}
] | 1
|
https://f1000research.com/articles/12-189
|
https://f1000research.com/articles/12-187/v1
|
16 Feb 23
|
{
"type": "Research Article",
"title": "Researchers on research integrity: a survey of European and American researchers",
"authors": [
"Nick Allum",
"Abigail Reid",
"Miriam Bidoglia",
"George Gaskell",
"Noémie Aubert-Bonn",
"Ivan Buljan",
"Simon Fuglsang",
"Serge Horbach",
"Panagiotis Kavouras",
"Ana Marušić",
"Niels Mejlgaard",
"Daniel Pizzolato",
"Rea Roje",
"Joeri Tijdink",
"Giuseppe Veltri",
"Abigail Reid",
"Miriam Bidoglia",
"George Gaskell",
"Noémie Aubert-Bonn",
"Ivan Buljan",
"Simon Fuglsang",
"Serge Horbach",
"Panagiotis Kavouras",
"Ana Marušić",
"Niels Mejlgaard",
"Daniel Pizzolato",
"Rea Roje",
"Joeri Tijdink",
"Giuseppe Veltri"
],
"abstract": "Background: Reports of questionable or detrimental research practices (QRPs) call into question the reliability of scientific evidence and the trustworthiness of research. A critical component of the research ecosystem is the organization within which research takes place. We conducted a survey to explore the attitudes and beliefs of European and American researchers about the organisations in which they work, their own research practices and their attitudes towards research integrity and research integrity policies.\nMethods: We administered an online survey (International Research Integrity Survey (IRIS)) to 2,300 active researchers based in the US and 45,000 in Europe (including UK, Norway, Iceland and Switzerland). We employed a stratified probability sample of the authors of research articles published between 2016 and 2020 included in Clarivate’s Web of Science citation database. Coverage includes researchers in the humanities, social sciences, natural sciences and medical sciences, who hold at least a master’s level degree.\nResults: In comparison to researchers in the US, European researchers admit to more QRPs and are less confident in maintaining high research integrity (RI) standards. In the US and Europe, many researchers judge their organization to fall short of best RI practice. All researchers recognize the benefits of RI, reliable knowledge and the trust of colleagues and the public, and there is support for RI training particularly among Europeans.\nConclusion: To create and maintain a culture of integrity in scientific research, a collective commitment from researchers, their institutions and funders is needed. Researchers rely on many channels of communication about research integrity and thus the involvement of many different participants in the research system is required to make improvements. Policies must be developed to reinforce best practice rather than being seen as an irrelevance to the real business of research.",
"keywords": [
"research integrity",
"meta-research",
"survey",
"questionable research practices"
],
"content": "Introduction\n\nScientific research evolves within a set of processes and cultures that potentially shape the integrity/reproducibility of results. Without good research practices, the credibility and trustworthiness of research is called into doubt. Part of this research ecosystem is the organization within which research takes place. We conducted a survey to explore the attitudes and beliefs of 47,000 European and American researchers about the organisations in which they work and their attitudes and beliefs about research integrity and research integrity policies.\n\nIn 1992, reports of falsification, plagiarism and misconduct in science led the US National Academies of the Sciences, Engineering and Medicine (NASEM) to publish ‘Responsible Science: Ensuring the Integrity of the Research Process’ (National Academy of Sciences (US), National Academy of Engineering (US) and Institute of Medicine (US) Panel on Scientific Responsibility and the Conduct of Research, 1992). Three decades later, in response to serious cases of scientific misconduct, a disturbing increase in retractions, and low rates of reproducibility, NASEM published a new report in 2017, ‘Fostering Integrity in Research’ (National Academies of Sciences and Medicine, 2017). The National Science Foundation (NSF), which funds 27 % of federally supported research in universities and colleges in the US (At a Glance|NSF - National Science Foundation, n.d.), not only sets out detailed protocols on research integrity (RI) but also requires institutions submitting a proposal to certify that they provide training and oversight in the ethical conduct of research to all those supported by NSF. In addition to NSF’s oversight, the Office of Inspector General and the Office of Research Integrity have powers to investigate research misconduct and receive reports of possible misconduct or fraud from whistle-blowers (Whistleblower Protection|Office of Inspector General, n.d.).\n\nThe European Science Foundation and the All European Academies (ALLEA) took up the cause of RI in the early 2000s. Unlike the federal system of the US, Europe comprises independent and heterogenous countries, with autonomous political and educational systems and varying research cultures (Godecharle et al., 2013, 2014). Nonetheless, the recently updated European Code of Conduct for Research Integrity which defines four fundamental principles of RI: reliability, honesty, respect and accountability (The European Code of Conduct for Research Integrity - ALLEA, n.d.), calls for consistency across the European Member States in the handling of violations, describing the professional, legal and ethical responsibilities in a framework for self-regulation. Last year saw the introduction of an important pan-European policy; the European Union’s €95.5 billion research fund for 2021-2027 stipulates that to be awarded research funding, applicants must confirm compliance with the ALLEA Code of Conduct and have appropriate procedures, policies and structures in place to foster responsible research practices, to prevent questionable research practices and research misconduct, and to handle allegations of breaches of the principles and standards in the Code of Conduct (European Commission, 2022).\n\nWithin this context of external RI codes, expectations and requirements, we investigate the state of RI, as viewed by active researchers in the US and Europe. Europe and the US have taken different approaches to the promotion of research integrity, raising the question ‘what works?’ What should funding bodies, organisations producing research and researchers themselves be doing? We contribute evidence useful in answering these questions by illuminating the researchers’ perspectives, using data from a large-scale international survey of active researchers in the medical, natural, social sciences and humanities.\n\nIn it, we asked researchers about their attitudes to, and awareness of, RI policies in their organisations. We asked how much support they needed and in which areas. We also asked about researchers’ confidence in their ability to carry out high quality research and asked about their engagement in questionable research practices (QRPs). We focus particularly on comparisons between researchers in Europe and within the US, but also explore differences by scientific field, sex, career stage, employment contract and industry sector.\n\n\nMethods\n\nEthical approval for conducting the survey was obtained from the University of Essex, UK, Faculty of Social Sciences Ethics Committee (ETH2021-0441). The approval document can also be found on OSF (DOI 10.17605/OSF.IO/XB9RK). Informed consent was obtained by the provision of information to participants before they agreed to respond by clicking the survey link.\n\nThe survey was conducted as part of a larger study on RI. Standard Operating Procedures for Research Integrity (SOPs4RI) is a four-year project funded by the European Union under the ‘Science with and for Society’ programme (SOPs4RI – Promoting excellent research, n.d.). IRIS is based on a systematic, stratified probability sample of the authors of research articles published between 2016 and 2020 included in Clarivate’s Web of Science citation database. The full sample from 34 countries is over 60,000 respondents. The focus of this paper is 2300 researchers based in the US and 45,000 in Europe (including UK, Norway, Iceland and Switzerland). Few, if any, previous surveys on RI and related issues have been based on probability designs or cover such a wide range of research fields. Since 2004, a number of surveys have asked researchers about RI (Titus et al., 2008; Van den Eynden et al., 2016; Woolston, 2020), most recently a national study in the Netherlands (Gopalakrishna et al., 2022) but IRIS is the first survey to feature such a broad, representative international sample.\n\nThe online questionnaire focuses on the behaviors of researchers but also on what they think about RI practices and policies in their organizations. Respondents were asked about their self-confidence in supporting research with integrity; if they consider their organization is effective in delivering best RI practices; how much institutional oversight of RI is desirable; whether they had engaged in selected questionable (or detrimental) research practices (QRPs); how closely their organization aligns with best practice; what are the dominant channels of communication on RI topics, what would motivate them to engage with RI policies and procedures and on which topics they would welcome additional support.\n\nThe population of interest for this study was active researchers in the humanities, social sciences, natural sciences (including technical science), and medical sciences (including bio-medicine), who hold at least a master’s level degree and produce research for commercial or academic institutions within the EU, EFTA, U.K. and the US. The way we divide researchers into these broad fields follows the OECD Frascati Manual. We show a detailed breakdown of how subfields are allocated within each of the four main fields, along with their frequency distributions in the Extended data (Allum et al., 2022). The sampling frame was the Clarivate Web of Science bibliographic database, which contains details of publications produced by researchers in 21,894 scientific journals, books and conference proceedings. The sample was constructed from a background population of academics, identified in the bibliographic database, Web of Science (WoS). WoS contains article metadata for more than a million research articles annually. From these records we extracted information on author names, affiliations and e-mail addresses, for all articles published in the period 2016-2020, where at least one author had an affiliation to an institution in one of the target countries. We downloaded 8,159,772 metadata records and retrieved 3,929,283 e-mail addresses, from which we were able to create 3,759,814 author profiles. Of these 3,072,372 were from our countries of interest.\n\nOur objective was to obtain a sample that was both representative of the WoS population and contained sufficient numbers of observations within all countries and fields to enable robust comparisons to be made. To accomplish this, we generated a systematic sample with unequal selection probabilities with explicit and implicit stratification. We aimed to increase the precision of comparisons across four scientific fields by each country combinations through aiming for a similar effective sample size within each such combination. This naturally led to an unequal selection probability sample design with lower selection probabilities in those field-country combinations that have a larger number of publications in WoS. The explicit stratification categories were fully-crossed country by scientific field (natural, medical, social sciences and humanities) combinations. Within each such stratum a systematic sample was drawn, additionally using implicit stratification by a more granular indicator of scientific field and an indicator of the number of papers published by each author. The exceptions to this procedure include those countries, or fields within some countries, where the total number of authors was smaller than that required to achieve the planned effective sample size. In such situations all authors were included in the issued sample.\n\nThe survey was conducted entirely online, in English, using the Qualtrics platform. The survey rationale was developed and agreed in consultation with project partners as detailed in the survey protocol document (Reid and Allum, 2021). Survey questions were developed between November 2020 and April 2021 by authors NA and AR, guided by topic experts within the group of project partners. The full survey included sections covering: structural or demographic variables; values, beliefs and attitudes in relation to science practices, research integrity policies and the role of organisations in implementing them; the current research integrity landscape, including awareness of and satisfaction with current research integrity arrangements; personal efficacy and behaviour; and receptivity towards research integrity policies including specific examples of standard operating procedures. A set of items asking about questionable research practices (QRPs) was drawn from past research on the following criteria: breadth of coverage across research integrity areas, applicable regardless of discipline and ranging from common to rare behaviors (Gopalakrishna et al., 2022; Schneider et al., In preparation).\n\nCognitive testing of the questionnaire was conducted via online meetings due to COVID-19 during February and March 2021. A simple random sample of 5000 people were invited to take part in pilot testing from April to May 2021, following which some changes were made. Invitations and reminders to take part in the survey were distributed from 22nd June – 28th July 2021 and the survey closed on 14th September 2021.\n\nThe invitation emails included information about the project and funder, with links to the Qualtrics survey and to instructions for how to opt out from further communication. In addition, it included information about how the individual had been selected, the scope and purpose of the research for which personal data about them would be collected, how their personal data would be used, who would have access to it, the benefits of participation, and their right to withdraw at any time, including instructions on how to do so. Respondents were told that starting the survey after reading the information supplied implied written consent to participate. The full text of the emails and questionnaire can be found in the Extended data (Allum et al., 2022).\n\n73,757 people responded to the survey. Of these, 1,602 were ineligible due to their country of employment being outside our target countries, which were EU, UK, Norway, Switzerland, USA and Canada. A further 6,391 were excluded as they completed less than 25 % of the survey, which gave no information beyond demographics. Lastly, those who did not state that they were trained to at least master’s level were removed. The remaining 64,074 cases were retained. The overall response rate, computed using the American Association for Public Opinion Research’s standard definitions, was 7.2% (AAPOR Response Rate 2) (American Association for Public Opinion Research, 2016). For this study, we selected only those who had completed 75% of the survey or more and who were employed in Europe or the United States of America at the time of completing the survey.\n\nWe computed weights that we apply in our analyses to correct for the unequal selection probabilities of cases inherent in the sample design and for biases caused by differential non-response. Not all the authors in WoS had the same initial probability of selection, depending on the sizes of the WoS sub-populations used in the stratified design. We aimed to gather approximately 500 responses in each scientific field in each country. Hence those authors in smaller countries that had few authors in WoS had a higher probability of selection than those in countries that had much greater representation. The weighting reflects these relative selection probabilities. In addition to design-related adjustments, we used the information about the WoS authors that we included in the sample design to estimate the overall probability of responding, adjusting for both the study design and non-response. We modelled this using logistic regression. A binary variable that indicated whether a sample member provided a usable response to the survey (i.e. answered more than 25% of the questions) was specified as the dependent variable. The independent variables were country, field, country x field, number of papers and granular subfield. The model therefore takes into account simultaneously the unequal selection probabilities and the differential non-response propensity. The weight variable we derive from estimating this model this was computed as the inverse of the predicted response probability for each respondent and normalised so that the final weighted sample size matched the unweighted sample size. We also trimmed this weight at the 99th percentile so as not to over-inflate the design effect.\n\nOur analysis is largely descriptive and was not preregistered. We present mainly two-way cross-tabulations and bar charts for outcome variables of interest, split by region, scientific field, sex, employment contract, industrial sector and career stage. In some sections, we also present OLS multiple regression analyses to adjust for potential confounding relationships. In some cases, we show 95% confidence intervals around estimates. In many cases we do not, as tables would be unwieldy, but we include unweighted sample sizes. For all data tables, with confidence intervals for all of our estimates, see Extended data (Allum et al., 2022). Standard errors were estimated using Taylor linearization. All analyses were carried out using Stata 17 software with the svy prefix command to adjust for the sample design and weighting. Tables showing all of the weighted and unweighted frequencies for all variables are included in the Extended data (Allum et al., 2022). Details oƒ recodes and derived variables are described in the relevant sections alongside the results. All oƒ the Stata code used for preparation and analysis included in the Extended data along with the full dataset, permitting all of our results to be reproduced independently.\n\n\nResults\n\nWe asked respondents how confident they are that they are currently meeting high RI standards. While more than 95% of researchers report at least ‘some’ confidence, 74% of researchers in the US say they are ‘very confident’, compared to just 52% of European researchers (see Table 1).\n\nThis transatlantic confidence gap persists across researchers of different career stages, employment contracts and scientific fields (see Table 2). More established researchers, both in length of career and security of contract, report greater levels of confidence in the integrity of their research, across Europe and in the US.\n\nIn the US, high confidence in meeting RI standards rises from 64% among early career researchers to 82% in later career. The comparative figures for Europe are 43% (early career) and 62% (later career). In the US, those with permanent positions register 76% compared to 66% for those with temporary positions. The respective figures in Europe are far lower; 54% and 48%.\n\nThe same pattern emerges across the disciplinary fields. A comparison between the US and Europe in the natural, medical, social sciences and humanities shows approximately 20% fewer reporting high confidence in Europe across all fields.\n\n\nConfidence in organization to ensure integrity\n\nWe asked researchers how confident they are in their own organization’s effectiveness in ensuring that appropriate standards of research are maintained (the five response alternatives ranged from ‘complete’ to ‘no confidence’). In the US, 42% of researchers have either ‘complete’ or a ‘great deal’ of confidence in their organization’s effectiveness, as do 34% in Europe. At the same time, 22% of Americans and 29% of Europeans have ‘not much’ or ‘no’ confidence in their organization’s effectiveness in this regard (see Table 3).\n\nOne indicator of the effectiveness of an organization’s RI policy is the extent of awareness by members of the organization. 63% of researchers in the US report that their organization has a policy on research integrity, while 32% say they don’t know. In Europe the figures are 47% and 41% respectively (see Table 4).\n\nOverall, it appears that researchers express more confidence in themselves than in their organizations and that there are non-trivial levels of ignorance about organizational RI statements. To what extent this is troubling depends in part on where the locus of responsibility for RI is seen to lie. It was found that 61% of respondents think that responsibility for high standards of research should be shared between the individual and the organization. However, 31% think that there should be no organizational oversight at all. These proportions vary little between US and European researchers (see Table 5).\n\nFinally, when we look at the relationship between self-confidence and confidence in the organization, we found that 62% of European researchers who are least confident in their own ability also have no confidence in their organization’s effectiveness. The corresponding figure for the US is only 36% (see Table 6). This suggests that there is room for greater and more effective organizational support in RI to mitigate existing concerns among some researchers.\n\nQuestionable research practices (QRPs) (often referred to as ‘detrimental research practices’) are a recognized challenge to RI (National Academies of Sciences and Medicine, 2017). They fall short of outright misconduct but represent transgressions of best practice, improper use of data and ethically questionable behavior. QRPs potentially diminish the quality and trustworthiness of scientific findings. We selected eight QRPs, based mainly on work by Schneider et al. (In preparation). Figure 1 shows short descriptions of the QRPs and the full wordings are presented in Extended data (Allum et al., 2022).\n\nTo introduce the issue of QRPs, respondents were presented with the following statement:\n\n“The next few questions are about questionable research practices (QRPs). These are less than ideal research practices which might happen unintentionally. They are not research misconduct (i.e., fabrication, falsification, or plagiarism). We will present you with a set of research practices and ask you to what extent you have engaged in them when working towards producing your publications over the last three years.\n\nThinking about research carried out for your publications over the last three years, how often has the following occurred?”\n\nThe response alternatives were: often, sometimes, rarely, never, does not apply in my case.\n\nFigure 1 shows the admitted occurrence of each applicable QRP in the US and Europe (error bars represent 95% confidence intervals). ‘Rarely’, ‘sometimes’ or ‘often’ are counted as an admission. For each item respondents could select ‘does not apply’, which excludes them from the results for the corresponding QRP.\n\nThe most common QRPs are including authors who hadn’t contributed, not conducting a thorough review and inadequate supervision, to which at least half of respondents admitted. Occurrence of remaining QRPs is acknowledged by between 10 and 20% of researchers. It is worth noting that the most frequent QRP – inappropriate authorship – does not necessarily implicate the respondent directly. For some, an affirmative response could mean that other investigator(s) may have been responsible. Hence, we might expect to see this QRP reported more often as it could include both individual and third-party decisions.\n\nTurning to the contrast between US and European researchers, we find a consistent difference, with the latter admitting more QRPs on average than their US counterparts. The only exception to this is inadequate supervision, which US researchers are more likely to acknowledge. The largest disparities between regions are found for carrying out research without ethical approval and failing to disclose conflicts of interest. In both cases, the rate of admission is twice as high for European researchers.\n\nIn Figure 2, we present the mean number of QRPs admitted out of the total applying to each researcher, expressed as percentages. For instance, a researcher who admitted three QRPs, and said that two out of the eight did not apply to them, would be assigned a score of 50% (i.e., three admitted out of six applicable). We show these for the US and Europe, with breakdowns by field, sector, employment contract, career stage and sex. Only one QRP – carrying out research without ethical approval – is indicated as not applicable by more than 20% of respondents, and the non-applicable percentage for most QRPs is in single digits (see Extended data for further detail).\n\nThe percentage of QRPs reported by Europeans exceeds that of US researchers, although in some cases the difference is within sampling error. Overall, researchers admit to between 20 to 35% of applicable QRPs. The largest differences are between fields. For example, European medical researchers admit to just under 35% of QRPs while humanities researchers admit to less than 25%. Natural and medical sciences display the greatest tendency for questionable practice, while social sciences and humanities researchers in both US and Europe show a lower self-reported prevalence. University researchers admit fewer QRPs than those in non-academic sectors.\n\nAn interesting disparity emerges in relation to career stage; in Europe, early career researchers admit more QRPs than researchers in mid or late career, although the differences are not large. In the US, the pattern is reversed; they are reporting fewer QRPs than their more senior colleagues. Figure 3 presents results from an OLS multiple regression indicating the partial associations of the explanatory variables in Figure 2 with QRPs. Region, contract type, sector and field all show robust differences, after adjusting for all other factors.\n\nWhat are the most important topics in organizational policies to support RI? In a series of focus groups and co-creation workshops with researchers from a wide variety of backgrounds, the SOPs4RI study found broad consensus on what these topics are and what counts as good practice (for full descriptions of these features, as presented to respondents, see Extended data) (Mejlgaard et al., 2020; Sørensen et al., 2021). IRIS respondents were asked the extent to which their organization aligns with these policies and practices.\n\nIn a fully functioning research system, it might be expected that a high percentage of researchers would say their organization closely or very closely resembles best practice. In both US and Europe, researchers perceive a significant gap between best practice and their organization’s arrangements. In Table 7, we present the percentage of respondents who think that their organization ‘closely’ or ‘very closely’ resembles the ideal on the nine features of RI, broken down by field. Looking first at the bottom row of Table 7, the mean assessments across the nine RI features show that only 52% of researchers in the US and 45% in Europe consider their organizations to be close to the ideal.\n\n* RI features ordered by mean assessment, closest to least close resemblance (US); logit models for each RI area showing the statistical significance of field and region differences can be found in SM table 11.\n\nConsidering transatlantic disparities within each field, only in the case of humanities is there no mean overall difference, although this masks variation within each of the elements. Only 38% in the US and 21% in Europe think integrity training is close to the ideal. Here then, is an area where organizations have considerable scope to improve the situation. Only a minority of researchers in both the US and Europe regard organizational practice around supervision, integrity breaches and publications and communications to be close to ideal. In all but the latter topic, US organizations are viewed as more closely matching the ideal than those in Europe.\n\nWe have shown that the amount of support provided by researchers’ organizations is regarded by many as less than ideal. At the same time, some researchers do not think that the responsibility for RI lies with their organization at all. This raises the question of who are the actors, communities and organizations whose opinions are most valued? For the many researchers, it is their scholarly community – those that publish in the same journals and attend the same conferences – whose opinions researchers value the most. This is true for 76% of Americans and 62% of Europeans. Researchers’ departments, organizations and professional bodies are each cited by no more than 12% of respondents as having the most important opinions (see Table 8).\n\nWhere do researchers gain information about RI? Figure 4 shows the percentages who say they obtain ‘some’ or ‘a lot’ of knowledge from eleven sources. Both in the US and in Europe it is scholarly communities and research collaborators from whom the most knowledge is acquired. Perhaps unsurprisingly, there is a gradient in the amount of knowledge acquired from these more proximal sources (more opportunities, more contact) to more distant sources, such as funding bodies and academies committed to RI. Researchers’ organizations and departments are endorsed by around half of respondents as significant sources of information on RI. Thus, it appears that organizations have ready channels of information transmission to exploit.\n\nDrilling deeper into the roles of organizations and researchers, and what the scope for action might be, respondents were asked the following. Firstly, whether they thought RI policies would help to improve the quality of their own research; secondly, whether they considered these policies to be genuinely intended for the purposes of improvement or simply for meeting bureaucratic requirements (‘box-ticking’), and finally how positive they would feel about receiving RI training. Responses to the three questions were combined into a categorical indicator to identify those who are more enthusiastic and likely to be more engaged and those who are generally skeptical towards organizational measures (see Extended data, Allum et al., 2022).\n\nFigure 5 shows the percentages of enthusiasts for personal and organizational RI measures. Overall, researchers are significantly more enthusiastic, at 54%, than skeptical, at 30% (with neutrals at 16%). In absolute terms (chi square test), consistently across the demographic breakdowns, Europeans are more positive than American researchers, although the differences in most cases are not statistically significant. The highest levels of positivity are found amongst women, medical scientists and those working outside of the university sector. Figure 6 shows the results of a multivariate analysis showing the associations of the explanatory variables in Figure 5 considered as a whole. Region, field, sector and sex show robust differences, after adjusting for all other factors.\n\nFor organizations to successfully implement appropriate procedures and protocols for ethical and responsible research, researchers must be motivated to engage with them. Based on previous qualitative research (Sørensen et al., 2021; Sorensen and Ravn, 2020) we presented respondents with a list, shown in Figure 7, of possible motivations for complying with RI practices. We wanted to understand what researchers consider to be the benefits of engaging with these policies, and what kind of incentives could be important to them.\n\nThe top incentives for scientists in complying with RI procedures concern intrinsic scientific benefits, ‘truth’ and ‘trust’, specifically: more reliable scientific knowledge; more trust from colleagues; more trust from the general public; and a better reputation in my field. It is of note that the extrinsic benefits of promotion and salary prospects are reported to be the least motivating.\n\nThere are some differences between researchers based in US and Europe. In the US, the possibility of higher salary is more motivating than it is for Europeans. Europeans are more likely to be motivated by enhanced opportunities to collaborate with others and to gain more self-confidence.\n\nHow do these overall attitudes and motivations translate into welcoming additional support in each of the nine RI areas? Figure 8 shows that between 20% and 35% of researchers in US and Europe would welcome further support on the majority of the nine RI topics, with European researchers showing greater demand than researchers in the US. Particularly striking is the fact that twice as many Europeans (28%) as Americans (14%) would welcome additional RI training. Additional support in cases of integrity breaches is also an issue where European researchers appear much more open than their American counterparts. This suggests that formal professional development programs in RI would be welcomed by many European researchers, although a majority in both regions remain unpersuaded.\n\n\nDiscussion\n\nIn this paper we have examined researchers’ beliefs, values and behaviors, and what they think about their organization’s practices and performance. The results point to problems in workstyles, behaviours and organizational practices. Set against this, are positive signs of a readiness to adopt research and organizational practices which are believed to be conducive to enhancing responsible research conduct.\n\nWith the common experience of three decades of policy making on RI, four in five senior researchers in the US are confident about the integrity of their own research, while the same is true for only three in five in Europe, falling to two in five for Europe’s early career researchers. Confidence in their organizations’ effectiveness in supporting RI is expressed by less than half of Americans and less than a third of European researchers. Admissions of QRPs ranging from superficial peer reviewing, selective reporting and researching without ethical approval, are not uncommon and are more frequent in Europe than the US, most noticeably for carrying out research without ethical approval and failing to disclose conflicts of interest. In both cases, the rate of admission is twice as high for European researchers. In some instances, this may be indicative of sloppier practice in Europe, but it may also reflect variability in the formal requirements for ethical approval and declarations of interest in different national and institutional contexts.\n\nOur estimates of the frequency of QRPs exceed those in the meta-analyses of Fanelli and more recently of Xie et al. (Fanelli, 2009; Xie et al., 2021) but are more consistent with recent surveys carried out in the Netherlands and Norway (Gopalakrishna et al., 2022; Kaiser et al., 2021).\n\nAsked to assess whether their organization has high standards on nine RI topics, while agreement is higher in the US than Europe and among the medical science disciplines, overall, half of researchers say their organization does not have high standards.\n\nThere are, however, positive indications regarding the development of individual competences and organizational policies and practices. Researchers value the intrinsic benefits of RI, in terms of delivering greater research quality and trustworthiness far more than the extrinsic benefits of promotion and salary. Most researchers recognize that responsibility for RI is shared between them and their organization. In Europe a majority say they are willing to engage in RI training, consider that RI policies are well intentioned and should improve research quality. A non-trivial percentage of European and American researchers would welcome additional support across the nine RI topics.\n\nWhat are the lessons of the IRIS survey for researchers and their organizations? While there is concern about the current state of health of integrity in research conduct and a recognition of its benefits, the findings from the US and Europe show that there are no magic bullets, no quick fixes. After three decades promoting ethics and integrity in research conduct, we find integrity deficits in both researchers’ behaviors and in how they judge their organization’s practices. This leads to a cornerstone in the framing of RI; it is the responsibility of multiple actors – researchers, their organizations, research funders, professional bodies and academies. A particular responsibility for research performing organizations (RPOs) is the provision of training in ethics and research conduct for all involved in the research cycle including students at all levels, researchers and administrators. The pro-active commitment of the NSF in the US shows that funding organizations have a vital role in setting the agenda on RI for research funding organizations (RFOs) and for monitoring compliance. Horizon Europe is in a unique position in Europe to make similar demands of RPOs and the researchers.\n\nChanging organizational cultures and individual norms and standards of behavior towards greater RI will take time, commitment and resources. It is notable that researchers rely on many channels of communication about RI; their colleagues, departments, organizations, funding agencies and the academies, suggesting that the involvement of many different participants in the research system would be efficacious. Policies must be developed to reinforce best practice rather than being seen as an irrelevance to the real business of research. The SOPs4RI study has published guidelines for ‘Research integrity Promotion Plans’ which organizations may find useful in achieving a healthy research culture (“Toolbox – SOPs4RI,” n.d.). The empirical foundations laid by the IRIS can provide clarity on how RI might be facilitated, and which actors should play a role, enabling comparisons across multiple dimensions, highlighting commonalities and divergences across groups, in the continued efforts towards heightened research integrity.\n\nFinally, to our knowledge, this is the first dataset with which systematic comparison jointly between countries, regions and scientific fields has been possible. The IRIS data also allow for comparisons to be made between European countries, and there is much more insight that can be mined.",
"appendix": "Data availability\n\nOpen Science Framework: International Survey on Research Integrity (IRIS), https://doi.org/10.17605/OSF.IO/XB9RK (Allum et al., 2022).\n\nThis project contains the following underlying data:\n\n• Data file 1. (Full dataset in Stata and .csv formats)\n\n• Data file 2. (Stata replication code in .do format)\n\nOpen Science Framework: International Survey on Research Integrity (IRIS), https://doi.org/10.17605/OSF.IO/XB9RK (Allum et al., 2022).\n\nThis project contains the following extended data:\n\n• Data file 1. (Supplementary material (SM) and D6.2 Final report and recommendations)\n\n• Data file 3. (Survey protocol, questionnaire and ethics approval)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International Licence (CC-BY-4.0)\n\n\nAcknowledgments\n\nThe authors would like to acknowledge the work of Jens Peter Andersen for assisting with the construction of the sampling frame and Olena Kaminska for the sample design.\n\n\nReferences\n\nAllum NN, Mejlgaard N, Sorensen M, et al.: International Survey on Research Integrity (IRIS). Open Science Framework. 2022.Reference Source\n\nAmerican Association for Public Opinion Research: Standard Definitions: Final Dispositions of Case Codes and Outcome Rates for Surveys. 9th edition.AAPOR;2016.Reference Source\n\nAt a Glance|NSF - National Science Foundation:n.d.Reference Source\n\nEuropean Commission: Horizon Europe Programme: Standard Application Form. HE RIA, IA;2022.\n\nFanelli D: How Many Scientists Fabricate and Falsify Research? A Systematic Review and Meta-Analysis of Survey Data. PLoS One. 2009; 4: e5738. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGodecharle S, Nemery B, Dierickx K: Heterogeneity in European research integrity guidance: relying on values or norms? J. Empir. Res. Hum. Res. Ethics. 2014; 9: 79–90. PubMed Abstract | Publisher Full Text\n\nGodecharle S, Nemery B, Dierickx K: Guidance on research integrity: no union in Europe. Lancet. 2013; 381: 1097–1098. PubMed Abstract | Publisher Full Text\n\nGopalakrishna G, ter Riet G , Vink G, et al.: Prevalence of questionable research practices, research misconduct and their potential explanatory factors: A survey among academic researchers in The Netherlands. PLoS One. 2022; 17: e0263023. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKaiser M, Drivdal L, Hjellbrekke J, et al.: Questionable Research Practices and Misconduct Among Norwegian Researchers. Sci. Eng. Ethics. 2021; 28: 2. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMejlgaard N, Bouter LM, Gaskell G, et al.: Research integrity: nine ways to move from talk to walk. Nature. 2020; 586: 358–360. PubMed Abstract | Publisher Full Text\n\nNational Academies of Sciences Engineering, Medicine: Fostering Integrity in Research. Washington, DC:The National Academies Press;2017. Publisher Full Text\n\nNational Academy of Sciences (US), National Academy of Engineering (US) and Institute of Medicine (US) Panel on Scientific Responsibility and the Conduct of Research: Responsible Science: Ensuring the Integrity of the Research Process: Volume I. Washington (DC):National Academies Press (US);1992.\n\nReid A, Allum N: Protocol for Survey Study (No. D6.1). SOPs4RI.2021.\n\nSchneider JW, Allum N, Andersen JP, et al.: Is ‘something rotten in the state of Denmark’? Cross-national evidence for systemic self-reported use and prevalence of 25 questionable research practices across all fields of research.In preparation.\n\nSOPs4RI – Promoting excellent research:n.d.\n\nSorensen MP, Ravn T: Report on the results of the focus group interviews.2020. Publisher Full Text\n\nSørensen MP, Ravn T, Marušić A, et al.: Strengthening research integrity: which topic areas should organisations focus on? Humanit. Soc. Sci. Commun. 2021; 8: 1–15. Publisher Full Text\n\nThe European Code of Conduct for Research Integrity - ALLEA:n.d.\n\nTitus SL, Wells JA, Rhoades LJ: Repairing research integrity. Nature. 2008; 453: 980–982. Publisher Full Text\n\nToolbox – SOPs4RI:n.d.\n\nVan den Eynden V, Knight G, Vlad A, et al.: Survey of Wellcome researchers and their attitudes to open research. Wellcome Trust. 2016. Publisher Full Text\n\nWhistleblower Protection|Office of Inspector General:n.d.Reference Source\n\nWoolston C: Postdoc survey reveals disenchantment with working life. Nature. 2020; 587: 505–508. PubMed Abstract | Publisher 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; 27: 41. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "163833",
"date": "22 Feb 2023",
"name": "Dorothy Vera Margaret Bishop",
"expertise": [
"Reviewer Expertise Neuropsychology",
"Child Development",
"Research Integrity"
],
"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 very nice piece of work that provides important information on research integrity. It is impressive because not only is there a large sample size, but the sampling strategy was far more sophisticated than in previous surveys of this kind. A great deal of thought has gone into the survey design. A complex data set is clearly presented with appropriate graphics, and the full dataset is available for others to peruse.\nI have only minor suggestions for improvement.\nI was initially unclear whether author position was taken into account in either selecting respondents or in analysis. I think it wasn’t, which is fine, but it may be worth explicitly stating that.\n\nSimilarly, I assume no incentives were used to encourage people to respond?\n\nI have a particular interest in how whistleblowers are treated by institutions, and so I looked at the reference at the end of para 2 of the introduction. It was not clear that this applied to academics: It seemed to come from the Department of Homeland Security. Some clarification would help here.\n\nUse of commas as numeric separator for thousands is inconsistent in text and in figures/tables.\n\nIn line 9 of paragraph p 5 Analysis/statistical methods, the letter f is twice replaced by another font – I noticed this as it did not print on my printer.\n\nTables 2 and 6 – my preference would be for these to be reformatted so the top level is US vs Eur, and the next level is confidence level. I found it quite difficult to scan across the table to appreciate the differences, especially with on-screen viewing. This is particularly true for Table 6, where the interest is in how many scores are on the diagonal. I don’t see this as essential: all the information is there, but maybe change if others agree it could be more clearly laid out.\n\nI was initially confused in Figure 1 by “Not conducting a thorough peer review”, as I had thought the questions pertained to one’s own research, so I wondered if it meant the researcher had not adequately evaluated their own protocol before doing the study – or perhaps had published work in non-peer-reviewed outlets. Subsequently, I realised this was referring to the case when researchers peer review the work of others. I think minor rewording could clarify this.\n\nP 14 , on incentives. “It is of note that the extrinsic benefits of promotion and salary prospects are reported to be the least motivating”. I think this might need unpicking a bit. A major problem in my experience is that researchers tend to believe that in order to advance their careers it helps to adopt QRPs! So my suspicion is that researchers are certainly motivated by promotion and salary prospects, but they just don’t believe that the way to achieve these is by working with integrity – indeed quite the opposite is often assumed. I assume you don’t have data to test that interpretation, but it may be worth flagging up.\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": "182505",
"date": "14 Jul 2023",
"name": "Simon Kolstoe",
"expertise": [
"Reviewer Expertise Research Ethics",
"Integrity and Governance"
],
"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\nI enjoyed reading this study, and especially the fact that it focussed on both European and American researchers. Of course this misses out the rest of the world, but you do have to start somewhere! It was also reassuring that they managed such a large sample size.\nAssessments as to the reliability of research are clearly essential to the overall value of research. In recent years this assessment (some may call it a concern) has been given various names, one of which is research integrity. In once sense integrity can be considered as quite specifically focused on the data itself, however a more useful way to use the phrase is to consider the overall behaviour of researchers, wherein a researcher acting with high levels of integrity will subsequently produce reliable data (data integrity) but more widely will also contribute to the creation and maintenance of a healthy research culture. The opposite of acting with integrity is thus engaging in questionable research practices (QRPs). As a consequence trying to determine levels and trends in QRPs is essential if trying to assess the current levels of integrity within the research community, and identify areas where more work is required.\nThis paper adds to the literature by providing an up to date survey of QRPs alongside gathering information on what researchers think about research integrity practices/initiatives. The large sample size, sophisticated sampling strategy, and comparison between the US and EU provide a level of reassurance that the data presented here is more than just an interesting anecdote.\nThus said the research community is wide with a large variety of roles, academic practices, and career pathways. As a consequence any large survey is bound to miss subtleties no matter how careful the analysis, so I do not entirely agree that a survey like this is truly representative (as claimed by the authors). But again, the authors have done a good job of trying to break down the data into relevant subgroups, that will add constructively to wider discussions.\nAs an aside, I was astounded that the pilot testing involved 5000 people, surely about 50 or so would have sufficed? Also, as I am not a statistician, I cannot really pass comment on the details of the sample selection and analysis, but the technical description does at least provide a level of existential reassurance that this was carefully thought through!\nAre the results novel or surprising - possibly not for those familiar with this area, but what they are is relatively systematic and, as mentioned above, more than the anecdotal figures that we normally use to talk about these things. So from this perspective this paper (and data therein) is definitely a valuable contribution, and one that I have already referenced in a plenary conference presentation. Indeed I also note that the newly established UK Committee on Research Integrity (UKCORI) also referenced this data in their first annual report, again providing evidence of its value.\nThere are, of course, weaknesses, or at least points that can be objected to by a reviewer. For instance I would disagree with the statement that \"[QRPs]... fall short of outright misconduct but represent transgressions of best practice\". Increasingly QRPs are seen as a spectrum with innocent errors on the minor end, and misconduct on the major end1. Likewise, the eight QRPs shown in Figure 1 seem to be selected somewhat arbitrarily and are perhaps not the ones I would have chosen. Indeed if, as I contend above, QRPs represent a spectrum with misconduct at one end, I would have wanted to ask about ignoring datapoints, fabrication, and covering up inadequate analyses.\nI also wonder how many of the differences between the US and EU researchers come down to definitions that are not quite the same on both sides of the Atlantic. US culture and world view is increasingly divergent from Europeans, and while we try to communicate in the same language, the baggage that comes with certain statements or ideas can be quite different. Thus said, it is fascinating that US researchers seem to have more confidence in their institutions handling of RI, despite Americans generally being considered as being less trusting of institutions and governance structures. However, conversely, the US researchers are also less enthusiastic about RI measures in general. A qualitative analysis of such views is about the only way these issues could be further explored (and given the size of the project that this work comes from, I will look forward to reading this analysis in due course!).\nFinally I was bemused by the statement: \"four in five senior researchers in the US are confident about the integrity of their own research, while the same is true for only three in five in Europe, falling to two in five for Europe’s early career researchers.\" I wonder whether, far from being an indictment on the quality of European research (which was perhaps implied in the discussion), this may instead be an indication that European researchers are more realistic about the nature of research and the serious challenges that need to be addressed?\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? Yes",
"responses": []
},
{
"id": "182504",
"date": "18 Jul 2023",
"name": "Bibek Dahal",
"expertise": [
"Reviewer Expertise Academic Integrity",
"Research Integrity",
"Research Ethics",
"Knowledge Equity 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\nVery intense and insightful survey on research integrity! The methodological rigour is exceptional. The presentation of data along with interpretation helps to follow the survey results.\n\nFrom the reader's viewpoint, I have realized the following rooms for improvement:\n\nA clear statement regarding the rationale of comparing a country (US) with a continent (EU) is required to understand the overall implication of this study.\n\nIt is better to unpack the concept of ‘responsible research practice’, ‘questionable research practice’, ‘detrimental research practice’ and ‘breaches of the principle/code of conduct’. This will help the readers to understand the meaning of these terms in this study's case.\n\nIt is better to explain with examples, how ‘questionable research practice’ is different than ‘research misconduct’, if these two terms were conceptualized differently during the survey in this study.\n\nWrite a conclusion explaining the implication of the study and suggestions for 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? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-187
|
https://f1000research.com/articles/12-186/v1
|
16 Feb 23
|
{
"type": "Software Tool Article",
"title": "AMAW: automated gene annotation for non-model eukaryotic genomes",
"authors": [
"Loïc Meunier",
"Denis Baurain",
"Luc Cornet",
"Denis Baurain",
"Luc Cornet"
],
"abstract": "Background: The annotation of genomes is a crucial step regarding the analysis of new genomic data and resulting insights, and this especially for emerging organisms which allow researchers to access unexplored lineages, so as to expand our knowledge of poorly represented taxonomic groups. Complete pipelines for eukaryotic genome annotation have been proposed for more than a decade, but the issue is still challenging. One of the most widely used tools in the field is MAKER2, an annotation pipeline using experimental evidence (mRNA-seq and proteins) and combining different gene prediction tools. MAKER2 enables individual laboratories and small-scale projects to annotate non-model organisms for which pre-existing gene models are not available. The optimal use of MAKER2 requires gathering evidence data (by searching and assembling transcripts, and/or collecting homologous proteins from related organisms), elaborating the best annotation strategy (training of gene models) and efficiently orchestrating the different steps of the software in a grid computing environment, which is tedious, time-consuming and requires a great deal of bioinformatic skills. Methods: To address these issues, we present AMAW (Automated MAKER2 Annotation Wrapper), a wrapper pipeline for MAKER2 that automates the above-mentioned tasks. Importantly, AMAW also exists as a Singularity container recipe easy to deploy on a grid computer, thereby overcoming the tricky installation of MAKER2. Use case: The performance of AMAW is illustrated through the annotation of a selection of 32 protist genomes, for which we compared its annotations with those produced with gene models directly available in AUGUSTUS. Conclusions: Importantly, AMAW also exists as a Singularity container recipe easy to deploy on a grid computer, thereby overcoming the tricky installation of MAKER2",
"keywords": [
"Genome annotation",
"non-model unicellular eukaryotes",
"gene prediction",
"evidence data acquisition",
"Singularity container",
"automation"
],
"content": "Introduction\n\nCoding sequences (CDS) and, more generally, gene structures from an organism, are essential genomic data, especially for phylogenomics and gene mining, for which accessing reliable protein sequences from publicly available emerging draft genomes is invaluable (Keeling and Burki, 2019). These can be more or less accurately obtained through the structural annotation of a genome, for which the collection of evidence data and the use of annotation pipelines are tricky at best (Yandell and Ence, 2012).\n\nFollowing the decrease in sequencing costs due to the advent of Next Generation Sequencing and the concomitant explosion of sequenced organisms, new genomic data from emerging model organisms allow researchers to access unexplored taxonomic groups (Keeling and Burki, 2019). However, eukaryotic genomes, whose biodiversity is predominantly represented by protist lineages (Adl et al., 2019, Burki et al., 2020), present special features which complexify the structural annotation process: large genomes with a low gene density, long intergenic regions, as well as introns (Yandell and Ence, 2012). Although pipelines for eukaryotic genome annotation have been developed for more than a decade, it is still challenging to obtain an accurate annotation of the gene structures, a shortcoming that is often revealed in phylogenomic studies (Di Franco et al., 2019). MAKER2 (Holt and Yandell, 2011) has been, for more than a decade, one of the most popular annotation pipelines for eukaryotes.\n\nAlthough MAKER2 (Holt and Yandell, 2011) enables individual laboratories to annotate non-model organisms (for which pre-existing gene models are not available), the use of this tool remains complex, as it implies the orchestration and fine-tuning of a multi-step process (Campbell et al., 2015). First, an evidence dataset must be compiled by collecting phylogenetically related proteins and species-specific transcripts, which often requires the assembly of RNA-Seq data for new organisms. Next, iterative runs of MAKER2 (Holt and Yandell, 2011) must also be coordinated to aim for accurate predictions, which includes intermediary specific training of different gene predictor models.\n\nHere we present AMAW (Automated MAKER2 Annotation Wrapper) (Loïc Meunier et al., 2022), a wrapper pipeline facilitating the annotation of emerging unicellular eukaryotes (i.e., protist) genomes in both small and large-scale projects in a grid-computing environment. This tool addresses all the above-mentioned tasks according to MAKER2 authors’ recommendations (Campbell et al., 2015) and is, to our knowledge, the first implementation automating the use of MAKER2. We also demonstrate that the use of AMAW yields genome annotation significantly improved in comparison to the use of MAKER2 with the AUGUSTUS (Stanke et al., 2008) gene models that are available by default.\n\n\nMethods\n\nAMAW is implemented in Perl 5 version 22 (Perl, 1994) (RRID:SCR_018313) and is available either in a standalone version or through a Singularity container. Basic inputs required by AMAW pipeline are a FASTA-formatted nucleotide genome file and the organism name. Alternatively, evidence data, such as proteins or transcripts/ESTs provided by the user, or even gene models, can also be directly used for genome annotation.\n\nThe MAKER2 annotation suite was chosen to be automated for its performance and interesting features: beside supporting gene prediction with evidence data, MAKER2 has been demonstrated to improve the accuracy of its internal gene predictors, to maintain this accuracy even when the quality or size of evidence data decreases, as well as to limit the number of overpredictions (Holt and Yandell, 2011).\n\nTaking MAKER2 as its internal engine, AMAW is able to gather and assemble RNA-Seq evidence, collect protein evidence, iteratively train the hidden Markov models (HMMs) of the predictors to yield the most accurate evidence-supported annotation possible without manual curation nor prior expertise of the organism (see AMAW subsection). Our tool, designed for non-model unicellular eukaryotic genomes, presents helpful applications in phylogenomics and comparative genomics. Indeed, some taxonomic lineages still lack high-quality genomic data (Burki et al., 2020), and filling these gaps would extend studies to these interesting groups.\n\nThe pipeline devised in AMAW (Figure 1) aims to reach three goals: (1) to achieve the most accurate annotation of a non-model genome without manual curation, (2) to automate the use of MAKER2 for supporting large-scale annotation projects, and (3) to simplify its installation and usage for users without a strong bioinformatics background.\n\nFirst transcripts and protein evidence are collected and deployed, if required. Then, three iterative runs of MAKER2 are performed to progressively train SNAP and AUGUSTUS gene predictors. The final genome annotation is generated after the third MAKER2 run.\n\nFirst, a key factor for achieving accurate genome annotation is to collect as much evidence data (transcripts and/or proteins) as possible. This is needed both to optimize the training of specific gene models of ab initio gene predictors and to improve the confidence level in predictions supported by experimental data (Holt and Yandell, 2011).\n\nSecond, building evidence datasets is a time-consuming task, which also implies a certain level of bioinformatics skills. This consists of, in the best cases, finding and downloading directly available transcript or protein datasets for the genome species to annotate. However, this process often further requires assembling raw RNA-Seq reads into transcripts and gathering a reasonably sized protein dataset, usually including sequences of taxa phylogenetically close to the organism of interest. If building evidence datasets is feasible for a few genomes to annotate, doing so repeatedly for dozens or hundreds of genomes is hardly conceivable. This is why AMAW addresses this issue by automating the acquisition of both available RNA-sequence and protein data from reliable public databases (“NCBI Sequence Read Archive (SRA)” for RNA- sequence data and a combination of “Ensembl genomes” and NCBI databases for protein sequences).\n\nThird, in addition of constructing a good input dataset for the annotation, AMAW automates the installation and the global use of the MAKER2 annotation pipeline based on good practices published by its authors (Campbell et al., 2015), and orchestrates the successive runs in a grid-computing environment. Even if MAKER2 is described as an easy to use pipeline, its handling and the optimal fine-tuning of its parameters demand that users take notice of its large documentation and, again, require a good bioinformatics understanding.\n\nThe complete workflow of AMAW can be summarized in three steps:\n\n1. Transcript evidence data acquisition: RNA-Seq acquisition, assembly into transcripts, quantification of the abundance of the transcripts and filtering of redundant transcripts and minor isoforms;\n\n2. Protein evidence deployment;\n\n3. MAKER2 iterative runs and progressive training of its internal gene predictors.\n\nIt is possible for the user to provide their own in-house protein and/or transcript dataset(s). Moreover, they can short-circuit the pipeline by choosing an existing gene model for AUGUSTUS (Stanke et al., 2008) and/or SNAP (Korf, 2004). However, unless available models are well-suited for the organism at hand (matching species), it is advised to rely on AMAW full analysis.\n\nAcquisition and building of transcript evidence data\n\nThe generation of a specific transcript dataset is carried out on the basis of the organism species name, provided by the user. This name is used to search for RNA-Seq experiments in NCBI SRA. Considering the divergence between nucleotide sequences at the genus level, only species-specific data is collected to perform direct nucleotide alignment (Campbell et al., 2015). The information of RNA-Seq experiment runs is collected with e-utilities and the corresponding FASTQ files are downloaded with fastq-dump v3.0.0. The acquisition of the RNA-Seq data prioritizes paired-end reads, when available, rather than single-end libraries, for more accurate transcript assembly. To limit the data volume to be stored in the case of well-represented organisms, two options are implemented: (1) a threshold on the maximal cumulative size of FASTQ files to download (by default: 25 GB) and (2) a threshold on the number of experiments (by default: none). Moreover, RNA-Seq experiments are sorted by ascending data volume before being selected in an attempt to maximize the diversity of RNA-Seq libraries.\n\nFASTQ read files are assembled into transcripts with Trinity v2.12.0 (Grabherr et al., 2013) (standard parameters). The abundance of transcripts is first assessed with “align_and_estimate_abundance.pl”, a Trinity utility script that uses RSEM (Li and Dewey, 2011), then a custom script removes the redundant transcripts (which are common when several samples are pooled) and minor isoforms (by default, with abundance < 10% for a Trinity-defined gene). Finally, assembled transcripts are pooled and fetched to MAKER2.\n\nDeployment of preloaded protein evidence data\n\nTo collect a set of curated protein sequences of eukaryotic microorganisms, Ensembl genomes (Kersey et al., 2018) were downloaded (Protists, Fungi and Plants - release 35.0, 08 May 2017) in combination with protist genomes available on the NCBI (March 2017) into a single database. However, to accelerate the computation time of MAKER2 annotations, this protein sequence database was subdivided following the major eukaryotic taxonomic clades. For this, we used the NCBI third taxonomic level (usually the phylum), which allows us to already considerably reduce the quantity of data to deploy for an annotation while ensuring enough sequence evidence for less studied lineages. Moreover, for further optimization of the computation time, these subsets were also dereplicated with CD-HIT version 4.6 (Li and Godzik, 2006): sequences sharing ≥ 99% identity were removed in favor of a single representative sequence. In practice, the taxonomy of the user-given organism species name is used to deploy the protein database corresponding to its taxon.\n\nMAKER2 runs and intermediate trainings of the gene predictors\n\nFollowing the good practices given by Campbell et al. (2015), the default AMAW workflow consists in three successive MAKER2 runs:\n\n1. The first MAKER2 round predicts the genes only based on alignment of the provided transcript and protein data on the genome assembly to annotate. The predicted gene sequences will then be used for training a gene model for the SNAP gene predictor.\n\n2. MAKER2 second round uses SNAP with the trained gene model and the evidence data will only be used for supporting the presence or absence of the predicted genes. Then, the SNAP gene model is trained again and a gene model is trained for AUGUSTUS.\n\n3. MAKER2 third and last round performs gene predictions with both trained SNAP and AUGUSTUS gene predictors.\n\nAt the end of these three annotation rounds, two sets of gene predictions containing the gene predictors consensus are returned: a first one containing those supported by evidence data and a second one with the unsupported ones. However, the latter dataset needs to be cautiously used as the false positive rate is expected to be higher.\n\nFor optimal performance of the pipeline, it is possible (and recommended when applicable) for the user to provide her/his own experimental transcript data.\n\nBeside the complete pipeline, AMAW also offers the possibility to shorten the analyses to only one round to:\n\n- annotate several genomes of the same species (or re-run a previous analysis) for which the evidence data has already been constructed and the SNAP and AUGUSTUS gene models already trained.\n\n- directly use an AUGUSTUS gene model (available in its library or provided by the user) without evidence data building. It is noteworthy that this mode does not use the SNAP gene predictor.\n\nIn this case, only the third round is launched according to the chosen mode.\n\n\nUse cases: structural genome annotation of protist lineages\n\nThe efficiency of MAKER2 being well known (Holt and Yandell, 2011), we illustrate the performance of AMAW by comparing its annotations with those of MAKER2 on a selection of 32 protist genomes in two very contrasted conditions (Cornet, Luc 2022a). In detail, the annotations generated with AMAW, where a gene model is specifically created for the genome from the available data, are compared with those produced with gene models directly available in AUGUSTUS (Stanke et al., 2008). The latter (control) condition corresponds to a basic usage of MAKER2.\n\nTo explore the impact of gene model choice, four AUGUSTUS models were used against AMAW generated ones: Homo sapiens, Arabidopsis thaliana, Aspergillus oryzae and the “closest” available model with respect to the organism to annotate. For this, a dataset of 32 genomes of protist organisms was designed and the quality of the different structural annotations was assessed using the completeness metrics provided by BUSCO v4 (Seppey et al., 2019) and the latest orthologous databases (Kriventseva et al., 2019). The genomes were downloaded from the NCBI and are available in the Supplementary Database (Cornet, Luc 2022a). For more details, see Supplementary Tables 1 (Cornet, Luc 2022e) and 2 (Cornet, Luc 2022f) for the complete taxonomy of these genomes, evidence data used to train the gene models and orthologous databases used with BUSCO.\n\nThe analysis of median values of BUSCO metrics shows that AMAW gene models significantly improve the quality of MAKER2 annotations (Figure 2A): with a median completeness of 90.6% (the closest gene model is the second most complete with a median of 68.7%), a median rate of fragmented annotations of 3.8% (second: closest gene model with 8.2%) and a median rate of missing annotations of 5.4% (second: closest gene model with 14.0%). Complete BUSCO results are provided as a table (see Supplementary Table 3 (Cornet, Luc 2022g)) and individual barplots for completeness, fragmented and missing genes (see Supplementary Figures 1 (Cornet, Luc 2022b), 2 (Cornet, Luc 2022c) and 3 (Cornet, Luc 2022d), respectively).\n\nAmong the five gene models used for each genome, AMAW performed best, giving the most complete annotation in 59.4% of cases, the least fragmented annotations in 34.4.8% of cases and the lowest proportion of missing proteins in 50.0% of cases (Figure 2B). AMAW annotations for which RNA-Seq data is available are of better quality (see Figure 3).\n\nAmong the five gene models assayed for each genome, AMAW performed best, giving the most complete annotation in 73.3% of cases (in comparison with 59.4% for the full genome dataset), the least fragmented annotations in 46.7% of cases (in comparison with 34.4%) and the lowest proportion of missing proteins in 60.0% of cases (in comparison with 50.0%).\n\n\nConclusions\n\nWe presented AMAW and its set of functionalities automazing the annotation of genomes, with a specific aim for non-model organisms. The application example shows how AMAW significantly improves the genome annotation quality in comparison of naive use of MAKER2 with pre-existing gene models, as well as the importance of providing specific evidence data. We aim with AMAW’s functionalities automating the acquisition and deployment of evidence data to contribute to the effort for achieving continually more complete and accurate annotations, especially for poorly represented eukaryotic lineages. Considering its streamlined installation and straightforward usage in grid-computing environments, we hope AMAW to be useful in future small and large genome annotation projects.\n\n\nAuthor contributions\n\nL. Meunier: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Software, Visualization, Writing - Original Draft Preparation.\n\nD. Baurain: Conceptualization, Funding Acquisition, Methodology, Resources, Validation, Writing - Review & Editing.\n\nL. Cornet: Conceptualization, Data Curation, Formal Analysis, Investigation, Software, Supervision, Writing - Review and Editing.",
"appendix": "Data availability\n\nThe genome assemblies used to assess AMAW are publicly available on the NCBI assembly database (https://www.ncbi.nlm.nih.gov/assembly/) and released as an archived database (https://doi.org/10.6084/m9.figshare.21757880):\n\nAcytostelium subglobosum:\n\nGenbank GCA_000787575.2\n\nAscogregarina taiwanensis:\n\nGenbank GCA_000172235.1\n\nAuxenochlorella pyrenoidosa:\n\nGenbank GCA_001430745.1\n\nBalamuthia mandrillaris:\n\nGenbank GCA_001185145.1\n\nBreviolum minutum:\n\nGenbank GCA_000507305.1\n\nChromera velia:\n\nGenbank GCA_000585135.1\n\nChlorella vulgaris:\n\nGenbank GCA_001021125.1\n\nCladosiphon okamuranus:\n\nGenbank GCA_001742925.1\n\nCoccomyxa subellipsoidea:\n\nGenbank GCA_000258705.1\n\nCrithidia acanthocephali:\n\nGenbank GCA_000482105.1\n\nCyclospora cayetanensis:\n\nGenbank GCA_000769155.2\n\nCymbomonas tetramitiformis:\n\nGenbank GCA_001247695.1\n\nDiplonema papillatum:\n\nGenbank GCA_001655075.1\n\nEndotrypanum monterogeii:\n\nGenbank GCA_000333855.2\n\nEuplotes focardii:\n\nGenbank GCA_001880345.1\n\nFragilariopsis cylindrus:\n\nGenbank GCA_001750085.1\n\nGonium pectorale:\n\nGenbank GCA_001584585.1\n\nHaemoproteus tartakovskyi:\n\nGenbank GCA_001625125.1\n\nHalocafeteria seosinensis:\n\nGenbank GCA_001687465.1\n\nHerpetomonas muscarum:\n\nGenbank GCA_000482205.1\n\nLotmaria passim:\n\nGenbank GCA_000635995.1\n\nMastigamoeba balamuthi:\n\nGenbank GCA_000765095.1\n\nMoneuplotes crassus:\n\nGenbank GCA_001880385.1\n\nNeospora caninum:\n\nRefSeq GCF_000208865.1\n\nParachlorella kessleri:\n\nGenbank GCA_001598975.1\n\nPilasporangium apinafurcum:\n\nGenbank GCA_001600475.1\n\nPorphyridium purpureum:\n\nGenbank GCA_000397085.1\n\nPseudoperonospora cubensis:\n\nGenbank GCA_000252605.1\n\nSaccharina japonica:\n\nGenbank GCA_000978595.1\n\nSarcocystis neurona:\n\nGenbank GCA_000727475.1\n\nTrebouxia gelatinosa:\n\nGenbank GCA_000818905.1\n\nUroleptopsis citrina:\n\nGenbank GCA_001653735.1\n\nSupplementary Database: Figshare: AMAW-genomes-used https://doi.org/10.6084/m9.figshare.21757880 (Cornet, Luc, 2022a)\n\nArchive containing the FASTA files of the 32-genomes selection used in the use case.\n\nFigshare: AMAW-Supplementary_Figure1.jpg https://doi.org/10.6084/m9.figshare.21603990 (Cornet, Luc, 2022b)\n\nThis project contains the following extended data:\n\n- AMAW-Supplementary_Figure1.jpg (BUSCO metrics: percentage of completeness for each of the 32 analyzed genomes using five gene models.)\n\nFigshare: AMAW-Supplementary_Figure2.jpg https://doi.org/10.6084/m9.figshare.21603996 (Cornet, Luc, 2022c)\n\nThis project contains the following extended data:\n\n‐ AMAW-Supplementary_Figure2.jpg (BUSCO metrics: percentage of fragmented genes for each of the 32 analyzed genomes using five gene models.)\n\nFigshare: AMAW-Supplementary_Figure3.jpg https://doi.org/10.6084/m9.figshare.21603999 (Cornet, Luc, 2022d)\n\nThis project contains the following extended data:\n\n- AMAW-Supplementary_Figure3.jpg (BUSCO metrics: percentage of missing genes for each of the 32 analyzed genomes using five gene models.)\n\nFigshare: AMAW-Supplementary_Table 1.csv https://doi.org/10.6084/m9.figshare.21604011 (Cornet, Luc, 2022e)\n\nThis project contains the following extended data:\n\n- AMAW-Supplementary_Table1.csv\n\nFigshare: AMAW-Supplementary_Table 2.csv https://doi.org/10.6084/m9.figshare.21604002 (Cornet, Luc, 2022f)\n\nThis project contains the following extended data:\n\n‐ AMAW-Supplementary_Table2.csv\n\nFigshare: AMAW-Supplementary_Table 3.csv https://doi.org/10.6084/m9.figshare.21750965 (Cornet, Luc, 2022g)\n\nThis project contains the following extended data:\n\n‐ AMAW-Supplementary_Table3.csv (BUSCO metrics results for each set of genome and used gene model, and the ortoDB database associated to the analysis)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Software Availability\n\nAMAW is released both as a Singularity container recipe and a standalone Perl script (https://bitbucket.org/phylogeno/amaw/)\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.7490001 (Loïc Meunier et al., 2022)\n\nLicense: GNU GPL v3\n\n\nAcknowledgments\n\nWe thank David Colignon (ULiège) and Olivier Mattelaer (UCLouvain) for their help with the CÉCI computing clusters\n\n\nReferences\n\nAdl SM, Bass D, Lane CE, et al.: Revisions to the Classification, Nomenclature, and Diversity of Eukaryotes. J. Eukaryot. Microbiol. 2019; 66(1): 4–119. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBurki F, Roger AJ, Brown MW, et al.: The New Tree of Eukaryotes. Trends Ecol. Evol. 2020; 35: 43–55. Publisher Full Text\n\nCampbell MS, Holt C, Moore B, et al.: Genome Annotation and Curation Using MAKER2 and MAKER-P (Vol. 3).2015.\n\nCornet L: AMAW-genomes-used. Dataset. figshare. 2022a. Publisher Full Text\n\nCornet L: AMAW-Supplementary_Figure1.png. figshare. Figure.2022b. Publisher Full Text\n\nCornet L: AMAW-Supplementary_Figure1.png. figshare. Figure.2022c. Publisher Full Text\n\nCornet L: AMAW-Supplementary_Figure3.png. figshare. Figure. 2022d. Publisher Full Text\n\nCornet L: AMAW-Supplementary_Table1.csv. [Data]. figshare. 2022e. Publisher Full Text\n\nCornet L: AMAW-Supplementary_Table2.csv. [Data]. figshare. 2022f. Publisher Full Text\n\nCornet L: AMAW-Supplementary_Table3.csv. [Data]. figshare. 2022g. Publisher Full Text\n\nDi Franco A, Poujol R, Baurain D, et al.: Evaluating the usefulness of alignment filtering methods to reduce the impact of errors on evolutionary inferences. BMC Evol. Biol. 2019; 19: 21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGrabherr MG, Haas BJ, Joshua MY, et al.: Trinity: reconstructing a full-length transcriptome without a genome from RNA-Seq data. Nat. Biotechnol. 2013; 29(7): 644–652. Publisher Full Text\n\nHolt C, Yandell M: MAKER2: An annotation pipeline and genome-database management tool for second-generation genome projects. BMC Bioinformatics. 2011; 12(1): 491. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKeeling PJ, Burki F: Progress towards the Tree of Eukaryotes. Curr. Biol. 2019; 29(16): R808–R817. Publisher Full Text\n\nKersey PJ, Allen JE, Allot A, et al.: Ensembl Genomes 2018: An integrated omics infrastructure for non-vertebrate species. Nucleic Acids Res. 2018; 46(D1): D802–D808. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKorf I: Gene finding in novel genomes. BMC Bioinformatics. 2004; 5: 59. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKriventseva EV, Kuznetsov D, Tegenfeldt F, et al.: OrthoDB v10: Sampling the diversity of animal, plant, fungal, protist, bacterial and viral genomes for evolutionary and functional annotations of orthologs. Nucleic Acids Res. 2019; 47(D1): D807–D811. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLi B, Dewey CN: RSEM: Accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011; 12. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLi W, Godzik A: Cd-hit: A fast program for clustering and comparing large sets of protein or nucleotide sequences. Bioinformatics. 2006; 22(13): 1658–1659. Publisher Full Text\n\nMeunier L, Baurain D, Cornet L: AMAW - Automated MAKER2 Annotation Wrapper (0.223430). Zenodo. [Code].2022. Publisher Full Text\n\nSeppey M, Manni M, Zdobnov EM: BUSCO: Assessing Genome Assembly and Annotation Completeness.Kollmar M, editor. Gene Prediction. Methods in Molecular Biology. New York, NY.: Humana; 2019; vol 1962. .\n\nStanke M, Diekhans M, Baertsch R, et al.: Using native and syntenically mapped cDNA alignments to improve de novo gene finding. Bioinformatics. 2008; 24(5): 637–644. PubMed Abstract | Publisher Full Text\n\nYandell M, Ence D: A beginner’s guide to eukaryotic genome annotation.2012; 13(May): 329–342."
}
|
[
{
"id": "255599",
"date": "02 Apr 2024",
"name": "B. Franz Lang",
"expertise": [
"Reviewer Expertise genomics",
"bioinformatics",
"gene finding",
"RNA structure and prediction"
],
"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 Meunier et al. aims to simplify the use of MAKER2, a genome annotator developed over a dozen years ago by Holt and Yandell, by automating its installation and usage processes. While the initiative to aid non-specialist users through this automation is commendable, the manuscript falls short in critically evaluating MAKER2's limitations compared to more recent annotators like Braker, Gemoma, and Funannotate. These newer tools, which address some of MAKER2's conceptual and practical shortcomings, are neither mentioned nor evaluated for annotation quality. The literature review in the manuscript is notably brief and lacks depth, undermining the manuscript's contribution to the field, even if considered a brief technical note.\nTo strengthen the manuscript, it is essential to include a comprehensive literature review on the current state of genome annotation, highlighting the advancements and shortcomings of existing tools, including MAKER2. A detailed comparison of annotation quality among these tools should also be provided, moving beyond mere gene counts to assess the quality of predicted gene models. Such analyses are crucial for justifying the automation of the MAKER2 pipeline and ensuring that potential users are not choosing this approach just because it is so easy. Extensive revisions and additional analyses are necessary to address these significant gaps and to honour the contributions of previous work in the field.\n\nIs the rationale for developing the new software tool clearly explained? Partly\n\nIs the description of the software tool technically sound? Partly\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? Partly\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? No",
"responses": []
},
{
"id": "267742",
"date": "10 May 2024",
"name": "Guifré Torruella",
"expertise": [
"Reviewer Expertise Evolutionary protistology. I am a user of genome assembly and annotation tools. I have experience in various genome projects of non-model eukaryotic genomes."
],
"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\nOverview: The manuscript by Meunier et al. is about an automated pipeline to annotate eukaryotic genomes using various rounds of MAKER2. I have found it relevant, so I thank the authors for their work. The analyses are sound, but the authors do not present them in enough detail. It reads more like an abstract and not like a software manuscript. Overall, I think the manuscript could be much improved. Please see some comments below that I hope the authors find useful, since I would be really interested in using this software for my own projects.\nGeneral comments and questions:\nRegarding the workflow, I find it interesting that the authors try to clean the number of transcripts to train the model, but they do not explain why this is important. Does it improve accuracy or reduce computational time, as they say for the protein set? In this regard, did the authors compare Trinity to Spades? In my personal experience, I find that the former gives more isoforms, probably fake, but I have never done a proper comparison.\nI understand the pipeline is designed to study non-model organisms, and for the “use cases,” they cannot provide accuracy or sensitivity, but I wonder if they could validate the pipeline with the same model organisms for which they use the gene models. For example, how bad is the annotation if the gene set of a closely related species is done in Homo or Arabidopsis?\nThen, I don’t know if providing only the median values of the % completeness, fragmented, and missing markers is informative enough. It is known that the issues with annotation depend on genome complexity (size, number of introns, genetic code, etc.). I think they should add some extra validations, such as plotting the amount of complete BUSCO markers with various genome features. I understand the software is designed to help non-bioinformatic protistologists to improve their genome annotations, so I think it would benefit everybody if more details were given regarding the diversity of protist genomes. I assume it is easier to annotate condensed genomes of parasites compared to free-living organisms, but how does this change between amoebae or flagellates, or between heterotrophic or photosynthetic organisms? I understand this might be completely out of the scope of the authors, but as a protistologist, these are things that I would like developers to address.\nAgain, if there is no RNA-seq data from the same species, how AMAW compares to MAKER2 regarding all taxa is not informative. First, which species of the use cases have or have not available RNA-seq? Then, did the authors compare the same genome with and without RNA-seq input?\nAnother question: why does SNAP need to be run before AUGUSTUS? If the authors of MAKER2 provide evidence for that, it should be cited. Since there have not been many developments in genome annotation, I would suggest the authors explain a bit more about how previous software works, mostly since their pipeline is based on these methods.\nHow is the latest step of annotation done? How are the gene models refined?\nI strongly suggest the authors compare AMAW with the various modes in BRAKER, another widely used tool for structural genome annotation.\nOn a computational level, the authors mention the suitability for grid-computing environments (I guess it means in clusters and supercomputers?). So, can it take advantage of MPI? The authors should provide some details on how the pipeline works in this regard; e.g., what are the computational requirements and times. Related to the previous comment, I wonder how it compares with other structural annotation tools.\nDetailed comments:\nIn the first sentence of the conclusions, it’s written “automazing,” which I believe is incorrect.\nThen, the first part of the following sentence is cumbersome. I’d simplify it: “We aim with AMAW’s functionalities to automate the acquisition and deployment of evidence data to contribute to the effort for achieving continually more complete and accurate annotations, especially for poorly represented eukaryotic lineages.”\nFigure S3 has some issues with the upper and lower borders.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Partly\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? Partly",
"responses": []
},
{
"id": "267739",
"date": "10 May 2024",
"name": "James Titus-McQuillan",
"expertise": [
"Reviewer Expertise Biostatistics",
"genomics",
"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\nReview: AMAW: automated gene annotation for non-model eukaryotic genomes\nSoftware Tool Article\nOverview: MAKER2 is one of the most widely used annotation software for annotating non-model genomes. However, the learning curve of MAKER2 is steep and not tailor-made for every genome. The authors have constructed a container with a wrapper inside to help flatten the difficulty curve when using the MAKER2 software suite.\nMajor Revision:\nI think the conclusion section outpaces what this article aims to accomplish. As I read the article, looked over the code, and viewed the figures, I saw a well-executed wrapper for MAKER2. Similar to this tutorial - https://darencard.net/blog/2017-05-16-MAKER-genome-annotation/ from Card et al. 2019 [Ref-1]. I do not see any evidence that, “The application example shows how AMAW significantly improves the genome annotation quality in comparison of naive use of MAKER2 with pre-existing gene models, as well as the importance of providing specific evidence data.” Does this wrapper allow for much faster and user-friendly implementation of MAKER2 pipelines? I see evidence of that claim. However, the former conclusions are baseless, given that the pipeline could still be used if given the template sans AMAW.\nMinor Revision:\n“Moreover, they can short-circuit the pipeline by choosing an existing gene model for AUGUSTUS.” - I think the term short-circuit here may cause confusion. As colloquially, short-circuit usually means a device broke, i.e., this will not be interpreted as a shortcut. But instead that doing the above will break the pipeline. Supplemental materials Fig. 3. “It is desirable to a genome with the lowest proportion of missing genes.” This needs to be clearer. Maybe – “Lower scores are desirable.”?\nConclusion: To strengthen this article, I would ground the conclusions. This is a software release that solves a problem many scientists face – the learning curve of running gene annotations with MAKER2. I think it is worthwhile, as well, to mention other softwares which aims to accomplish similar tasks, e.g., BRAKER(1 & 2), Funannotate, etc. Plus, there is nearly an exhaustive list of annotation software out there for specific tasks like long reads (PacBio SMRT Analysis and Nanopore’s Software suite), proteomics approaches (AnnotaPipeline), finding isoforms (SQANTI and TranD), and a plethora of others that could be listed; which seem/are relatively as user-friendly as the AMAW (in my opinion). AMAW is just one of those software applications that uses MAKER2 as the engine.\nThis article could help many run annotations and further the knowledge for those lost in the world of annotation software. Using a tried-and-true method like MAKER2 with an easy-to-follow pipeline is perfect for getting results and understanding the processes of annotation. However, the claims currently need to be tailored to what this paper accomplishes: a user-friendly pipeline and software wrapper for genomic annotations.\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? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? No",
"responses": []
},
{
"id": "267741",
"date": "03 Jun 2024",
"name": "Laura Ruiz Torres",
"expertise": [
"Reviewer Expertise Population Genetics",
"Ecology",
"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\nIntroduction: page 3 parag2a: consider changing \"following the decrease in sequencing costs due to the advent of Next Generation Sequencing and the concomitant explosion of sequenced organisms\" to \"The advent of Next Generation Sequencing has decreased sequencing costs, leading to an explosion in the number of sequenced organisms\" page 3 parag2b: Please support \"MAKER2 has been, for more than a decade, one of the most popular annotation pipelines for eukaryotes\" with the number of citations in that period, for instance. This would also be a good place to mention other software choices beyond MAKER2. page 3: Not sure the data presented supports \"We also demonstrate that the use of AMAW yields genome annotation significantly improved in comparison to the use of MAKER2 with the AUGUSTUS (Stanke et al., 2008) [Ref 1] gene models that are available by default.\"\nMethods: Implementation: which version of singularity container was used? page 3 paragraph-1: I am not sure the documentation at https://bitbucket.org/phylogeno/amaw supports the sentence \"simplify its installation and usage for users without a strong bioinformatics background\". As described there the installation of dependencies does not seem particularly easy, nor could I find instructions to install singularity on my system. Can't see either in the bitbucket landing page any instructions on grid instructions. page 4 Please fix \"AMAW automates the installation and the and orchestrates the successive runs in a grid-computing environment\" page5 please consider changing \"Moreover, RNA-Seq experiments are sorted by ascending data volume before being selected in an attempt to maximize the diversity of RNA-Seq libraries.\" to \"To enhance the diversity of RNA-seq libraries, experiments are strategically selected based on ascending data volume\" Use cases: Please consider changing \"For this, a dataset of 32 genomes of protist organisms was designed and the quality of the different structural annotations was assessed using the completeness metrics provided by BUSCO v4\" to \"To assess the impact of gene model choice, we designed a 32 protist genomes dataset and evaluated the quality of different structural annotations using BUSCO v4\" Please start this section explaining exactly what is being compared. Readers will know that AMAW automatizes several steps already, but we don't know exactly what non-automatic choices were made for running MAKER2, although it says \"basic\" later on. We need to know whether this is a fair comparison, this will also help understand figure 2. Figure 2: Please change figure colors and rewrite legend, as it is is really hard to understand which bars correspond to 32 protists, why is Arabipdsis (green) in both panels? Are human and Arabidopsis non-model species? Figure 3: The legend is identical to that on figure 2 but with 17 genomes instead of 32. From the text I can't really understand it.\nPlease rewrite the \"Use cases\" section, as it is we don't understand it at all.\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? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-186
|
https://f1000research.com/articles/12-185/v1
|
16 Feb 23
|
{
"type": "Research Article",
"title": "Effects of Ganoderma lucidum on chemical-induced and bacterial-infected corneal ulceration of rabbits’ eyes",
"authors": [
"Emmanuel Okenwa-Vincent",
"Alphonsinah Moogi",
"Phenard Odero",
"Afe Dania",
"Khathutshelo Mashige",
"Alphonsinah Moogi",
"Phenard Odero",
"Afe Dania",
"Khathutshelo Mashige"
],
"abstract": "Background: Corneal ulcerations pose risks to blindness, and their treatment presents huge challenges, in part due to increased resistance to anti-bacterial drugs, accessibility and cost issues, particularly in developing countries. This study investigated the pharmacological effect of Ganoderma Lucidum, on chemical-induced and bacterial-infected corneal ulceration of rabbits’ eyes. Methods: This was a randomized-controlled experiment of 16 healthy New Zealand rabbits, randomly assigned into four groups (A–D). The right eye cornea was injured using a drop of 1 Molar sodium hydroxide and followed by infection with Pseudomonas aeruginosa after 12 hours, in all groups except group A. Treatment with freshly prepared crude aqueous extract of G. lucidum (40 μg/mL) for groups A and B, the standard treatment protocol for group C, and atropine alone for group D commenced after 24 hours and continued every four hours for seven days. All data collected, pre-and post-tests, were analysed at α=0.05 using Wilcoxon signed-rank test for correlated variables and the Mann–Whitney U test for independent variables. Results: G. lucidum has significant clinical effects (74%) on corneal injury and ulcers (92%). The healing effects observed at the 168th hour were significantly better than those observed at the 24th hour (p<0.05). Although the difference between the healing effect of the standard treatment and the crude extract was not significant (p>0.05), the mean effect size was clinically significant (31%). Conclusion: This study demonstrates the potential antimicrobial potential of G. lucidum. G. lucidum may provide an alternative treatment option for chemical-induced and bacterial-infected corneal ulcers, particularly in resource-constrained countries.",
"keywords": [
"Ganoderma lucidum",
"chemical-induced corneal ulcer",
"bacterial-infected ulcer",
"anti-inflammatory",
"anti-infective"
],
"content": "Background\n\nCorneal ulcers are estimated to cause 7.2% of corneal blindness1 and are thus a significant contributor to blindness. In Kenya, corneal injuries have been reported to account for an estimated 2.7% of corneal blindness.2 While corneal injuries are common, access to treatment and medical care is limited, and this may be due to a lack of awareness of treatment options, lack of accessibility and high cost.3 Lack of appropriate and prompt management of ulcers leads to poor wound healing and subsequent formation of scars, resulting in partial or total vision loss.\n\nAntibiotics act by interfering with the metabolic processes or with the organism’s structures. However, there are growing concerns about the number of drug-resistant bacterial strains4 and many disease conditions are becoming more difficult to treat due to the emergence of antibiotic-resistant bacteria.5 In 2010, the World Health Organization (WHO) recommended that all countries implement control procedures to mitigate the effects of multi-drug-resistant bacteria.6 It emphasized the urgent need to identify alternative therapies against drug-resistant microorganisms in low- and middle-income countries, such as Kenya. In addition, Kenya has been reported to have a high utilization rate of unorthodox medical treatment due to challenges of access to orthodox medicine, cost and cultural beliefs.3\n\nA mushroom is a fruiting body of fungi that is non-photosynthetic and feeds on organic matter and plant organisms.7 Ganoderma lucidum is a type of mushroom which has basidiocarp, mycelia and spores that contain approximately 400 different bioactive compounds.8 G. lucidum as a mushroom is in the family of Ganodermataceae, a family consisting of a large group of tree fungi of the genus Ganoderma. G. lucidum has been classified into Kingdom Fungi, Phylum Basidiomycota, Class Basidiomycetes, Sub-class Homobasidiomycetes, Order Polyporales, Family Ganodermataceae, Genus Ganoderma and Species lucidum.9,10 The mushroom has been reported to have several pharmacological effects, such as immunomodulation, analgesic, anti-atherosclerotic, anti-inflammatory and antibacterial, among other medicinal benefits to the human body.8 The antibacterial effect of G. lucidum has been shown to have a healing effect on non-ocular related inflammatory injuries and infective ulcers in other parts of the human body.11 Many ulcerative conditions are becoming difficult to manage due to the increasing numbers of drug-resistant bacteria strains such as Staphylococcus aureus, Pseudomonas pyocyanea, Streptococcus pneumoniae, Pseudomonas aureginosa.5,12 G. lucidum has been proven to be effective in managing bacterial infections that have shown resistance,13 with reports indicating it to be an effective alternative to treating bacterial infections and inflammatory injuries to the human body.14 G. lucidum is commonly available in Kenya.7 This study aimed to investigate the effects of G. lucidum on chemical-induced and bacterial-infected corneal ulcers in rabbits’ eyes. Furthermore, the study aimed to compare the effects of G. lucidum with those of standard orthodox treatment approaches to chemical and bacterial corneal ulcers to establish a possible relatively cheaper alternative and/or complementary treatment to these corneal injuries.\n\n\nMethods\n\nThis randomized-controlled experiment was conducted in the animal house of Masinde Muliro University of Science and Technology (MMUST), Kakamega, Kenya, which is located in the western part of Kenya and 1 km from Kakamega central town. In this experiment, a pre-determined power analysis, assuming a large Cohen’s d effect size, 0.8, required a minimum total sample size of 15 to elicit 80% power for a 2-tailed test hypothesis at α=0.05, to detect a 10% mean difference between two homogenous groups in comparison. In this regard, 16 healthy New Zealand rabbits weighing 1.5 kg to 2.0 kg, without gender bias, were purchased from the local Kakamega animal market and were adapted for two weeks. These were randomly allotted to four groups of four animals each in separate housing. Each group of four animals were housed in a standard size cage with a floor area of 7.5 square feet and at least 18 inches high. These were cleaned on a daily routine, throughout the experiment. During the period of adaptation, they were dewormed with piperazine® (anti-helmintic drug), fed with Amilyte® food supplement – an anti-stress agent, as well as Bovitam® – a multivitamin. The animals were fed with pellets, elephant grass, cabbages (Brassica oleracea var. capitata L) and clean water for drinking. Before the commencement of the experiment, each animal was pre-tested for normal physiological functions, such as the eyelid, lacrimation and corneal statuses, and also re-tested 12 hours after the introduction of corneal injury for changes from the baseline physiological findings. The rabbits, before grouping, were labelled 1 to 16 and then randomly assigned to four groups of four animals each as follows: A: Experiment 1; B: Experiment 2; C: Positive control; and D: Negative control. This random assignment to groups was done using a computer-generated random system15 which was without bias to the gender or weight of the rabbits. All animals included in the experiment had equal physiological characteristics as per the baseline pretesting conducted.\n\nGroup A: Experimental group 1. The rabbits were treated with G. lucidum extracts following exposure of their cornea to a chemical-induced injury.\n\nGroup B: Experimental group 2. The rabbits were treated with G. lucidum extracts following exposure of their cornea to a chemical injury and the subsequent infection with P. aeruginosa.\n\nGroup C: Positive control group. The rabbits were treated with a standard treatment approach for corneal ulceration, that being two hourly drops of fluoroquinolones (ciprofloxacin), eight hourly atropine sulfate and four hourly betamethasone ophthalmic formulations.\n\nGroup D: Negative control group. The rabbits received eight hourly drops of atropine sulphate, both as a placebo and to relieve the pain, without the intention of providing normal treatment.\n\nInstruments for data collection included the pen torch, a magnifying loupe, Keeler® ophthalmoscope, 2-mL hypodermic syringes and needles, sample tubes, micropipettes and pipettes. Others included beakers, spatulas, a weighing scale, a water bath, a mortar and pestle, a sterilized laboratory grinder, Turtle stand, What-man® filter paper, Dettol®, gloves, a small bucket with a cover, as well as Methylated spirit, Vaseline® jelly, a razor blade and cotton wool. Dean–Stark apparatus, clean distilled water, double pocket condenser, a 5L-3-necked round-bottomed flask, Ganoderma mushrooms and a camera were also required. Drugs used for this experiment were: freshly prepared crude aqueous extract of G. lucidum, tetracaine hydrochloride 0.5%, atropine sulfate 1%, Probeta-N® (betamethasone-neomycin), Ceprolen® (ciprofloxacin), Nepuscein® (fluorescein) strips, Bovitam®, Amilyte®, Piperazine®, ketamine hydrochloride and 1 Molar sodium hydroxide.\n\nThe experimental procedure employed in this study commenced with two weeks of acclimatization of all 16 animals as described previously above. Additionally, in other to minimize pain and suffering among the animals during the procedure, both systemic and topical anesthetics were used and each animal was taken to a separate room, out of sight of the other animals during each experimental procedure. Generally, the experimental procedure commenced with the use of systemic anesthesia (1 mL/50 mg of ketamine hydrochloride) which was injected intramuscularly into each of the rabbits in groups A, B, C and D. Five minutes later, two drops (1 mL of 0.5%) of tetracaine hydrochloride (topical anesthesia) was instilled into the right eye only, of each rabbit. Three to five minutes later, a corneal sensitivity test was performed on each rabbit using the cotton swab test to ensure that the right eye cornea of each rabbit was fully anaesthetized. For confirmation, the same procedure was done on the left eye to verify their response to the cotton tips rubbed on the cornea. Following confirmation of corneal anesthesia in the right eye, a drop of 0.2 mL/1 Molar sodium hydroxide (NaOH) was gently instilled on the central corneal surface using a cotton swab. At the same time, the corneal periphery and conjunctiva areas were guided from the spread of the chemical with another set of cotton wool swabs. The cotton swabs were placed around the limbus of the right eye, while the chemical was being allowed to soak into the corneal epithelium.\n\nThis procedure was performed under minimal magnification, using a 10× magnifying loupe. The affected central cornea area was then assessed for successful induction of injury by applying a stain with a swipe of fluorescein strip and observing with the blue illumination of a Keeler® professional ophthalmoscope under 20× magnification. The right eyes were padded and left for 12 hours and then observed again. Ocular manifestation (signs of inflammations and possible infections) following the induction of chemical injury was observed after 24 hours. The following parameters were used to assess for ocular manifestations: eyelid and conjunctival status, lacrimation, epithelial disruption, corneal fluorescein staining, photophobia (using a flashlight), corneal oedema and infiltrates. The ocular manifestations were consistently graded on a scale of 0 to 5 (0: normal/no change observed; 1: very mild; 2: mild; 3: moderate; 4: severe; and 5: very severe).16 The rabbits in groups B, C and D were then infected with two drops of a laboratory-prepared solution of P. aeruginosa and padded for another 24 hours, after which they were examined for signs of active inflammation and infection, with heavy mucopurulent discharges and stuck eyelids being evident.\n\nThe G. lucidum extracts used for the treatment of the animals in groups A and B were prepared by dissolving 65 g of cleaned pieces of the mushroom, ground to fine powder, in 5 L of distilled water in a hydro distillation process, using the Dean–Stark apparatus. The process was set at 40°C and left to run for 9 h to obtain the saturated crude extract which was then stored at −10°C before bioassay. After 24 hours, treatment commenced with the animals in groups A and B with the fresh crude aqueous extract of G. lucidum now formulated into ophthalmic suspension at a concentration of 40 μg/mL.13 All the rabbits in the two groups were treated with G. lucidum extracts. Two drops of the suspension were instilled every two hours at the start, and then gradually tapered through seven days. Observed ocular changes following commencement of treatment were both photographed and recorded according to the stated grading system, both being taken systematically in an order of 1st hour, through the 12th, 24th, 48th, 72nd, 96th, 120th, 144th up to the 168th hour. Treatment was tapered following noticeable improvement (possible healing) on the ocular inflammations and infections.\n\nTreatment of the animals in group C also commenced 24 hours following the induction of ulcers on the right eye cornea of each animal. A standard treatment protocol for chemical (alkaline) induced ocular injury and bacterial-induced corneal ulcers was employed. This consisted of two hourly drops of fluoroquinolone (ciprofloxacin), six hourly drops of corticosteroid (betamethasone) initiated after 24 hours of treatment with fluoroquinolone, and eight hourly drops of atropine sulphate 1%.17,18 These were gradually tapered following the observation of significant reductions in ocular inflammations and infections. As with the experiment groups, photo shoots and recordings according to the stated grading system were done starting after the 12th hour of treatment with the standard protocol, through every 24 hours up to the 168th hour. While no positive active treatment was given to the rabbits in group D, in line with the treatment schedule in groups A, B and C, cycloplegic agent (atropine sulfate 1%) was instilled topically (1 drop), four hourly on the right eye cornea of each rabbit. The use of the cycloplegic agent applied to the animals in group D was an interventional protocol introduced in other to minimize pain, suffering and distress for animals in this group that served as a negative control in the experimental design. Observations (photographs and recording of parameter changes) were done according to the schedules of groups A, B, and C.\n\nIn keeping with ARRIVE guidelines on providing a humane endpoint for animals used for this experiment, a Veterinary expert from a local Agrovet store, was professionally engaged to euthanize all the rabbits at the end of the experiment period.\n\nAll data collected pre- and post-experiment were entered for groups A, B, C, and D into a statistics software (SPSS, version 23) for analysis according to within and between groups comparison. The findings for ocular morphologic changes were entered quantitatively and coded on the grading scale of 0 to 5 based on severity,16 with the findings in all groups being presented in tables. Considering the small sample size of this experiment, alternative non-parametric tests to paired t-tests and independent t-tests were used for statistical analysis of the results. All comparisons were made at α=0.05 (95% CI) using Wilcoxon signed-rank test for correlated (within groups) variables and the Mann–Whitney U test for independent (between groups) variables.\n\n\nResults\n\nData were collected from 16 healthy New Zealand rabbits weighing an average of 1.4±0.42 kg. Ocular parameters for various observations following treatment for 168 hours after the introduction of chemical injuries and subsequent infection with P. aeruginosa were coded according to the grading scale of 0 to 5 and these are presented in Tables 1 to 4. Table 1 shows a comparison of the healing effects of G. lucidum extract on various ocular parameters following induction of chemical injury, using 1 Molar sodium hydroxide, for animals in group A (experiment group 1) at two-time points: at the 24th and 168th hours of treatment. The statistical presentation shows that although treatment with G. lucidum extract had a significant anti-inflammatory effect on just a few ocular structures: eyelid and conjunctival status changes, reduced lacrimation, reduced corneal staining and oedema, the clinical effect of treatment with the extract in all ocular structures observed were highly significant, particularly with the reduction in corneal infiltrates (effect size=74%). These pictural findings are shown in Figure 1.\n\nAs shown, animals in group A (right) appeared to have healed, with fewer discharges, lacrimation and better corneal epithelial changes, after 168 hours of treatment with G. lucidum.\n\nTable 2 shows the manifestations of various ocular parameters for animals in group B (experiment group 2) at the first 24th hour following injury with 1 Molar sodium hydroxide, and subsequent infection with P. aeruginosa 12 hours thereafter (to induce bacterial ulcer), and at the last 168th hour of treatment with G. lucidum. The results show that treatment with G. lucidum extract had no significant difference (p>0.05), in the statuses of most of the ocular parameters after the 168th hours, except for a significant reduction in photophobia and lacrimation (p<0.05). However, the clinical effects of treatment with the extract of G. lucidum for bacterial infected corneal ulcers in all ocular parameters observed were clinically significant (effect size>5%), with reduction of ocular discharges being most significant (effect size=93%). This finding is also shown pictorially in Figure 2.\n\nAs shown, animals in group B (right) appeared to have healed better, with fewer discharges, lacrimation and better corneal epithelial changes, after 168 hours of treatment with G. lucidum.\n\nTable 3 shows a comparison between manifestations of various ocular parameters for the animals in groups B and C after 168 hours of treatments with G. lucidum in group B (experimental group 2) and the standard treatment protocol in group C (positive group). The results show that although treatment in group C had better clinical effects than in group B, the difference in the treatment was, nonetheless, not statistically significant (p>0.05). This finding is also shown pictorially in Figure 3.\n\nAs shown, animals in group C (right) did not physically appear (observation on burton blue lighting) to have healed better than group B animal (left), after 168 hours of treatment with G. lucidum.\n\nTable 4 shows a comparison between the manifestations of various ocular parameters for animals in group B (experiment group 2) and those in group D (negative control group) after 168 hours of treatments with G. lucidum on the former (group B) and atropine alone for the latter (group D). The results show that the difference in the treatment in both groups was not statistically significant (p>0.05). This finding is also shown pictorially in Figure 4.\n\nAs shown, Group D animals (right) appeared to have healed better.\n\n\nDiscussion\n\nIn this study, we found a progressively improved healing effect of the extract of G. lucidum, from the first 24th hour to the 168th (seven days of treatment). The indices adopted for the study to show improvement in the healing process of a deliberately induced corneal injury and then subsequently infected using P. aureginosa, a common, normal floral, but opportunistic microorganism, were eyelid status, conjunctival status, lacrimation, epithelial eruption, corneal staining, photophobia, ocular discharge, corneal oedema, and corneal infiltrates. In group A animals (Table 1), there were observable changes in this first experimental group exposed to chemical injury alone using 1 molar sodium hydroxide. Our findings showed that treatment with crude aqueous extract of G. lucidum had significant healing effects on just a few ocular parameters: eyelid status change, reduced lacrimation, reduced corneal staining and oedema. Nonetheless, there were improved clinical effects of treatment with the extract in observed ocular parameters as seen in Figure 1. This thus demonstrates that treatment with G. lucidum after the 168th hour improved the corneal healing process following an induced chemical (alkaline) injury. However, as can be seen from Figure 1, and as is typical with most chemical injuries, specifically from sodium hydroxide that causes corneal damage through pH change, ulceration, proteolysis and collagen synthesis defects to the cornea, healing from such injuries takes time, often longer than 7 days to achieve significant physically observable signs of healing.19 This time limitation was a key challenge in this study. Still, and as noted by Singh,20 chemical injuries, particularly those of alkaline origin, to the cornea are potentially blinding ocular injuries and constitute a true ocular emergency requiring immediate assessment and initiation of treatment.20 Our finding demonstrates that instituting treatment with an extract of G. lucidum as early as within the first 24th hour of occurrence has the potential to prevent extensive and penetrating damage to the cornea and other ocular surface tissues that present a risk of irreversible vision loss.\n\nFurthermore, among animals in group B (experiment group 2), as shown in Table 2, our finding demonstrates that treatment with crude extract of G. lucidum did not significantly change the ocular morphology of most of the animals after the 168th hours, except for a significant reduction in photophobia and lacrimation. Even though the differences in the quantitative morphological parameters at the two-time points, following the initiation of treatment with the crude aqueous extract of G. lucidum, compared were not significant, the converse (Table 2), was true for the clinical effects (effect size>5%). This, therefore, implies that the clinical effect of treatment with crude aqueous extract of G. lucidum for bacterial infected corneal ulceration is significant. Additionally, the clinical (healing) effects were found to be most significant with a reduction of ocular discharges, a good morphological indication of a reduction in microbial load.13 This finding, also shown pictorially in Figure 2, confirmed findings of previous studies,5,11,12 that the antibacterial effect of G. lucidum on non-ocular related inflammatory injuries and infective ulcers in other parts of the human body is clinically effective. In addition, our finding demonstrates that G. lucidum has proven to be effective in managing bacterial infections that have shown resistance,13 as well as an effective alternative to treating bacterial infections and inflammatory injuries to the human body,14 may as well be an effective alternative to the management of ulcerative conditions of the cornea resulting from bacterial infections.\n\nOur study also compared the treatment effect of the crude aqueous extract of G. lucidum with the existing standard treatment protocol for chemical (alkaline) induced ocular injury and bacterial-induced corneal ulcers consisting of two hourly drops of fluoroquinolone (ciprofloxacin), six hourly drops of corticosteroid (betamethasone), and eight hourly drops of atropine.17,18 We found that after the 168th hour of treatments, while animals in group C had better clinical healing (effect size>5%), the difference between the two treatment protocols was not statistically significant (p>0.05) as can be seen in Table 3. The implication of this finding, therefore, is a demonstration that treatment with the crude aqueous extract of G. lucidum may be an effective approach to the treatment of bacterial-induced corneal ulcerative and inflammatory injuries. This further justifies a previous finding on the healing effects of extracts of G. lucidum on infective and inflammatory injuries to other non-ocular tissues of the human body.14\n\nFinally, we sort to further demonstrate the healing effects of crude aqueous extract of G. lucidum on ulcerative injuries to the cornea and other ocular adnexa. To do this, we compared the results, after 168 hours of treatment, of animals treated with the crude extract to those of a negative control group that only received atropine treatment (Table 4). As shown, even though we found no significant difference (p>0.05) in the two groups, treatment with the crude extract showed less clinical healing effect (Figure 4). This was an interesting finding of our study that the animals in group D (negative control) that were administered with atropine sulphate alone showed better clinical improvement than those treated with G. lucidum. Atropine sulphate was purposively administered to control ciliary spasms in the eyes of the animals in the negative control group. It was interesting to observe that atropine (primarily a cycloplegic agent) also known to show anti-inflammatory secondary effects,21,22 resulted in significantly better healing effects compared with the crude aqueous extract of G. lucidum. This finding may explain the importance of introducing an anti-inflammatory treatment protocol as early as possible in the management of both chemical and bacteria-induced corneal ulcerations.\n\nTo summarize, we note that there is a dearth of empirical knowledge on the ocular-related healing effects of extracts of G. lucidum in literature to compare our findings with. Nonetheless, our study demonstrates an observable reduction in the severity of damages to the ocular adnexa from induced ulcerative chemical injury and bacterial infection. These reductions are evident from the positive changes in the ocular parameters affected following the induction of chemical injury and subsequent bacterial infection of the cornea. Specifically, we note a significant reduction in eyelid swelling and lacrimation in animals treated with G. lucidum after 168 hours of treatment. This is evident with the animals in groups A and B, where the eyelid and conjunctival severity were significantly reduced progressively (Figures 1 and 2). Although no significant change was noticeable in a few parameters (epithelial eruption, epithelial staining, corneal fluorescein staining, and corneal oedema), we found the clinical healing effects of the crude aqueous extract of G. lucidum extracts to be highly significant, particularly for the reductions observed with ocular discharges, photophobia and corneal infiltrations. This we found, while not consistent with the healing effect observed in a study on paw oedema following intra-muscular instillation of G. lucidum,23 was nonetheless consistent with the healing effect observed in another study on gastric ulcers.24 Other studies that compared the clinical healing effects of extracts of G. lucidum with commonly used antibiotics, such as gentamycin sulfate13 and fluoroquinolones,22 found it to be equally effective in other body structures. We found this to not be the case with ocular healing effects, as standard treatment with a combination of fluoroquinolone, corticosteroid and atropine sulfate, and even with using atropine sulphate alone, turned out to show better clinical effect than treatment with the crude aqueous extract of G. lucidum alone.\n\n\nConclusion\n\nCrude aqueous extracts of G. lucidum have shown the potential to be an alternative treatment approach for chemical (alkaline) and bacterial (P. aeruginosa) induced corneal ulceration. The healing (anti-inflammatory and anti-infective) effects of G. lucidum have shown clinically significant healing effects after 168 hours of treatment compared with that of 24 hours. Although the cornea of animals treated with standard protocol showed better clinical effects than those treated with G. lucidum, the current investigation has shown the importance of the early institution of the anti-infective and anti-inflammatory protocol in the management of corneal ulcers. Therefore, G. lucidum, where available, may be a useful anti-infective alternative for chemical-induced and bacterial-infected corneal ulcerative conditions. In this regard, therefore, our study notes that despite the limitation of time, crude aqueous extract of G. lucidum has bioactive compounds that have the potential to be used as an alternative treatment approach for chemical-induced and bacterial-infected corneal ulcerations in resource-constrained settings. Hence, the study recommends further research to explore the anti-inflammatory potentials of crude extract G. lucidum in population-controlled settings. The study further recommends research to characterize the bioactive compounds in the crude aqueous extract as well as cytotoxicity assay of the bioactive compounds in the crude aqueous extract, as with tests to demonstrate the effectivity levels of extracts of the mushroom from other less polar and non-polar solvents.\n\n\nDeclarations\n\nApproval for this study was obtained from the Institutional Ethics Review Committee of Masinde Muliro University of Science and Technology (MMUST, IERC) (MMU/COR: 403009 (VOL. 1). This study was conducted per the ethical guideline of the Prevention of Cruelty to Animals Act of Kenya.25,26 Additionally, all methods applied in this study adhered to the Committee on Animal Research and Ethics’ guideline for ethical conduct in the care and use of animals, including responsible and ethical disposal of animals during clinical and laboratory research.27 All procedures in this study were conducted and reported in accordance with ARRIVE guidelines.\n\nNot applicable.\n\nNot applicable.\n\n\nAuthors’ contribution\n\nEOV was involved in the study design, data collection, data analysis, drafting and reviewing of the manuscript. AKM was involved in the study design, data collection, data analysis, drafting and reviewing of the manuscript. POO was involved in data collection, drafting and reviewing the manuscript. AVD was involved in drafting and reviewing the manuscript to its final stage. KPM was involved in drafting and significant review of the manuscript to its final stage. All authors have read and approved the final version of the manuscript.",
"appendix": "Data availability\n\nFigshare: Underlying data for ‘Effects of Ganoderma lucidum on chemical-induced and bacterial-infected corneal ulceration of rabbits’ eyes’. https://doi.org/10.6084/m9.figshare.21789026.v1.28\n\nThe project contains the following underlying data:\n\nEffects of Ganoderma lucidum on Corneal Ulceration_Raw Data.csv\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 acknowledge the support received from Masinde Muliro University’s IERC, the Department of Pure and Applied Chemistry, and the Department of Medical Laboratory Science both of Masinde Muliro University. We also acknowledge the efforts of the optometry students and other university staff who assisted both in the data collection for this study and the handling and care of the animals during the duration of this study.\n\n\nReferences\n\nWhitcher JP, Srinivasan M, Upadhyay MP: Corneal blindness: a global perspective. Bull. World Health Organ. 2001; 79: 214–221. PubMed Abstract\n\nMinistry of Health K: Health Sector Human Resources Strategy 2014 – 2018.2014. Reference Source\n\nNahata A: Ganoderma lucidum: A Potent Medicinal Mushroom with Numerous Health Benefits. Pharm. Anal. Acta. 2013; 04(10). Publisher Full Text\n\nKoutsogiannou M, Drougka E, Liakopoulos A, et al.: Spread of multidrug-resistant pseudomonas aeruginosa clones in a university hospital. J. Clin. Microbiol. 2013 Feb [cited 2021 Apr 30]; 51(2): 665–668. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPittet D: Infection control and quality health care in the new millenium. Am. J. Infect. Control. 2005 Jun 1; 33(5): 258–267. Publisher Full Text\n\nWHO: Drug-resistant tuberculosis now at record levels. WHO Media centre. World Health Organization; 2010 [cited 2021 Apr 30]; vol. 15. : 224–226. Reference Source\n\nNecofa K: Network for Eco-Farming in Africa, Kenya Chapter.2019 [cited 2021 Apr 30]. Reference SourceReference Source\n\nSanodiya B, Thakur G, Baghel R, et al.: Ganoderma lucidum: A Potent Pharmacological Macrofungus. Curr. Pharm. Biotechnol. 2009 Nov 29; 10(8): 717–742. PubMed Abstract | Publisher Full Text\n\nEkandjo LK, Chimwamurombe PM: Traditional medicinal uses and natural hosts of the genus Ganoderma in north-eastern parts of Namibia. J. Pure Appl. Microbiol. 2012; 6(3): 1139–1146.\n\nBuchanan PK: A taxonomic overview of the genus Ganoderma with special reference to species of medicinal and neutriceutical importance. Proc. Int. Symp. Ganoderma Sci. 2001; 4: 1–8.\n\nMailoa MN, Mahendradatta M, Djide N: Antimicrobial activities of tannins extract from guava leaves on pathogens microbial. Int. Asian Res. J. 2014; 2(1): 43–50.\n\nDonadio S, Carrano L, Brandi L, et al.: Targets and assays for discovering novel antibacterial agents. J. Biotechnol. 2002 Nov 13; 99(3): 175–185. Publisher Full Text\n\nQuereshi S, Pandey AK, Sandhu SS: Evaluation of antibacterial activity of different Ganoderma lucidum extracts. People’s J. Sci. Res. 2010; 3(1): 9–13. Reference Source\n\nGao Y, Zhou S, Chen G, et al.: A Phase I/II Study of a Ganoderma lucidum (Curt.: Fr.) P. Karst. Extract (Ganopofy) in Patients with Advanced Cancer. Int. J. Med. Mushrooms. 2002 [cited 2021 Apr 30]; 4(3): 8. Publisher Full Text Reference Source\n\nRandom.org: Random Integer Generator.2013 [cited 2018 Mar 2]; 9–10. Reference Source\n\nAsonye C, Okenwa E, Alonge P: The Pharmacological effects of leaf extract of Piliostigma thonningii (Schum) on chemically induced and bacterially infected corneal ulceration of rabbit eyes. J. Heal. Vis. Sci. 2007; 9(1): 6–14. Reference Source\n\nMangan BR: Quickly Douse Chemical Burns. Rev. Optom. 2015 [cited 2021 Apr 30]; 2–4. Reference Source\n\nTrief D, Chodosh J, Colby K, et al.: Chemical (Alkali and Acid) Injury of the Conjunctiva and Cornea - EyeWiki. American Academy of Ophthalmology. 2001 [cited 2021 Jun 9]. Reference Source\n\nFish R, Davidson RS: Management of ocular thermal and chemical injuries, including amniotic membrane therapy. Curr. Opin. Ophthalmol. 2010 Jul [cited 2021 Apr 30]; 21(4): 317–321. PubMed Abstract | Publisher Full Text Reference Source\n\nSingh P, Tyagi M, Kumar Y, et al.: Ocular chemical injuries and their management. Oman J. Ophthalmol. 2013 [cited 2021 Apr 30]; 6(2): 83–86. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarcía Del Valle I, Alvarez-Lorenzo C: Atropine in topical formulations for the management of anterior and posterior segment ocular diseases. Expert Opin. Drug Deliv. 2021 [cited 2021 Apr 30]; 18(9): 1245–1260. Publisher Full Text\n\nKatz JN, Smith SR, Collins JE, et al.: Cost-effectiveness of nonsteroidal anti-inflammatory drugs and opioids in the treatment of knee osteoarthritis in older patients with multiple comorbidities. Osteoarthr. Cartil. 2016 Mar 1; 24(3): 409–418. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhou X, Lin J, Yin Y, et al.: Ganodermataceae: Natural Products and Their Related Pharmacological Functions.2012 Apr 5; 35(4): 559–574. Publisher Full Text\n\nRony KA, Mathew J, Neenu PP, et al.: Ganoderma lucidum (Fr.) P. Karst occurring in South India attenuates gastric ulceration in rats. Indian J. Nat. Prod. Resour. 2011 [cited 2021 Apr 30]; 2(1): 19–27. Reference Source\n\nNational Council for Law Reporting: Prevention of Cruelty To Animals Act.2012; (3(41)). Reference Source\n\nKSPCA Kenya: Kenya’s Constitution on Animal Rights and Prevention of Cruelty to Animals – KSPCA Kenya.[cited 2021 Apr 30]. Reference Source\n\nCommittee on Animal Research and Ethics (CARE): Guidelines for ethical conduct in the care and use of animals. J. Exp. Anal. Behav. 1986 [cited 2021 Apr 30]; 45(2): 127–132. Publisher Full Text Reference Source\n\nOkenwa-Vincent E, Moogi A, Odero P, et al.: Effects of Ganoderma lucidum on Corneal Ulceration_Raw Data.csv. figshare.2022 [cited 2023 Jan 14]. Reference SourcePublisher Full Text"
}
|
[
{
"id": "192726",
"date": "08 Aug 2023",
"name": "Robert M Q Shanks",
"expertise": [
"Reviewer Expertise Ocular microbiology",
"bacteriology",
"ocular host-pathogen interactions",
"molecular pathogenesis"
],
"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\nPeer review of “Effects of Ganoderma lucidum on chemical-induced and bacterial-infected corneal ulceration of rabbits’ eyes” by Okenwa-Vincent, et al for consideration by F1000Research.\nThis study tested whether an extract of the fungus Ganoderma lucidum would be tolerated by the ocular surface of rabbits and whether it could reduce inflammation caused by sodium hydroxide burns and application of Pseudomonas aeruginosa.\nWhile overall quite readable, there is some ambiguity that is discussed below.\nWhile the concept is intriguing, there are many major issues that are of concern and overwhelmingly undermine the study. For example, it appears that the manuscript describes a single experimental iteration rather than a reproduced experiment.\n1. Major issue: while it is typical to have one or two citations and overstatement errors in a manuscript under review, this manuscript has too many. The source articles used to support claims in the introduction and throughout often had little or nothing to do with the statement. The references seem almost arbitrarily chosen. Only a subset of references were reviewed for matching the statement, so more may be misattributed.\nFor example:\nIntroduction “The antibacterial effect of G. lucidum has been shown to have a healing effect on non-ocular related inflammatory injuries and infective ulcers in other parts of the human body.11” - Reference 11 did not include G. lucidum extracts - please use the correct reference or remove the sentence.\n\nIntroduction “G. lucidum has been proven to be effective in managing bacterial infections that have shown resistance,13 with reports indicating it to be an effective alternative to treating bacterial infections and inflammatory injuries to the human body.14” - Reference 13 uses G. lucidum in vitro antimicrobial tests, so the comment that it was useful in “managing bacterial infections” is an inaccurate statement. Reference 14 - this is an overstatement as the reported study was for cancer treatment and the impact on bacterial infections was not directly measured.\n\nDiscussion “This finding, also shown pictorially in Figure 2, confirmed findings of previous studies,5,11,12 that the antibacterial effect of G. lucidum on non-ocular related inflammatory injuries and infective ulcers in other parts of the human body is clinically effective.” - None of the cited references (5, 11, or 12) evaluated G. lucidum in inflammatory injuries or infective ulcers.\n\nDiscussion “This further justifies a previous finding on the healing effects of extracts of G. lucidum on infective and inflammatory injuries to other non-ocular tissues of the human body.14” - The referenced study did not deal infection, so it isn't clear that this paper supports the role of G. lucidum in infection.\n2. Major issue – concerning use of \"clinical significance\" versus \"statistical significance\". Because these are both used, it is at times difficult to know which is being discussed. Using a synonymous phrase such as “clinically meaningful” or similar should be used to improve clarity for the reader. Moreover, the significant clinical effects are defined as a greater than 5% effect. This means that all but one observed data point in the entire study was considered clinically significant. It is not clear that a 5% or even a 25% change in discharge or lacrimation (etc) are that meaningful.\n3. Major issue – in the absence of a microbiological output, even a simple one, it cannot be determined whether an infection was established. It can be difficult to cause an ocular surface infection in the absence of a method to penetrate the cornea – often by needle scarification or corneal injection.\n\n4. Major issue – there was not a no treatment control for the NaOH and Pseudomonas aeruginosa application group. This is a limitation of the study and should be recognized in the discussion.\n5. Major issue – methods. There is some missing information in the methods section:\nIn the description of groups (it was good that this was included), please specify the groups that were treated with sodium hydroxide. It is mentioned for group B but not C or D in the text.\n\nPlease indicate the concentration of ciprofloxacin used and whether the formulation had an antimicrobial preservative such as benzalkonium chloride.\n\nInformation on the Pseudomonas strain and preparation are needed. What strain was used? Was it a keratitis isolate from human patients? How was the Pseudomonas prepared in the laboratory and was the concentration determined? - if yes, what concentration was used?\n\nPlease indicate the method of euthanasia.\n\nIt appears that the manuscript describes a single experimental iteration rather than a reproduced experiment.\n6. Major concerns: Results section.\n“the clinical effect of treatment with the extract in all ocular structures observed were highly significant, particularly with the reduction in corneal infiltrates (effect size=74%).” Please restate - the reduction in corneal infiltrates were not significantly different (p=0.23) - yet listed here as \"observed were highly significant, particularly with reduction in corneal infiltrates\".\n\n“The results show that although treatment in group C had better clinical effects than in group B, the difference in the treatment was, nonetheless, not statistically significant (p>0.05). This finding is also shown pictorially in Figure 3.” - While this matches the P-values listed in table 3, the P-value listed for corneal infiltrates 0.867 by Mann-Whitney U test did not appear to match the data. Upon analysis of the given numbers Mann-Whitney and found p=0.029 using Graphpad software. Please recheck the statistics in the tables and rephrase the statement to note that corneal infiltrates are significantly different.\n\nTable 4, the Mann-Whitney value for corneal infiltrates again seems incorrect.\n7. Discussion section “We found that after the 168th hour of treatments, while animals in group C had better clinical healing (effect size>5%), the difference between the two treatment protocols was not statistically significant (p>0.05) as can be seen in Table 3.” -Please specify the group that is being compared to group C.\n8. The clinical effect percentages should be better spelled out – what is being compared to determine these effect sizes. In the abstract this comes across as ambiguous.\n9. Minor – methods. “All the rabbits in the two groups were treated with G. lucidum extracts.” Please define the groups that are being mentioned.\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?\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": "10043",
"date": "09 Aug 2023",
"name": "Emmanuel Okenwa-Vincent",
"role": "Author Response",
"response": "On behalf of the co-authors of this article, i wish to appreciate the reviewer for reading and giving invaluable and useful comments and suggestions to improving the quality of our paper, titled: Effects of Ganoderma lucidum on chemical-induced and bacterial-infected corneal ulceration of rabbits’ eyes. While we await the rest of the reviewers' comments to be published, we wish to affirm that we have noted and will take all the comments and points for improvements made to the different section of the article in our revised and subsequent versions of the article. Thank you once again for the positive comments."
}
]
},
{
"id": "186813",
"date": "29 Aug 2023",
"name": "Ahmed Elmassry",
"expertise": [
"Reviewer Expertise Infective keratitis",
"endophthalmitis",
"experimental animal corneal and ocular infections."
],
"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 discusses the efficacy of Ganodema lucidum Mushroom on chemical injury and bacterial infection of ulcerative keratitis on 16 New Zealand rabbits.\nThe number of eyes is too small to have a reliable statistical results.\n\nThe study on chemical and bacterial infections which is a mix and should be done only on one disease as there is a big difference between chemical injury and bacterial infection pathologies.\n\nThere is no definite staging of the chemical burn or stage of ulceration on the cornea.\n\nThe discussion is weak and needs to compare the studies with the present study.\n\nThe pictures are not clear in regards the stage of ulceration, or the chemical burn status.\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?\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": []
}
] | 1
|
https://f1000research.com/articles/12-185
|
https://f1000research.com/articles/11-179/v1
|
14 Feb 22
|
{
"type": "Research Article",
"title": "Sustainability of mangrove forest management in the former bauxite mining area on Bintan Island",
"authors": [
"Diana Azizah",
"Rasoel Hamidy",
". Mubarak",
". Efriyeldi",
"Tengku Said Raza’i",
"Wahyu Muzammil",
"Hilfi Pardi",
"Rasoel Hamidy",
". Mubarak",
". Efriyeldi",
"Tengku Said Raza’i",
"Wahyu Muzammil"
],
"abstract": "Background : The bauxite mining area on Bintan Island continues to expand into the mangrove forest area. Mangrove forests have ecological, economic, and social importance, which must be managed accordingly to maintain their sustainability. This research was conducted to examine the sustainability of mangrove forest management in the former bauxite mining area on Bintan Island.\n\nMethods: The approach used is Multi Dimensional Scaling- Rapid Appraisal for Sustainability through the modified Rapfish ordinance software technique for the Mangrove Ecosystem. The type of data used is quantitative, covering five dimensions of sustainability, namely ecological, economic, social, legal and institutional as well as technology.\n\nResults: The results showed that the sustainability index status of the ecological, social, legal and institutional dimensions was quite sustainable, while the sustainability index of the economic dimension was unsustainable, and the technological dimension was less sustainable. Attributes of levers that are sensitive to the sustainability of mangrove forest management are: 1) Mangrove density, 2) Substrate fraction, 3) sedimentation, 4) Mangrove importance index, 5) Bio-concentration factor, 6) Benefit value direct, 7) Indirect benefit value, 8) Dependence on mangrove forest as a source of livelihood, 9) Corporate Social Responsibility funding support, 10) Community income, 11) Community health level, 12) Community perception, 13) Legality of mangrove area and mining, 14) Pollution monitoring technology in ex-mining areas and 15) Mangrove rehabilitation technology.\n\nConclusions:The status of the mangrove forest sustainability index on Bintan Island is quite good. the economic and technological dimensions can be upgraded to sustainable status by carrying out management that is more focused on the lever attributes of the ecological, social, legal and institutional dimensions.",
"keywords": [
"Bintan Island",
"bauxite mine area",
"mangrove forest",
"sustainability"
],
"content": "Introduction\n\nBintan Island in the Riau Archipelago Province of Indonesia has a high potential for bauxite extraction. This particular advantage has encouraged many mining entrepreneurs, both local and foreign, who are interested in exploiting bauxite. The highest production was reported from 2001 to 2019 with an estimated 1.6 million metric tons extracted per year.1 Bauxite mines that are still operating legally or illegally can be found in Tanjungpinang City and Bintan Regency, such as those in Koyang Island, Wacopek Village, and Tembeling. Land clearing for mining continues to expand into limited production forests and conservation forests, including mangrove forests.2 It has been reported that in general, the bauxite mining activities on Bintan Island have not been carried out according to good mining practices, both during operation and post-mining. Although some mining activities have already stopped, the environmental damage sustained from these activities can still be observed in many ex-mining areas, especially the affected mangrove area in the coastal area of Bintan Island. There has been no effort to reverse the damage done to the mangrove forest around the mining site. Until now, only PT. Antam is the only mining company that carries out post-mining activities via reclamation and revegetation in the Bintan Regency, as well as corporate social responsibility (CSR) programs to restore the disturbed environment and accelerate the economic independence of communities around ex-mining areas.2 However, all these activities are still limited to land areas, while mangrove forest restoration has still not been carried out optimally. The government has restored damaged mangrove areas through mangrove rehabilitation in collaboration with universities and private companies. However, they often experience growth failure.3 Consequently, there are still many areas of unrestored mangrove forest that have been damaged and lost due to bauxite mining. According to the Central Bureau of Statistics of the Riau Archipelago Province,4 there have been around 90 hectares of mangrove land in Tembeling District since 2010, which have been damaged due to land clearing for bauxite mining and have not been rehabilitated after the end of their operations. This condition has persisted for years. If left unchecked, the impact will not only result in ecological losses but also disturb the economic and social values of the people who depend on the existence of mangroves.\n\nThe existence of mangrove forests needs to be optimized so that they can continue to function as spawning grounds for fish, land protectors, a barrier to abrasion by waves and strong winds, filters for seawater entering the land, wildlife habitats, bird migration sites, and even helps in phytoremediation of heavy metal content and filtration of pollutants.5–7 Given that the benefits and functions of mangroves do not only present the ecological value but also the economic and social values, maintaining, preserving, and revitalizing the functions of the mangrove ecosystem around the former bauxite mining area must be carried out through a multidimensional approach. The mangrove ecosystems around the former bauxite mining area can only continue to function if the forest is maintained. Therefore, this study aimed to analyze the sustainability of mangrove forest management around the ex-bauxite mining area in Bintan Island on a multidimensional basis. It is hoped that the mangrove forests can restore the damaged environment in the former bauxite mining area and become a resource with multiple values for the residents of Bintan Island.\n\n\nMethods\n\nThe research was carried out from June to November 2021 in Bintan Regency (Tembeling Tanjung and Wacopek Villages) and Tanjungpinang City (Senggarang Village and Air Raja Village) as presented in Figure 1. The location of the former bauxite mine is visible with reddish-yellow land openings with Mangrove ecosystem still found around the area.\n\nThe data used in this study include primary and secondary data. Primary biophysical data were obtained directly through field observations, while economic, social, institutional, and technological data were obtained using a Focus Group Discussion (FGD) involving 17 respondents. The selection of key respondents was carried out using a purposive sampling technique, namely experts in the field such as the village head/Lurah, community leaders, community organizations, and the government. Secondary data were obtained from the Tanjungpinang City Government, Bintan Regency, and related literature. The dimensions and attributes of the analysis on the sustainability of mangrove forest management on Bintan Island are presented in Table 1.\n\nSustainability analysis was carried out via the MDS (multidimensional scaling) approach using the software RAPFISH (Rapid Appraisal for Fisheries) 1.08 which was modified into RApMEc (Rapid Appraisal for Mangrove Ecosystem) to evaluate the sustainability of mangrove forests in multidimensionality. The sustainability index value of each dimension can be visualized in the form of a kite diagram and analyzed multidimensionally to determine the point or position of the sustainability of mangrove forest management. The grouping of sustainability index values is presented in the range of 0 (bad) to 100 (good), which consists of 0-25 (bad), 25-50 (poor), 51-75 (enough), and 76-100 (good).9 Leverage analysis was used to determine the leverage factor while Monte Carlo analysis was used to see the effect of errors in the scores of each attribute.10\n\n\nResults and discussions\n\nBauxite mining activities on Bintan Island have continued to grow, reaching 1.1 million metric tons in 2013 and 1.6 million metric tons in 2019.1 The general characteristics seen in ex-bauxite mining areas include severe land damage, missing soil layers, and a soil structure, texture, and density that does not support the development of root systems, thereby interfering with plant growth.11 Pollutants detected in bauxite mines on Bintan Island typically include minor elements, namely Fe and Mn. In addition, the trace elements found in the area include Cu, Cr, Cd, Pb, Ni, and Zn. The reported values obtained from the analysis of metal contents in the area indicated non-compliance with the environmental quality standard.12 The results from the previous study13 showed that the environmental conditions around the former bauxite mining area on Bintan Island are not polluted but have been contaminated with heavy metals from mining activities. The conclusion was derived based on the Pollutant Load Index (PLI) value which was <1 for Pb and Cr, and the Geo-Accumulation Index (I_geo) which was 0<I_geo<1 for Pb and Cr. On the other hand, it was reported that the sediment fraction in Carang River, Tanjungpinang City is dominated by sand (74.65-97.7%), while the Tembeling Tanjung and Wacopek in Bintan Regency are dominated by gravelly sand to slightly gravelly sand.14\n\nThe survey13 found 11 mangrove species at the site, namely Avicennia alba, A. marina, Rhizophora apiculata, R. mucronata, Ceriops tagal, Bruguiera gymnorhiza, B. cylindrical, Sonneratia alba, Xylocarpus granatum, X. mollucensis, and Lumnitzera littorea. The most dominant species were R. mucronata, R. apiculata, and A. marina with mangrove density values classified as moderate (1300 trees/Ha) to damaged (678 trees/Ha). Assessment of the damage level in mangrove trees revealed that 43.5% of the trees in the samples were found damaged with the remaining 56.5% found as healthy. The mangrove tree species with the largest Significance Index determined in the tree, sapling, and seedling strata was R. mucronata.\n\nBased on the results from a study,13 the accumulation of heavy metal, Pb, in the sediment was found between 0.06 and 0.24 ppm. Besides, the concentration of Pb found in the leaves of R. mucronata was between 0.04 and 0.37 ppm, 0.05-0.71 ppm in the stems, and 0.08-0.87 ppm in the roots. On the other hand, the concentration of Cr in sediment was found between 0.01 and 0.04 ppm, with the concentration of Cr in the leaves of R. mucronata found between 0.02-0.09 ppm, 0.01-0.09 ppm in the stems, and 0.01-0.10 ppm in the roots.\n\nA Sustainability Index of 52.48 was obtained from an analysis using RApMEc, which was carried out based on 27 attributes. This value reflects the sustainable management of mangrove forests in the former bauxite mining area in a multidimensional manner. Sustainability index values for each dimension, stress value, and R2 are presented in Table 2.\n\nTable 2 shows that the small difference between the index values obtained from the MDS analysis and that of the Monte Carlo analysis indicates the relatively small scoring errors, relatively small variation in opinions, a stable repeated analysis process, and errors in data entry or lost data can be avoided. The results confirmed the validity of the MDS used in assessing the sustainability of mangrove forest management on Bintan Island. The validity of the results obtained from the MDS analysis was also demonstrated by the Goodness of Fit value, which was represented by the stress value and the coefficient of determination (R2) at the 95% confidence level. Table 2 shows that the stress value was less than 0.25 and the R2 value was close to 1, demonstrating the statistically valid results obtained from the analysis and the sufficient number of attributes used which represented the actual condition adequately. The attributes used in the analysis were sufficient to assess the sustainability of mangrove forests, whereby the results demonstrated a high level of confidence in the RApMEc analysis. The multidimensional sustainability indices are shown in Figure 2.\n\nThe sustainability of the ecological dimension is an indicator of the biophysical sustainability of mangrove forests related to environmental aspects such as physical, chemical, and biological. A sustainability index of 69.94 was obtained for the ecological dimension indicating quite a sustainable management in this aspect. This finding also demonstrates that the ecological dimension is sufficient to prove the sustainability in the mangrove forest management around the former bauxite mining area on Bintan Island. On the other hand, the leverage analysis revealed the five attributes related to the sustainability of the ecological dimension, namely 1) mangrove density, 2) substrate fraction, 3) sedimentation, 4) mangrove importance value index, and 5) metal bioconcentration factor. These attributes are presented in Figure 3.\n\nThe density level of various mangrove tree species deserve attention and should ideally be increased because they greatly affect the health of the mangrove forest, and consequently, the sustainability of the mangrove forest ecosystem on Bintan Island. Although the emergence of seedlings and saplings has been reported in the area, the Important Value Index indicates a disturbance in the mangrove community.13 The growth of mangrove seedlings and saplings must be preserved to maintain the availability of seeds for mangrove forest regeneration.\n\nSedimentation that occurs around the former bauxite mining area has been reportedly low. Sedimentation has resulted in the formation of red mud sediment in the mangrove area, indicating a very low organic content in the soil. Therefore, it is necessary to prevent the rate of erosion and sedimentation so the quality of the water and sediments in the former bauxite mining area can be improved, which consequently supports the life of the surrounding mangroves.\n\nBased on the results from the analysis of the Bioconcentration Factor (BCF), it was found that R. mucronata and A. marina can absorb heavy metals, namely Pb and Cr present in the environment. Although the metal accumulation value was reportedly low, a test on the metal absorption mechanism revealed that R. mucronata is a hyperaccumulator of metals while A. marina was found the opposite.13 The BCF revealed the potential use of mangrove species for the accumulation of heavy metals from the former bauxite mining area to eliminate pollution.\n\nA value of 17.62 was obtained to represent the sustainability status of the mangrove forest around the ex-bauxite mining area on Bintan Island, indicating unsustainability (bad). This value demonstrates that the management of mangrove forests around the former bauxite mining area has been experiencing pressure from an economic standpoint. This pressure could be due to the poor ability of mangrove natural resources and the surrounding ecosystems to provide environmental benefits and services. The results obtained from the leverage analysis showed that all attributes are the levers that require attention in the management of mangrove forests. The graph of economic dimension leverage is presented in Figure 4.\n\nThe values obtained for direct and indirect benefits of mangrove forests around the former bauxite mining area revealed that the current utilization of mangrove forests is not optimal.12 Therefore, there is an immediate need to increase the economic value of mangrove forests, either directly or indirectly, so that people can also benefit from healthy mangrove forests. The status of the mangrove forest area around the former bauxite mining area does not prohibit its development based on usefulness values, especially for fisheries and environmental services.16\n\nThe dependence of the community around the mangrove forest is still very low as some people choose to be entrepreneurs. Fishermen are the only group of people in the community whose livelihood depends on mangrove forests. Moreover, the community does not view the mangrove forests as an asset in supporting their household economy. Awareness of the importance of mangrove forests must be raised so the community can benefit from the forests economically, either directly or indirectly.\n\nCurrently, the mangrove forest rehabilitation activities have mostly been funded by the CSR organizations located on Bintan Island such as the Ecology Foundation and Banyantree, PT. Various Mines. To date, such support still prevails on the island but is not yet optimally available. Furthermore, the support from CSR funding also influences the sustainability of mangrove forests on Bintan Island in terms of economic dimension. When funding is available, the management and utilization of mangrove forests by the community and the authority will run well.15\n\nTo improve the sustainability of the economic dimension in the mangrove forest management around the former bauxite mining area on Bintan Island, it is important to develop the economic values of the mangrove forests for community use and plan for integrated mangrove forest rehabilitation activities with various parties. The attribute of community dependence on the role of mangrove forests as a source of livelihood can be used as social capital to encourage communities to participate in the sustainable management of mangrove forests.16–18\n\nA value of 65.40 obtained from the analysis of the sustainability status of mangrove forests based on the social dimension indicated sustainability in the management. The level of public health and public perception of mangrove management were the two attributes that are sensitive and can greatly affect the social dimension. The graph of the leverage identified in the social dimension is presented in Figure 5.\n\nThe level of public health and public awareness in the management of an area are both very important for the success of any efforts in managing the area. The perception of the coastal community greatly determines the level of understanding among the community about the importance of the mangrove area and its sustainable management for the survival of the community.19–22\n\nA value of 54.95 obtained from the analysis of the sustainability index for the legal and institutional dimensions indicated sustainability in the management. Based on the leverage analysis, only one of the five attributes, namely the legality of the mangrove forests and the bauxite mine was identified as the lever in the legal and institutional dimensions. The graph of the leverage is presented in Figure 6.\n\nThe legality of mangrove forests and bauxite mining areas is necessary for resource management on Bintan Island. Within the mangrove ecosystem, many resources such as mangrove forests, fisheries, waters, and non-aquatic biota must be managed to ensure sustainability. In addition, Bintan Island is also rich in bauxite, one of the mineral resources.23,24 The potential value of bauxite minerals can be exploited to support the economy of the locals. To avoid overlapping, it is necessary to make clear arrangements regarding area zoning, forms of utilization, and management efforts according to the laws or regional regulations. This attribute should be given great attention in the implementation of mangrove forest management policies, considering the influence of these attributes on the sustainability of the management of mangrove forest and ex-bauxite mining areas.\n\nA value of 49.52 was obtained for the sustainability index of the technological dimension, indicating a lack of sustainability in the management. The value indicates the condition of the mangrove forest around the former bauxite mining area on Bintan Island, which is currently under pressure from the technological aspect. Based on leverage analysis, all attributes were identified as the levers. The chart of the leverage analysis is presented in Figure 7.\n\nThe technology for monitoring environmental pollution around the bauxite mining area is still inadequate in anticipating the impacts of erosion, abrasion, water quality degradation, and metal accumulation. Although the available mangrove rehabilitation technology is still simple, namely planting with a seed and fruit system and embroidery techniques, this technology has not been able to reduce threats that can reduce the factors and intensity of threats to the mangrove ecosystem around the former bauxite mining area on Bintan Island.6 One of the reasons is the absence of integration programs between local and central governments (cross-sector). In addition, the miners have also not practiced environmentally friendly mining techniques (good mining practice) as mining activities are still carried out with an open mining system without the implementation of any post-mining restoration efforts. These two in the technological dimension need great attention for the implementation of mangrove forest management policies to support the sustainability of mangrove forest management in the future.\n\n\nConclusion\n\nIn general, the mangrove forest management around the ex-bauxite mining area on Bintan Island was found quite sustainable (52.48) based on the multidimensional dimension. On the other hand, the management was found moderately sustainable based on the ecological (69.94), social (65.40), and legal and institutional (59.94) dimensions, less sustainable (49.52) based on technological dimension, and unsustainable (17.62) based on the economic dimension. Findings made in this research revealed the attributes in each dimension, which are the determining factors that can also be used as a reference for the implementation of mangrove ecosystem management programs in the former bauxite mining area on Bintan Island.\n\nThe identified leverage attributes that are sensitive to the sustainability of mangrove forest management in the ex-bauxite mining area on Bintan Island are 1) mangrove density, 2) substrate fraction, 3) sedimentation, 4) mangrove importance index, 5) bioconcentration of metal factors, 6) the value of direct benefits, 7) the value of indirect benefits, 8) dependence on mangrove forests as a source of livelihood, 9) CSR funding support, 10) community income, 11) community health level, 12) community perception, 13) the legality of mangrove areas and mining, 14) technology for monitoring pollution of ex-mining areas, and 14) technology for mangrove rehabilitation. All of these attribute levers must be prioritized by the government and relevant stakeholders in preparing and implementing appropriate policies to ensure sustainable mangrove forest management on Bintan Island.\n\n\nData availability\n\nAll data concerning the results are available as part of the article and no additional source of data is required.",
"appendix": "Acknowledgment\n\nThe results of this study are part of the research funded by the University of Maritime Raja Ali Haji Leading Research scheme for the 2021 fiscal year. Therefore, the authors thank Maritime Raja Ali Haji University for facilitating the financing of this research. The authors also express gratitude to the manager of mangrove forests.\n\n\nReferences\n\nReport of a specific working visit of Commission VII DPR RI to the Riau Islands province. Overview of Tanjung Uban Oil Fuel Terminal PT. Pertamina (Persero) and Bauxite Mine Inspection PT. Mount Bintan Abadi In Bintan Regency. March 8-10, 2019.\n\nKunjana G: 2011. Reference Source\n\nFirdaus LN, Wulandari S, Mulyeni GD: Growth of Rubber Plant Roots on Ex-Bauxite Mine Soil With Application of Organic Materials. Biogenesis. 2013; 10: 53–63.\n\nThe Central Bureau of Statistics of the Riau Islands Province: Riau Islands in Numbers.2020.\n\nHeriyanto NM, Subiandono E: Absorption of heavy metal pollutants (Hg, Pb and Cu) by mangrove species. J. Forest Res. Nature Cons. 2011; 8: 177–188.\n\nDeswati H, Pardi HS, Rahmi I: Adsorptive stripping voltammetry for the simultaneous determination of Cd, Cu, Cr, and Pb in water samples using Fluorexon: An optimization single factor. Anal. Bioanal. Electrochem. 2018; 10: 1491–1505.\n\nDeswati H, Suyani AK, Muchtar EF, et al.: Copper, iron and zinc contents in water, pakcoy (Brassica rapa L.) and tilapia (oreochromis niloticus) in the presence of aquaponics. Rasayan J. Chem. 2019; 12: 40–49. Publisher Full Text\n\nKuvaini A, Hidayat A, Kusmana C, et al.: A multidimensional assessment technique to evaluate the sustainability of mangrove forests on Kangean Island, East Java Province. Regional Environ. J. 2019; 7: 137–152.\n\nSafe'I R, Kasykoyo H, Darmawan A: Analysis of Tree Health Using the Forest Health Monitoring Method (Case Study on Three Forest Functions in Lampung Province.). SemNASN MAPIAUB; 2020.\n\nFauzi A: Sustainability Analysis Techniques. Gramedia Pustaka Utama: Jakarta; 2019.\n\nPutra RD, Apriadi T: Study of Post-Bauxite Mining Heavy Metal Contamination (Pb and Cr) as Potential Locations for Aquaculture Activities. J. Aquacul. Intek. 2018; 2: 1–15.\n\nZulfikar A: Analysis of Metal Content in Bauxite Mine Tailings Waste (Red Mud). Journal of Maritime Dynamics. 2015; 5. UMRAH PRESS.\n\nAzizah D: Phytoaccumulation of Pb and Cr Heavy Metals in Rhizophora mucronata Around the Former Bauxite Mine Area, Bintan Island. Indonesian Environ. Dynam. 2021; 8: 121–147. Publisher Full Text\n\nYolanda OAP, Melani WR, Muzammil W: Characteristics of Sediment in Sei Carang Waters, Tanjungpinang City – Indonesia. Habitus Aqua. 2020; 1: 11–20. Publisher Full Text\n\nSuryawan A: Mangrove Rehabilitation on Alo Beach (Karakelang Island, Talaud) Using Propagules Rhizopora mucronata Lamk. Research and Development Center for Environment and Forestry Manado, North Sulawesi. WASIAN J. 2017; 4: 69–78. Publisher Full Text\n\nPardi H, Deswati HS, Widya Edelwis T: Cathodic stripping voltammetric determination of essential element (Copper and zinc) in drinking water. Anal. Bioanal. Electrochem. 2019; 11: 691–702.\n\nDeswati H, Suyani IR, Pardi H: Application of central composite design optimization technique for determination of copper in fruit and vegetable samples with adsorptive stripping voltammetry in the presence of calcein. Rasayan J. Chem. 2017; 10: 1359–1367.\n\nMinistry of Environment of the Republic of Indonesia: Decree of the Minister of the Environment Number 51 of 2004 Appendix III concerning Quality Standards for Marine Biota. 2004.\n\nParizanganeh AH, Bijnavand V, Zamani AA, et al.: Concentration, Distribution and Comparison of Total and Bioavailable Heavy Metals in Top Soil of Binab District in Zanjan Province. J. Soil Sci. 2012; 02(2012): 123–132.\n\nSham TM, Ray S, Kabir T, et al.: Assessment of heavy metals contamination in incinerated medical waste. ARPN J. Sci. Technol. 2012; 2: 904–911.\n\nHeriyanto NM, Subiandono E: Absorption of Heavy Metal Pollutants (Hg, Pb and Cu) by Mangrove Types. J. Forest Res. Nature Cons. 2011; 8: 177–188.\n\nParingsih NC, Setyono P, Sunarto.: TRM-Based Mangrove Conservation (Tanam Rawat Monitoring) To Protect Marine Resources In Cengkrong, Trenggalek. J. Bioexperiments. 2018; 4(2018): 22–34.\n\nOlfie LS, Jean T, Rin K, et al.: Economic Valuation of Mangrove Forest Resources in Palaes Village, Likupang Barat District, North Minahasa Regency. ASE. 2011; 7: 29–38.\n\nRismika T, Purnomo EP: Marine Ecosystem Management Policy Due to Tin Mining in Bangka Belitung Province. J. Publication. 2019; 4: 23–33.\n\nSari SP, Rosalina D: The Success Rate of Mangrove Planting on Land Post Tin Mining in South Bangka Regency. Maspari J. 2014; 6: 71–80."
}
|
[
{
"id": "146849",
"date": "12 Sep 2022",
"name": "Nuddin Harahab",
"expertise": [
"Reviewer Expertise Coastal resource economy"
],
"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\nOn abstract: In the method section, please explain how to determine the sample and how many there are.\nIn the results section, the attributes of the levers are grouped by dimension.\nIn the conclusion section, how can you conclude that the sustainability index is quite good, even though from the 5 dimensions analyzed, 2 dimensions are unsustainable. Then how is it possible, to increase the sustainability of the economic and technological dimensions, by carrying out management that focuses more on the attributes of levers? From the ecological, social, legal and institutional dimensions. This does not make sense.\nMethods: At the study site, the explanation does not match the picture 1. In picture one everything must be in English.\nNeed to be given clear boundaries \"in the former bauxite mining area” is this the area of the ex-mining point, or the area outside the ex-mining point but around it?\nIn Table1. please explain how to give an assessment or score for each attribute.\n\nResults and discussions: The findings on the environmental conditions of the former mining area on Bintan Island, the sediment fraction is dominated by sand and gravel, does this support the life of mangrove vegetation? Considering the findings of the leverage factor, the mangrove density is high. What is the explanation?\nRegarding water quality, which quality is used for human needs or vegetation needs? All of that has not been explained in the measurement or scoring on all the attributes used. (see in table 1.)\nThe sustainability value of the ecological dimension is quite good (69.94), what does this have to do with the fact that the environmental conditions of the former mining area does not support the development of root systems? (a contradictory research finding, and no explanation yet).\nOverall, the results and discussion require a more in-depth discussion, therefore it is necessary to read several articles related to reforestation of the mangrove ecosystem.\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?\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? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/11-179
|
https://f1000research.com/articles/10-1265/v1
|
09 Dec 21
|
{
"type": "Systematic Review",
"title": "Simulation framework for connected vehicles: a scoping review",
"authors": [
"Siti Fatimah Abdul Razak",
"Sumendra Yogarayan",
"Afizan Azman",
"Mohd Fikri Azli Abdullah",
"Anang Hudaya Muhamad Amin",
"Mazzar Salleh",
"Sumendra Yogarayan",
"Afizan Azman",
"Mohd Fikri Azli Abdullah",
"Anang Hudaya Muhamad Amin",
"Mazzar Salleh"
],
"abstract": "Background: V2V (Vehicle-to-Vehicle) is a booming research field with a diverse set of services and applications. Most researchers rely on vehicular simulation tools to model traffic and road conditions and evaluate the performance of network protocols. We conducted a scoping review to consider simulators that have been reported in the literature based on successful implementation of V2V systems, tutorials, documentation, examples, and/or discussion groups. Methods: Simulators that have limited information were not included. The selected simulators are described individually and compared based on their requirements and features, i.e., origin, traffic model, scalability, and traffic features. This scoping review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). The review considered only research published in English (in journals and conference papers) completed after 2015. Further, three reviewers initiated the data extraction phase to retrieve information from the published papers. Results: Most simulators can simulate system behaviour by modelling the events according to pre-defined scenarios. However, the main challenge faced is integrating the three components to simulate a road environment in either microscopic, macroscopic or mesoscopic models. These components include mobility generators, VANET simulators and network simulators. These simulators require the integration and synchronisation of the transportation domain and the communication domain. Simulation modelling can be run using a different types of simulators that are cost-effective and scalable for evaluating the performance of V2V systems in urban environments. In addition, we also considered the ability of the vehicular simulation tools to support wireless sensors. Conclusions: The outcome of this study may reduce the time required for other researchers to work on other applications involving V2V systems and as a reference for the study and development of new traffic simulators.",
"keywords": [
"V2V",
"network simulator",
"mobility generator",
"simulations",
"connected vehicles",
"microscopic models"
],
"content": "Introduction\n\nIn recent decades, a significant increase in vehicle use has increased traffic congestion and fatalities1. According to the World Health Organization, 1.25 million people are killed and severely injured involving vehicle accidents2. Hence, connected vehicle technology responds to this constraint, aiming to leverage inter-vehicle communication to produce safe, user-friendly, and fuel-efficient vehicle assistive technologies3,4. One of the main aspects of connected vehicle research is to optimise traffic flow through the exchange of information5. This communication can be sorted in terms of vehicle (V2V), infrastructure (V2I), a pedestrian (V2P), and network (V2N)6,7. The exchange of information, collectively known as V2X communications, could assist drivers in preventing accidents by providing warnings of danger invisible to drivers and other sensors (e.g. collision avoidance, lane departure warning and speed limit alert)8,9.\n\nNevertheless, the adoption of connected vehicle technology poses a range of challenges, particularly in urban environments. It is challenging to analyse the effectiveness of the application of connected vehicles under traffic conditions10–12. As such, simulations using traffic and network simulators as well as mobility generators are viable alternatives to modelling and determining the effectiveness of such deployments in the real world13,14, as it provides an affordable and scalable method for analysing model compliance in various contexts and parameters.\n\nTraffic simulations are categorised by level of detail into three separate categories15. First, the most precise information on each vehicle in the system is microscopic simulations16. Second, mesoscopic simulations exploit aggregate velocity-density functions to represent their behaviour and view traffic as a continuous stream of vehicles17. Finally, macroscopic simulation is the large-scale traffic model, which focuses on combined traffic status18. Microscopic simulations provide the highest degree of detail for modelling, although they are the slowest to execute19,20.\n\nIn addition, mobility generators are a possible option for modelling vehicle elements such as traffic, temporal and spatial mobility, and generating mobility traces21,22. These traces are then uploaded to a network simulator, which mimics vehicle-to-vehicle communication. Furthermore, these traces can be generated by observing real-world vehicles on the road and then used in network simulations23,24. The effect of network parameter modifications on traffic mobility is a strategic objective simulation25. It is also restricted to the use of the trace controlled by the mobility model. Another option is to use a simulator that directly integrates the mobility framework.\n\nFor Vehicular Adhoc Networks (VANET), it is necessary to rely on network protocols to assess their performance22,23, given that actual experiments are not possible. Over the last decade, efforts have been made to produce a full transport simulator for VANET solutions, including a wireless network simulator for modelling and evaluation24,25. A wide range of simulators can be used for VANET simulation modelling, both commercial and open source. Older simulators provide a network simulator to communicate with stationary mobility models. Many researchers have examined various mobility models with simulation tools for several contexts. Such simulator tools are not yet well explored since many researchers base their simulations depending on their use case settings. Thus, this motivates the identification of different simulators do not yet exist. Therefore, this study conducted a systematic scoping review to identify the applicability and availability of existing mobility generators, network simulators, and combination simulators.\n\n\nMethods\n\nA popular approach to synthesize research evidence which have no definitive procedure established is known as a scoping review. To conduct the review process, we adopted the PRISMA Extension for a Scoping Review26. The process involves determining the subjective and objective outcomes, identifying and selecting relevant studies, organising and summarising the findings, and reporting the outcomes (see Figure 1). Review questions were developed as follows:\n\n1. What are available mobility generators which are currently active in vehicle simulations?\n\n2. What is the criteria of network simulators commonly used in vehicle simulation active development?\n\n3. Which mobility networks and network simulators have been integrated to study vehicle communication protocols?\n\nRelevant studies were identified from IEEE and ScienceDirect, only including journal and conference papers with a published status. All searches were initiated in November 2019, and articles published in English starting from 2015 were considered for evaluation as our analysis of the literature shows that it is a relatively new but rapidly growing field of academic endeavour.\n\nControlled phrases and free-text word phrases related to vehicular communications that investigated V2V safety applications, vehicle network performance, driver behaviour, vehicle simulation tools, and VANET were considered for inclusion (see Box 1).\n\nMendeley was used to import the search results (www.mendeley.com) and remove duplicate articles.\n\n\n\n\"VANET\"\n\n#1 AND Simulation\n\n#1 AND #2 AND Simulators\n\n#1 AND #2 AND #3 AND Routing\n\n#1 AND #2 AND #3 AND #4 AND Mobility\n\n#1 AND #2 AND #3 AND #4 AND #5 AND Urban\n\nOnce duplicate articles had been removed, further screening was performed at the title or abstract level based on the inclusion criteria. In addition, related technical reports were also included from Google Scholar. For confirmation, filtering (e.g. possible synonyms or other related terms) was also done at the full-text level afterwards. Citations of the articles included were searched for other relevant articles.\n\nTo facilitate the screening task, we imported the bibliographic citation file in RIS format from Mendeley into Rayyan (https://www.rayyan.ai/). Three reviewers (S.Y., A.A., and M.F.A.A.) were involved in the screening process to minimise bias and ensure the consistency of the selected articles. The first screening process ended in April 2020 and was later updated in January 2021.\n\nAll reviewers reviewed the same article and reports during the data extraction phase before collating their findings in an MS Excel spreadsheet. Data related to objective outcomes were collected from each included article wherever available, including year, type of traffic model, architecture and simulation language, type of network simulator, type of mobility generator, implementation or experimentation scenario and type of license. The spreadsheets were compared to ensure consistent data extraction by all reviewers. The contribution of the studies was further analysed based on descriptions provided in the publications paper to consider in our scoping review. In March 2021, the data extraction and analysis were finalised by consensus among the reviewers.\n\n\nResults\n\nA total of 269 publications were found initially. After removing duplicates, a total of 184 titles and abstracts were screened, from which 72 publications were subjected to full-text review after excluding those not of interest to this study. In total, ten studies and reports fulfilled the criteria for inclusion and were included in the analysis (see Figure 1).\n\nWe found that open-source mobility and network simulators were popular among researchers. Microscopic models were preferable for research related to vehicular communications since the simulations provide the most precise information of each vehicle or mobile node and the highest degree of detail for modelling compared to macroscopic and mesoscopic models. Common network simulators were NS-2, Ns-3 and OMNeT++. However, not all mobility simulators supported active development, which is important in current active research domains such as vehicular communications. The summary of mobility generators and network simulators found are in Table 1 and Table 2, respectively. A list of all ten studies can be found in Table 3.\n\nY = Supported, N = Not Supported\n\nY = Supported, N = Not Supported\n\nN/A – Not Applied\n\n\nDiscussion\n\nSince this area of study is considered as a relatively new but rapidly growing field, this scoping review process only considers relevant papers published from 2015 onwards, which shows that extensive research has been conducted to create security standards for communication technologies, particularly the vehicular network. Although various simulators can be enhanced with library extensions, none of the simulators is related to security and privacy. Ultimately, researchers and professionals cannot compare their security measures to a given circumstance. For instance, ensuring the privacy of a vehicular user in a fast-moving network and disseminating messages in a secure vehicular environment. However, there is no simple practice of extending existing simulators to the desired security standard, which implies that future development research will need to be done.\n\nIn addition, the quality of a simulation depends largely on the precision of the models. The range of precision has increased dramatically recently, where several modules contain signal attenuation components, multiple antenna models, and environmental interferences. However, one continuous barrier to producing accurate simulations is the evolution of rapid prototyping and its increasing use in-vehicle networks. For example, vehicle nodes would depend on three-dimensional scenarios to communicate with other nodes. It would be crucial for current and future simulators to extend the current simulators to these new conditions.\n\nIntegration with real-time system modelling based on non-real-time events creates additional challenges. Due to resource limitations, current simulators do not correspond with the physical properties of the hardware prototype while simulating a comprehensive network with multiple vehicles. Several alternatives have been put forward to reduce the complexity that could speed the simulation. However, this approach usually does not include indirect outcomes, which could seriously impact the behaviour of real-world network components. It is, therefore, necessary to examine the interconnection between simulators and hardware devices with the security standards concerned.\n\n\nConclusions\n\nStudies have led to the discovery of comprehensive and realistic simulation tools due to the increasing popularity and interest for the future transportation system. This work has examined the current availability of simulators. Although several simulators have many features, it is worth exploring further the improvement of the simulators for specific scenarios.\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\nZenodo: PRISMA-ScR checklist for ‘Simulation framework for connected vehicles: a systematic review’, https://doi.org/10.5281/zenodo.563780254\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nRetallack AE, Ostendorf B: Current Understanding of the Effects of Congestion on Traffic Accidents. Int J Environ Res Public Health. 2019; 16(18): 3400. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKarim F, Albrka Ali SI: Evaluation of Most Influential Factors Affecting Road Traffic Accidents in Sidon, Lebanon. Jurnal Kejuruteraan. 2020; 32(3): 467–473. Reference Source\n\nUkkusuri S, Sagir F, Mahajan N, et al.: Strategic and Tactical Guidance for the Connected and Autonomous Vehicle Future. West Lafayette, IN Aug. 2019. Publisher Full Text\n\nFeng Y, Zheng J, Liu HX: Real-time detector-free adaptive signal control with low penetration of connected vehicles. Transp Res Record. 2018; 2672(18): 35–44. Publisher Full Text\n\nShladover SE: Connected and automated vehicle systems: Introduction and overview. J Intell Transport S: Technology, Planning, and Operations. 2018; 22(3): 190–200. Publisher Full Text\n\nChoi YJ, Hur J, Jeong HY, et al.: Special Issue on V2X Communications and Networks. J Commun Netw. 2017; 19(3): 205–206. Publisher Full Text\n\nDomínguez JML, Mateo Sanguino TJ: Review on V2X, I2X, and P2X Communications and Their Applications: A Comprehensive Analysis over Time. Sensors (Basel). 2019; 19(12): 2756. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhan UA, Lee SS: Distance-based resource allocation for vehicle-to-Pedestrian safety communication. Electronics (Switzerland). 2020; 9(10): 1–17. Publisher Full Text\n\nArena F, Pau G: An overview of vehicular communications. Future Internet. 2019; 11(2): 27. Publisher Full Text\n\nBezai NE, Medjdoub B, Al-Habaibeh A, et al.: Future cities and autonomous vehicles: analysis of the barriers to full adoption. Energy and Built Environment. 2021; 2(1): 65–81. Publisher Full Text\n\nGavanas N: Autonomous Road Vehicles: Challenges for Urban Planning in European Cities. Urban Sci. 2019; 3(2): 61. Publisher Full Text\n\nWen L, Kenworthy J, Guo X, et al.: Solving Traffic Congestion through Street Renaissance: A Perspective from Dense Asian Cities. Urban Sci. 2019; 3(1): 18. Publisher Full Text\n\nDurán JM: What is a Simulation Model? Mind Mach. 2020; 30(3): 301–323. Publisher Full Text\n\nGray J, Rumpe B: Models in simulation. Softw Syst Model. 2016; 15(3): 605–607. Springer Verlag. Publisher Full Text\n\nKim J, Kim JH, Lee G, et al.: Microscopic Traffic Simulation Calibration Level for Reliable Estimation of Vehicle Emissions. J Adv Transport. 2020; 2020: 4038305. Publisher Full Text\n\nZehe D, Grotzky D, Aydt H, et al.: Traffic simulation performance optimisation through multi-resolution modeling of road segments. In SIGSIM-PADS 2015 - Proceedings of the 3rd ACM Conference on SIGSIM-Principles of Advanced Discrete Simulation. 2015; 281–288. Publisher Full Text\n\nYuan H, Li G: A Survey of Traffic Prediction: from Spatio-Temporal Data to Intelligent Transportation. Data Sci Eng. Springer Science and Business Media Deutschland GmbH. 2021; 6(1): 63–85. Publisher Full Text\n\nGrzybek A, Danoy G, Bouvry P: Generation of realistic traces for vehicular mobility simulations. In DIVANet’ 12 - Proceedings of the ACM Workshop on Design and Analysis of Intelligent Vehicular Networks and Applications. 2012; 131–138. Publisher Full Text\n\nRivoirard L, Berbineau M, Wahl M, et al.: Using Real-World Car Traffic Dataset in Vehicular Ad Hoc Network Performance Evaluation. 2016. Publisher Full Text\n\nLee CH, Lim KG, Chua BL, et al.: Progressing toward urban topology and mobility trace for Vehicular Ad Hoc Network (VANET). In ICOS 2016 - 2016 IEEE Conference on Open Systems. 2017; 120–125. Publisher Full Text\n\nMatcha BN, Namasivayam SN, Hosseini Fouladi M, et al.: Simulation Strategies for Mixed Traffic Conditions: A Review of Car-Following Models and Simulation Frameworks. Journal of Engineering (United Kingdom). Hindawi Limited. 2020. Publisher Full Text\n\nYasser A, Zorkany M, Abdel Kader N: VANET routing protocol for V2V implementation: A suitable solution for developing countries. Cogent Eng. 2017; 4(1): 1362802. Publisher Full Text\n\nTripp-Barba C, Zaldívar-Colado A, Urquiza-Aguiar L, et al.: Survey on routing protocols for vehicular ad Hoc networks based on multimetrics. Electronics (Switzerland). MDPI AG. 2019; 8(10): 1177. Publisher Full Text\n\nKim J, Sridhara V, Bohacek S: Realistic mobility simulation of urban mesh networks. Ad Hoc Networks. 2009; 7(2): 411–430. Publisher Full Text\n\nKang S, Aldwairi M, il Kim K: A survey on network simulators in three-dimensional wireless ad hoc and sensor networks. Int J Distrib Sens N. 2016; 12: 10. Publisher Full Text\n\nTricco AC, Lillie E, Zarin W, et al.: PRISMA extension for scoping reviews (PRISMA-ScR): Checklist and explanation. Ann Intern Med. American College of Physicians. 2018; 169(7): 467–473. PubMed Abstract | Publisher Full Text\n\nShaban AM, Kurnaz S, Shantaf AM: Evaluation DSDV, AODV and OLSR routing protocols in real live by using SUMO with NS3 simulation in VANET. In 2nd International Congress on Human-Computer Interaction, Optimisation and Robotic Applications. 2020; 1–5. Publisher Full Text\n\nMa X, Hu X, Weber T, et al.: Evaluation of accuracy of traffic flow generation in SUMO. Appl Sci. 2021; 11(6): 2584. Publisher Full Text\n\nAji Pratama R, Rosselina L, Sulistyowati D, et al.: Performance Evaluation on VANET Routing Protocols in the Way Road of Central Jakarta using NS-3 and SUMO. In 2020 International Seminar on Application for Technology of Information and Communication. 2020; 1–6. Publisher Full Text\n\nHorni A, Nagel K, Axhausen KW: The multi-agent transport simulation MATSim. London: Ubiquity Press Ltd, Accessed: Aug. 15, 2021. Publisher Full Text\n\nNguyen J, Powers ST, Urquhart N, et al.: An Overview of Agent-based Traffic Simulators. 2021. Reference Source\n\nCampanile L, Gribaudo M, Iacono M, et al.: Computer network simulation with ns-3: A systematic literature review. Electronics. 2020; 9(2): 272. Publisher Full Text\n\nZhou X, Taylor J, Pratico F: DTAlite: A queue-based mesoscopic traffic simulator for fast model evaluation and calibration. Cogent Eng. 2014; 1(1): 961345. Publisher Full Text\n\nRamamohanarao K, Xie H, Kulik L, et al.: SMARTS: Scalable microscopic adaptive road traffic simulator. ACM Trans Intell Syst Technol. 2016; 8(2): 1–22. Publisher Full Text\n\nXie H, Tanin E, Ramamohanarao K, et al.: Generating Traffic Data for Any City using SMARTS Simulator. SIGSPATIAL Special. 2019; 11(1): 22–28. Publisher Full Text\n\nReza I, Ratrout NT, Rahman SM: Calibration protocol for PARAMICS microscopic traffic simulation model: Application of neuro-fuzzy approach. Canadian Journal of Civil Engineering. 2016; 43(4): 361–368. Publisher Full Text\n\nKumar P, Shukla S: A Survey of Simulation Tools for VANET. Journal of Analysis and Computation (JAC). 2019; XII(I): 1–12. Reference Source\n\nZeidler V, Buck SH, Vortisch P: Simulation of Autonomous Vehicles Based on Wiedemann’s Car Following Model in PTV Vissim. In Proceedings of the 2019 98th Annual Meeting of the Transportation Research Board (TRB). 2019; 13–17.\n\nWu J, Radwan E, Abou-Senna H: Determination if VISSIM and SSAM could estimate pedestrian-vehicle conflicts at signalized intersections. Journal of Transportation Safety and Security. 2018; 10(6): 572–585. Publisher Full Text\n\nSharma R, Vashisht V, Singh U: Modelling and simulation frameworks for wireless sensor networks: A comparative study. IET Wireless Sensor Systems. 2020; 10(5): 236–241. Publisher Full Text\n\nWeber JS, Neves M, Ferreto T: VANET simulators: an updated review. Journal of the Brazilian Computer Society. 2021; 27(1). Publisher Full Text\n\nToor AS, Jain AK: A survey on wireless network simulators. Bulletin of Electrical Engineering and Informatics. 2017; 6(1): 62–69. Publisher Full Text\n\nXie D, Li J, Gao H: Comparison and Analysis of Simulation methods for TSN Performance. In IOP Conference Series: Materials Science and Engineering. 2020; 768(5). Publisher Full Text\n\nBouras C, Gkamas A, Aniceto S, et al.: Comparison of LoRa Simulation Environments. In International Conference on Broadband and Wireless Computing, Communication and Applications. 2019; 374–385. Publisher Full Text\n\nZarrad A, Alsmadi I: Evaluating network test scenarios for network simulators systems. Int J Distrib Sens N. 2017; 13(10): 1–17. Publisher Full Text\n\nMahdi HF, Abood MS, Hamdi MM: Performance evaluation for vehicular ad-hoc networks based routing protocols. Bulletin of Electrical Engineering and Informatics. 2021; 10(2): 1080–1091. Publisher Full Text\n\nRajhi M, Madkhali H, Daghriri I: Comparison and Analysis Performance in Topology-Based Routing Protocols in Vehicular Ad-hoc Network (VANET). In 2021 IEEE 11th Annual Computing and Communication Workshop and Conference, CCWC 2021. 2021; 1139–1146. Publisher Full Text\n\nSenapati BR, Khilar PM, Swain RR: Fire Controlling Under Uncertainty in Urban Region Using Smart Vehicular Ad hoc Network. Wirel Pers Commun. 2021; 116(3): 2049–2069. Publisher Full Text\n\nAbdulhafidh Dael F, Yavuz U, Jabbar WA: Performance Evaluation of DYMO and OLSRv2 Routing Protocols in VANET. International Journal of Integrated Engineering. 2020; 12(1): 50–58. Publisher Full Text\n\nChehri A, Chehri H, Hakim N, et al.: Realistic 5.9 GHz DSRC Vehicle-to-Vehicle Wireless Communication Protocols for Cooperative Collision Warning in Underground Mining. Smart Innovation, Systems and Technologies. 2020; 185: 133–141. Publisher Full Text\n\nFahad TO, Ali AA: Compressed fuzzy logic based multi-criteria AODV routing in VANET environment. International Journal of Electrical and Computer Engineering (IJECE). 2019; 9(1): 397. Publisher Full Text\n\nShafi S, Venkata Ratnam D: A Cross Layer Cluster Based Routing Approach for Efficient Multimedia Data Dissemination with Improved Reliability in VANETs. Wireless Pers Commun. 2019; 107(4): 2173–2190. Publisher Full Text\n\nMalik S, Sahu PK: A comparative study on routing protocols for VANETs. Heliyon. 2019; 5(8): e02340. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbdul Razak SFB, Yogarayan S, Azman A, et al.: V2V simulators. Zenodo. 2021. http://www.doi.org/10.5281/zenodo.5637802"
}
|
[
{
"id": "143137",
"date": "19 Jul 2022",
"name": "Lionel Nkenyereye",
"expertise": [
"Reviewer Expertise Vehicular technology",
"edge computing",
"and software-defined networks"
],
"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 surveys the existing simulation framework for connected vehicles. The works proposed a method based on PRISMA Extension for a Scoping Review. The previous study table is short but relevant contributions are presented. These contributions summarize the routing concept, dissemination of the information, and performance measures in terms of throughput and packet delivery ratio.\nThe following comments could enhance the quality of this work:\nIn the conclusion, I request the authors to specify the type of mobility generator and mobility network that are efficient for real-time system modelling.\n\nAt the Screening section, authors focus much on VANET. How about other vehicular network that support V2V? For instance software-defined based VANET or vehicular Edge/Fog technology or Vehicular Cloud network in their Search string. Is the current work includes different type of vehicular technology in general? Therefore, rewrite in the introduction that this study focuses particularly on VANET.\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? Partly",
"responses": [
{
"c_id": "9263",
"date": "16 Feb 2023",
"name": "Siti Fatimah Abdul Razak",
"role": "Author Response",
"response": "The paper is mainly focusing on VANET deployment. The introduction has been revised as suggested (page 2 and 3). The conclusion has been revised to specify the type of mobility generator and mobility network that are efficient for real-time system modelling (page 9)."
}
]
},
{
"id": "158671",
"date": "04 Jan 2023",
"name": "Mahmoud Zaki Iskandarani",
"expertise": [
"Reviewer Expertise Intelligent Transportation Systems",
"Artificial Intelligence",
"Mobile and wireless Communication",
"Sensors and systems."
],
"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 attempts to produce a guidance into the most appropriate simulators for V2V, and in general V2X communications. This effort is a good effort and in the right direction in terms of what is witnessed of V2X developments under cooperative driving. However, the authors can benefit from the following comments:\nAssigning the most appropriate simulator for a V2V or V2X application with in depth correlative analysis linked to different scenarios and protocols.\n\nComparative analysis of the used simulators per specific published article or group of articles sharing common objective, and the extent of benefit and development achieved using such simulator.\n\nMore detailed discussion and more comprehensive conclusion and recommendation will greatly improve the 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? Partly\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly",
"responses": [
{
"c_id": "9264",
"date": "16 Feb 2023",
"name": "Siti Fatimah Abdul Razak",
"role": "Author Response",
"response": "The applicability of V2V or V2I (V2X) has been added in Table 2 (page 7). The comparative analysis has been highlighted in Table 3 (page 7). The conclusion has been revised as suggested (page 9)."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1265
|
https://f1000research.com/articles/9-1258/v1
|
19 Oct 20
|
{
"type": "Research Article",
"title": "Healthcare providers’ perspective on barriers to optimal HIV index testing: an interview-based study",
"authors": [
"Cibangu Katamba"
],
"abstract": "Background: HIV testing services (HTS) and antiretroviral therapy have seen a substantial scale-up. Poorly targeted HTS have continued to miss people living with HIV who do not know their HIV status. This requires new and targeted approaches to reach undiagnosed people with HIV, such as HIV partner services. The aim of this study was to assess the barriers to optimal index testing for improved HIV testing yield in Lusaka, Zambia. Methods: One-to-one interviews were conducted with index testing providers to explore provider-related and client-related barriers to testing, and document other experiences arising during the process of HIV index testing. An interview guide was utilized for consistency of information collected. Results: Provider related challenges included inadequate elicitation skills among healthcare workers; low number of volunteers trained in index testing; inadequate index testing knowledge among staff; limited elicitation of index partners to only wife and husband (not eliciting all sexual partners); and limited transport for contact tracing. On the other hand, client-related challenges were mobile communities due to seasonal activities such as cross boarder trades, sex work and farming; some key populations and adolescent index clients do not have contact details for their casual relationships; provider’s age or gender difference for some clients; missing details on client locator forms or wrong details provided; and limited space dedicated to conduct elicitation of index clients. Discussion: The challenges identified have future implications for index partner testing. These barriers were also gender and age specific. HIV testing services need to adapt to the social context of Zambia where HIV-related stigma and discrimination is still persistent and overwhelming. As Zambia makes significant progress towards achieving HIV epidemic control, more effort is needed to reach specific high risk but hard to reach populations in HIV programs, such as men and adolescent girls and young women.",
"keywords": [
"Healthcare",
"Provider",
"Barriers",
"HIV",
"Index Testing"
],
"content": "Introduction\n\nGlobal HIV testing services (HTS) and antiretroviral therapy have seen a substantial scale up1. About 15 years ago, only an estimated 12% of the global population who required an HIV test were tested, and only 10% of people living with HIV (PLHIV) knew their HIV status in Africa1. It is now estimated that about 80% of PLHIV, and nearly 85% of PLHIV in southern and eastern Africa, know their HIV status, by the end of 20191. While this progress has been registered, poorly targeted HTS have continued to miss PLHIV who do not know their HIV status in many settings1. This requires new and targeted approaches to reach undiagnosed people with HIV, such as HIV partner services1.\n\nA study conducted in Zambia revealed that index testing coupled with targeted community-led HTS are useful strategies to diagnose men living with HIV2. Many studies have shown that index partner testing has the potential to increase HTS uptake, and identify and diagnose HIV infected partners (yield ranging from 35% to 62% without reported intimate partner violence)3. However, there are barriers to effective HIV index testing, for instance difficulties in notifying past or casual partners for both male and female index cases4. Disease symptoms are a motivating factor for HIV testing for men as well as women. Studies have shown that gender determinants, such as tolerant attitudes about intimate partner violence and unequal power dynamics within relationships, have noticeable effects for men and women on deciding to get tested for HIV5. Gender-specific barriers for female index clients to successful referral include the following: women face gender roles and inequalities in relationships such as lack of education, lack of resources or ability to access services; fear of abandonment, violence or other abuse associated with partner notification4,6,7. Therefore, they may need additional support to overcome challenges in the partner notification process. Antenatal care exposure makes women more likely to get tested for HIV. For men, especially those in sub-Saharan Africa, the following challenges to HIV testing and disclosure have been previously noted: stigma, gender and social roles prescribing that men should be healthy, strong, and dominant8,9. Studies have shown that men, compared to women, underestimate their level of risk of HIV infection7. However, once men are tested, they may be more likely to disclose their HIV status7. Some men believe that their role of breadwinner for the family protects them from rejection when disclosing their HIV positive status10.\n\nEffective approaches to HIV testing are needed to reach undiagnosed people and link them to HIV care and treatment as part of the UNAIDS 90-90-90 goals. Understanding barriers to index testing is crucial for planning appropriate interventions to improve HIV testing yield and to provide appropriate care for both index clients and their partners. In this context, the aim of this study was to assess the barriers to optimal index testing for improved HIV testing yield in Lusaka, an urban district of Zambia. The specific objectives are: 1) to understand the perceived facilitators and barriers to HIV partner testing from the perspective of the health-care provider; 2) to propose interventions necessary for improved HIV case finding.\n\n\nMethods\n\nAn explanatory qualitative study design was used. One-to-one interviews were employed to explore index testing providers’ views on barriers and other experiences arising during the process of HIV index testing. An interview guide was utilized for consistency of information collected. The aim of this study was to assess the barriers to optimal index testing for improved HIV testing yield in Lusaka urban district of Zambia.\n\nThe study was facility based, conducted at Matero First Level Hospital, Matero Main Clinic, and George Health Centre in Matero sub-district of Lusaka, Zambia. This study was conducted between January and March 2020.\n\nParticipants were interviewed face-to-face during their free time to avoid disruption of services.\n\nHIV index testing providers involved in patient care and management were interviewed. A total of 18 key informant interviews were conducted with two medical officers, two head of HIV testing services departments, three health systems strengthening nurses, five index community liaison officers, and six index testing counselors). A saturation of findings was used to guide the sample size.\n\nEighteen participants in the qualitative component of the study were selected on a convenience basis from the index testing services providers. There are more female HTS providers than their male counterparts in Matero sub-district; therefore, one third quota was given to male participants to ensure gender representability. The index providers were selected from male and female index testing services providers who have been providing index testing for more than one year.\n\nIndex providers were selected by the principal investigator (PI) who is trained in qualitative and quantitative studies for participation in a face to face interview on a convenience basis. A rough quota was given to each facility, balancing out male and female participants, and those providers who were invited to participate, agreed and consented were interviewed.\n\nEveryone approached to participate were interviewed. No repeat interviews were carried out. Field notes were made during and after the interviews (Underlying data11). The summary was read back to the participants to ensure validation.\n\nHIV index testing providers were interviewed by the PI. It was an onsite (at the medical facilities), face-to-face interview, conducted in English, and audio-recorded using an ‘audio-recorder’ application after obtaining consent from participants. Only the participant and the PI were present during the key informant interview. An interview guide (Extended data12) was used to explore the challenges and make suggestions for improving index contact testing outcome for HIV. The interview guide consisted of open ended questions and probes prepared for various healthcare providers.\n\nThe PI is a qualified male medical doctor and has a Master’s degree in Public Health. He is currently a PhD candidate, conducting research for his doctorate thesis in Public Health. The purpose of the research was explained to participant prior to the interview. Participants were provided information sheet to explain the purpose and usage of the study findings.\n\nAudio-recorded interviews were transcribed verbatim on the same day by the PI. A descriptive content analysis by manual coding was performed by two independent, trained researchers (HIV/TB mentors) to generate categories or themes. These were reviewed by the PI to avoid subjective bias and strengthen interpretive credibility. Any disagreements were resolved through discussion.\n\nParticipants gave their written informed consent to be interviewed on the understanding that data would be reported in de-identified form to prevent the identification of all key informants.\n\nPermission to conduct research was obtained from the Lusaka Provincial Health Office before the commencement of the study. Ethical clearance was sought and obtained from the ERES Converge Zambian Institutional Review Board (IRB; Ref. No. 2019 – Nov – 009). Authority to conduct research was also sought from the National Health Research Authority.\n\nReporting of the methods and results comply with the consolidated criteria for reporting qualitative studies (COREQ) checklist13. A completed COREQ checklist is available here14.\n\n\nResults\n\nA total of 18 participants (index providers) were interviewed; 13 women and 5 men. Table 1 presents demographic characteristics of participants.\n\nMFLH, Matero First Level Hospital; MMAIN, Matero Main Clinic; George, George Health Centre; HTS, HIV Testing Service\n\nMajor activities of an index testing provider in the past one year included ensuring that all newly tested HIV clients were listed, counseling was provided to them on partner notification service, elicitation of sexual contacts, contact tracing, testing of contacts and linkage of positive contacts to care.\n\n“My major activities concerning index is if we find a positive, making sure that the client is indexed and elicitation is supposed to be done also. If the client says that I have got sexual contacts, I am supposed to book those sexual contacts and follow them either at home or at the facility if the client agrees to bring them”. (Participant 1)\n\nIndex testing workers worked together with other providers and implementing partners to provide index testing. Specifically, index testing providers from respective facilities worked hand in hand with program implementation partners to ensure activities were coordinated.\n\n“For index testing to work, we need a multidisciplinary team. In working with other, being a nurse by profession, I need to work with counselors as I also provide testing. We need to identify people who are very skillful, who can spend more time with the client to get information on their contacts”. (Participant 16)\n\nThere were many successes or experiences reported by respondents arising from index testing. Providers were open to share their experiences and lessons learned while providing services.\n\n“My experience or successful story it was one time when we had a session with a certain index client. That client was able to open up and give us 6 contacts of whom 5 tested positive and 1 negative. That person was polygamous”. (Participant 1)\n\n“Through index testing, there was a certain man who had tested 7 years ago. When he came he was not feeling well. After we tested he said in the eyes of the public he only has one sexual partner (his wife). According to him he is a God fearing man. After eliciting we discovered that he had 3 extra girlfriends. Little by little after interacting with him those names were given to me. After that he said he may not be able to disclose to them because they will suspect that he may have infected them….” (Participant 12)\n\nBarriers and facilitators to effective index testing were also identified by respondents.\n\n“The index client may give you the correct contact information. But the contact might have lied to the index client. …hard to reach clients that are out of town (Lusaka) or out of the country. …the contact, when followed, two of them have really brought up their religious believes strongly: “you are not going to test me, I cannot do an HIV test, I don’t believe in HIV”. (Participant 7)\n\n“Like earlier mentioned, index testing is a concept that is new. It is a concept that was not long ego embedded in our understanding as healthcare providers. One of the barriers in delivering this service has been its acceptance among healthcare workers or among facility based workers as well as community based workers. Because we have had to ask on sexual contacts from clients that come out positive. And looking at our culture, it is one thing that we don’t easily talk about to bring out sexual relations to clients. Many staff tend to bring out they traditions, they cultural believes, they religious believes when it comes to them getting sexual partners. It has limited the number of sexual partners that we are getting from the client…” (Participant 16)\n\nSpecific challenges related to index clients’ identification and elicitation of index contacts. Some clients did not open up easily (as this was the first time to meet a counselor) or immediately and others were not providing full contact information. This was usually resolved within two weeks of follow-up, as clients become more comfortable interacting with ART providers.\n\n“One of the challenges of finding positives when doing index is most clients do not open up easily. Being the first time of meeting you as a counselor they can’t open up just there and then. And then the other thing when it comes to elicitation, we elicit the client, you will find that when calling the sexual contacts, you are asked questions like where did you get my contact from? It is not everyone who will agree right there and then. It is not a one-day thing if I may say”.\n\n“… elicitation on the other hand is a skill. So one big challenge is they are very few staff who are skillful when it comes to elicitation. So you will find out that if you have a client in front of you, but if you don’t have the skill and if you do not perfect this skill, the client will be in front of you but you will not be able to get out this information from them”. (Participant 16)\n\nSpecific challenges related to testing of index contacts. Various logistic challenges were noted with regards to tracing and testing of contacts.\n\n“Number 1, transport must be readily available at all times. Number 2, … in short I can say logistics must be available at all times. If one says right now I have left my wife at home. If at all you are ready let’s go together so that you can test her. You will find that we don’t have transport at the facility at that particular time. The time you will be calling the client maybe he will say this time she is not around, maybe she is busy with something else. We know these clients; they’ve got a lot of things to do beside accessing services from the hospital”. (Participant 1)\n\nPerceived factors causing/contributing to sub-optimal index testing were reported as gender, age, stigma, social status, health system, facility structure, staff, and skill level.\n\n“…when it comes to age, this is another challenge because elicitation is also age sensitive. By this I mean you cannot get a youth to elicit from a senior citizen for example who is maybe above 65. They will perceive the youth as a young boy or a young girl who has no concept of living, and they would close up on giving information….” (Participant 16)\n\n\nDiscussion\n\nIn this research, barriers to accessing HTS were divided into provider- and client-related challenges.\n\nProvider-related challenges: Inadequate elicitation skills among the newly trained community healthcare workers, treatment supporters and counsellors; trained providers such as healthcare workers not fully involved; low number of volunteers trained in index testing; inadequate index testing knowledge among staff; limiting elicitation of index partners to only wife and husband (not eliciting all sexual partners); and limited transport for contact tracing (long distances to reach contacts).\n\nClient-related challenges: Mobile communities due to seasonal activities such as cross boarder trades (e.g. truck drivers), sex work and farming; some index clients do not live in the same district/town as the index clients; key populations and adolescents index clients do not have contact details for some of their contacts; missing details on client locator forms or wrong details provided; and limited space dedicated to conduct elicitation of index clients (lack of privacy).\n\nThese findings are in keeping with evidence from other studies2–5, that showed that non-disclosure of HIV status (due to fear of marital discord), non-disclosure and under-disclosure of the number of sexual partners by the index clients, fear of negative consequences, difficulties notifying past or casual partners, geography/remote partners, and risk perception were major barriers for using testing services. Key populations and people with casual partners were less able or willing to identify partners. Barriers to partner notification services also included concerns around privacy/confidentiality and intimate partner violence. Lack of awareness of risk for HIV infection/misconceptions; structural, psychological, financial, were barriers to being tested.\n\nFollowing the interviews with key informants, the following were proposed as solutions to address identified challenges:\n\n(1) Peer pairing approach using experienced counselors and hand holding mentorship; Pairing treatment supporters to newly tested HIV positives clients for index testing and treatment support;\n\n(2) Training facility-based volunteers and healthcare workers (Nurses, Clinical officers, Medical officers etc.) in index testing;\n\n(3) Setting up network of counselors to reach contacts not in the same catchment as the index clients;\n\n(4) Provide transport to follow up clients (index contacts): additional vehicles needed or support transport refunds;\n\n(5) Identify and allocate dedicated space for elicitation using experience counsellors;\n\n(6) Improve appointment system: after hours, weekends and men’s clinics;\n\n(7) Ensure correct, complete and consistent documentation in all registers.\n\nSome studies have tackled the issues of barriers to successfully referring partners for testing4,9, but were not specific to gender or age. Alternative strategies to target and provide acceptable and accessible HIV testing services to gender and age-specific populations are addressed in this study. This study also addresses the gap of limited literature on HIV index testing in developing settings.\n\nWe used convenience sampling to explore barriers and facilitators of index testing. One other limitation was that the key informants in this research were only healthcare providers. The perspective of HIV positive clients themselves was not explored in this study to balance the information bias.\n\n\nConclusion\n\nThe challenges identified have future implications for index partner testing. These barriers were also gender and age specific. HIV testing services need to adapt to the social context of Zambia where HIV-related stigma and discrimination is still persistent and overwhelming. HIV programs need to explore and address barriers to HIV partner testing services to maximize HIV case identification. As Zambia makes significant progress towards achieving HIV epidemic control, more effort is needed to reach specific high risk, but hard to reach populations in HIV programs, such as men, adolescent girls and young women.\n\n\nData availability\n\nThe underlying data for this study is the audio recordings of the participants. Since participants may be identified from their voices, the data cannot be shared in order to protect participant identity. De-identified field notes are instead provided, along with quotes in the article, as intermediary data. If readers would like to access the underlying data, they can contact the corresponding author who will facilitate access to the data. Conditions for access: submission of a proposal for how researchers will use the data.\n\nHarvard Dataverse: Replication Data for: HEALTHCARE PROVIDERS’ PERSPECTIVE ON BARRIERS TO OPTIMAL HIV INDEX TESTING, https://doi.org/10.7910/DVN/FHNY2V11.\n\nThis project contains the following underlying data:\n\n- Field Notes\n\nHarvard Dataverse: Replication Data for: HEALTHCARE PROVIDERS’ PERSPECTIVE ON BARRIERS TO OPTIMAL HIV INDEX TESTING, https://doi.org/10.7910/DVN/BUXS2X12.\n\nThis project contains the following extended data:\n\n- Interview guide.\n\nHarvard Dataverse: COREQ checklist for ‘Healthcare providers’ perspective on barriers to optimal HIV index testing: an interview-based study’, https://doi.org/10.7910/DVN/CFZX0N14.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgments\n\nThe author would like to thank the Lusaka Provincial Health Office (LPHO), the Lusaka District Health Office leadership, the Matero Health Management teams, and PEPFAR through the LPHO/CDC CoAg for their leadership and support during this study. Special thanks to my colleagues (medical mentors) for their support during the creation of themes. I also thank the study participants who consented and participated in this investigation. I am also grateful to Dr. Monde Muyoyeta for her supervision, guidance and support.\n\n\nReferences\n\nWorld Health Organization: Consolidated guidelines on HIV testing services for a changing epidemic. 2019. Reference Source\n\nMwango LK, Stafford KA, Blanco NC, et al.: Index and targeted community-based testing to optimize HIV case finding and ART linkage among men in Zambia. J Int AIDS Soc. 2020; 23 Suppl 2(Suppl 2): e25520. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPartner and Family based Index case testing. A Standard Operating Procedure (SOP). Reference Source\n\nPlotkin M, Kahabuka C, Christensen A, et al.: Outcomes and Experiences of Men and Women with Partner Notification for HIV Testing in Tanzania: Results from a Mixed Method Study. AIDS Behav. 2018; 22(1): 102–116. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGari S, Malungo JRS, Martin-Hilber A, et al.: HIV testing and tolerance to gender based violence: a cross-sectional study in Zambia. PLoS One. 2013; 8(8): e71922. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: HIV status disclosure to sexual partners: rates, barriers, and outcomes for women. Geneva; 2003. Reference Source\n\nObermeyer CM, Osborn M: The utilization of testing and counseling for HIV: a review of the social and behavioral evidence. Am J Public Health. 2007; 97(10): 1762–1774. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSelvaraj K, Kumar AMV, Chawla KS, et al.: Are partners of HIV-infected people being tested for HIV? A mixed-methods research from Gujarat, India. Public Health Action. 2017; 7(1): 46–54. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSkovdal M, Campbell C, Madanhire C, et al.: Masculinity as a barrier to men's use of HIV services in Zimbabwe. Global Health. 2011; 7: 13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nObermeyer CM, Sankara A, Bastien V, et al.: Gender and HIV testing in Burkina Faso: an exploratory study. Soc Sci Med. 2009; 69(6): 877–884. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCibangu K: Replication Data for: HEALTHCARE PROVIDERS’ PERSPECTIVE ON BARRIERS TO OPTIMAL HIV INDEX TESTING. Harvard Dataverse, V1, 2020. http://www.doi.org/10.7910/DVN/FHNY2V\n\nCibangu K: Replication Data for: HEALTHCARE PROVIDERS’ PERSPECTIVE ON BARRIERS TO OPTIMAL HIV INDEX TESTING. Harvard Dataverse, V1, 2020. http://www.doi.org/10.7910/DVN/BUXS2X\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 Heatlh Care. 2007; 19(6): 349–57. PubMed Abstract | Publisher Full Text\n\nHarvard Dataverse, Cibangu K: Replication Data for: Healthcare providers’ perspective on barriers to optimal HIV index testing: an interview-based study. Harvard Dataverse, V1, 2020. http://www.doi.org/10.7910/DVN/CFZX0N"
}
|
[
{
"id": "75516",
"date": "16 Dec 2020",
"name": "Chido Dziva Chikwari",
"expertise": [
"Reviewer Expertise Epidemiology: HIV and Sexual and Reproductive 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 is a useful paper that reflects some of the barriers and facilitators of index linked HIV testing which is a strategy that has potential to increase the yield of undiagnosed HIV. There are however, some comments for the Author below.\nAbstract\nDiscussion section includes new findings not mentioned in the results such as variation by gender and age. May be best to move to the results section.\n\nThe conclusions mentioned in the abstract are not in line with the results presented in the abstract. There is a need for the two to be aligned. See comment above. Additionally, stigma and discrimination not mentioned as a barrier in the results.\nManuscript Introduction\nPlease including timing of the study in Zambia - year.\n\nThere is no comparator for increasing yield of index partner testing that is reported in the introduction “Many studies have shown that index partner testing has the potential to increase HTS uptake, and identify and diagnose HIV infected partners (yield ranging from 35% to 62% without reported intimate partner violence)”. Is the increase in yield from 35%-65%?\n\nReference the UNAIDS 90-90-90 goals?\n\nMay be useful to define index testing as this term is not very common.\nMethods\nIn the data management and analysis section the author notes that any disagreements were resolved through discussion; who was this discussion with? The interviewees? Another study staff member?\nResults\nWould it be possible to summarise the demographic data provided in Table 1? Given the low number of participants from only two facilities, presenting the data in such a format could make it easy for the participants identity to be decoded.\n\nWere all the providers who were interviewed “index testing workers”? Are index testing workers different from Index testing providers? It may be beneficial to describe the different roles of the health workers.\nDiscussion\nIt appears the discussion is providing results in the first two paragraphs when instead it should be providing a summary. The split between provider and client related challenges should be introduced in the results rather than the discussion where findings should be summarised.\n\nFirst two paragraphs of the discussion are listing findings. These should be discussed rather than listed. The presentation here reads more like a results section.\n\nYour results do not present anything about key populations; however, you mention these in the discussion as part of your findings?\n\nThese barriers are listed in the discussion but not presented in the results. “Barriers to partner notification services also included concerns around privacy/confidentiality and intimate partner violence. Lack of awareness of risk for HIV infection/ misconceptions; structural, psychological, financial, were barriers to being tested.”\n\nThe gender and age variations that are discussed in the conclusion are not presented on 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? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/9-1258
|
https://f1000research.com/articles/12-178/v1
|
15 Feb 23
|
{
"type": "Clinical Practice Article",
"title": "Autoimmune hepatitis in young Somalian men – experience from a German tertiary care center",
"authors": [
"Theresa Kirchner",
"Björn Hartleben",
"Sophia Köhler",
"Frank Schuppert",
"Irina Berger",
"Heiner Wedemeyer",
"Ingmar Mederacke",
"Theresa Kirchner",
"Björn Hartleben",
"Sophia Köhler",
"Frank Schuppert",
"Irina Berger",
"Heiner Wedemeyer"
],
"abstract": "Background: Autoimmune hepatitis (AIH) is a rare liver disease predominantly affecting women. Data on AIH in African patients is rare. A previous study from the UK reported an unusual form of AIH in Somalian patients. Methods: To examine whether this form of AIH can also be found in Germany, we screened the database of a major tertiary liver transplantation center. Results and conclusions: Among 17 Somalian patients presenting to our hospital between 2008 and 2021 three male patients were admitted with liver disease. All three of them were diagnosed with AIH. Here, we present the clinical courses highlighting diagnostic challenges and the particular severity of liver disease. These cases emphasize the need to consider AIH as an important differential diagnosis in Somalian patients presenting with new onset of hepatopathy.",
"keywords": [
"Autoimmune hepatitis",
"Somalian",
"liver disease",
"hepatopathy",
"liver transplantation"
],
"content": "Introduction\n\nAutoimmune hepatitis (AIH) is a rare disease characterized by increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hypergammaglobulinemia (elevated immunoglobulin G, IgG) and interface hepatitis or/and lobular necroinflammation in liver biopsy.1 The diagnosis of AIH is based on circulating antibodies (antinuclear antibodies (ANA), smooth muscle antibodies (SMA), liver kidney muscle antibodies (LKM)) and exclusion of other causes of liver disease including viral hepatitis. Diagnostic scoring systems from the International Autoimmune Hepatitis Group (IAIHG) have been created to established the diagnosis of AIH.2\n\nAIH mainly affects women and is often diagnosed between the age of 40 to 70. Genome wide association studies (GWAS) associate HLA A1, B8, Cw7 and DR3 haplotype with AIH in European patients.1,3 Significant diversity in disease severity has been identified for autoimmune disorders in general and AIH before.3 Yet, data on AIH in non-European/non-Asian patients is very limited, especially for African patients. Compared to European AIH patients, non-European patients present at younger age, with a cholestatic laboratory pattern and a poorer response to standard therapy.4 A recent study from England reported a small cohort of six Somalian men with an unusual form of AIH with cholestatic features.3 These patients responded poorly to standard immunosuppressive therapy. In this context, we recently treated two Somalian patients with AIH in our tertiary care center. The aim of this study was to identify additional Somalian patients with liver disease in our electronic hospital database and analyze the cause of liver disease, the clinical course and outcome of these patients.\n\n\nMaterial and methods\n\nWe screened our electronic hospital database for patients presenting to our tertiary care hospital (Hannover Medical School (MHH)) between 2008 and 2021 and with place of birth in Somalia. A total number of 17 patients (47.1% male) were identified. Of these patients, 14 had no history of liver disease or elevated transaminases at the time of presentation and were excluded from this study. Three patients met the inclusion criteria and were considered for this analysis.\n\nClinical and laboratory patient data were assessed by retrospective chart review. Available liver biopsies were reviewed by an experienced liver pathologist.\n\nWritten informed consent for publication of their clinical details and histological images was obtained from the patients. The study followed the principles of the Declaration of Helsinki.\n\n\nResults\n\nAll three male patients were referred from other hospitals to our Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology for further diagnostic and therapy. Two of the three patients presented with acute onset of hepatitis, while one patient had a history of autoimmune hepatitis and a recent episode of variceal bleeding. Detailed patients’ characteristics are presented in Table 1.\n\nA 38-year-old Somalian man was admitted to our hospital shortly after acute variceal bleeding that required transfusion of packed red blood cells. The initial diagnosis of AIH type 1 was made in another hospital five years prior to presentation. At this time, antibody screening revealed an ANA of 1:80 and a SMA 1:80 with an elevated IgG (17.2 g/l) and liver biopsy showed fibrosis but no cirrhosis and typical features of AIH including lymphoplasmacellular inflammation (Figure 1A). Immunosuppressive treatment with azathioprine (1.5 mg/kg per os once a day) was initiated. The patient denied any herbal drugs or hepatotoxic medication history and there was no family history of liver diseases or alcohol abuse.\n\nA. Liver biopsy of case no 1 shows fibrosis with incomplete cirrhosis, ductular reaction and lymphoplasmacellular inflammation. B. Liver biopsy of case no 2 shows subacute subtotal necrosis of the liver parenchyma (95%) with fibrosis, ductular reaction, hepatocyte rosettes and lymphoplasmacellular inflammation. C. Liver biopsy of case no 3 shows ballooning of hepatocytes, apoptosis and portal plasmacellular inflammation. No modifications have been made to the images.\n\nAt the current admission the patient was treated with azathioprine and showed no relevant elevation of transaminases while cholestasis parameters were slightly elevated (Table 1). Liver function corresponded to Child Pugh Score B. Total IgG was within normal range under immunosuppressive therapy. Abdominal ultrasound and computed tomography revealed signs of liver cirrhosis and a thrombosis of the mesenteric and portal vein and therapeutic anticoagulation was initiated. As the patient suffered from recurrent episodes of variceal bleeding, we implanted a transjugular intrahepatic portosystemic shunt (TIPS). During the clinical course the patient developed an increase of transaminases (AST 284 U/l, ALT 131 U/l, AP 154 U/l, GGT 95 U/l, total bilirubin 18 μmol/l) and we intensified immunosuppression by adding prednisolone at a dose of 20 mg/day (per os once a day) with good response. After TIPS placement the patient developed recurrent pleural effusion which could not be managed by diuretics alone. A pleurodesis was performed followed by the placement of a long-term indwelling pleural catheter.\n\nIn the following months the patient was readmitted several times for complications of liver cirrhosis including infection (spontaneous bacterial peritonitis, infection of pleural effusion) and hepatic encephalopathy. Esophageal varices improved after TIPS insertion. IgG was within normal range under immunosuppressive therapy. However, the general condition of the patient worsened over time. While the patient presented with another episode of acute-on-chronic liver failure and a Model of End Stage Liver Disease (MELD)-Score of 32 he was evaluated for liver transplantation. There were no contraindications for solid organ transplantation. He was listed for liver transplantation and successfully transplanted (extended right lobe) six months after he presented to our hospital for the first time.\n\nA 53-year-old Somalian man with acute-on-chronic liver failure was admitted to our hospital for further investigation. A diagnosis of liver cirrhosis was made in another hospital some days prior to presentation. However, the cause of liver cirrhosis was still unknown. The patient reported no regularly or recent intake hepatotoxic medication/substances or alcohol abuse. There was no family history for liver diseases.\n\nInitial laboratory showed elevated liver enzymes and cholestatic parameters, laboratory MELD was 25. Liver function corresponded with Child Pugh Score C during acute decompensation. Serological markers showed no acute viral hepatitis but status post viral hepatitis B (HBsAg negative, anti-HBc positive). Rare liver diseases such as hemochromatosis or Wilson’s disease were excluded. SMA and ANA autoantibodies were detectable (Table 1) and total IgG was highly elevated. Liver biopsy showed liver dystrophy with 95% necrosis, histological features were comparable with AIH (Figure 1B). Based on the simplified AIH score2 AIH type 1 was diagnosed and we started an immunosuppressive therapy with prednisolone (1 mg/kg body weight intravenously once a day). Under immunosuppression liver enzymes, cholestatic parameters and IgG rapidly decreased additionally confirming the diagnosis of AIH. The patient was discharged with 60 mg prednisolone per os once daily. Four weeks later the patient presented in our outpatient clinic, liver enzymes further decreased (AST 46 U/l, ALT 102 U/l, GGT 933 U/l, AP 219 U/l, total bilirubin 38 μmol/l, IgG 19.24 g/l) and liver function partly recovered (INR 1.3). Azathioprine (50 mg per os once daily) was initiated and prednisolone was tapered.\n\nA young 24-year-old Somalian man was admitted to our hospital in 2018 for further investigation with a new onset of hepatopathy. There was no personal or family history of liver disease. He lived with his family and denied any medical or herbal medication history. Initial laboratory showed markedly elevated liver enzymes, elevated bilirubin and IgG with AP and GGT within normal range (Table 1). Laboratory studies for AIH related autoantibodies revealed a positive SMA and ANA. A liver biopsy performed five months prior to presentation in an external hospital showed portal plasmacellular inflammation consistent with drug-induced liver injury (DILI) or autoimmune hepatitis. An interferon gamma release assay showed a positive result so immunsuppressive therapy had not been started until admission to our hospital. Based on all available results, we calculated the revised AIH score5 with 15 points and made the diagnosis of AIH type 1. Immunosuppressive therapy with prednisolone (1 mg/kg bodyweight/day per os) was started, liver enzymes and bilirubin decreased and the patient was discharged.\n\nIn the subsequent months in an outpatient setting azathioprine (dose unknown) was initiated. Given that a latent tuberculosis was diagnosed isoniacide (INH) prophylaxis was co-administered (300 mg/day per os). One year later the patient presented with a flare of AIH after not taking his immunosuppressive treatment on a regular basis. Steroids were intensified (100 mg/day per os) and the dose of azathioprine was increased (200 mg/day per os), INH prophylaxis was discontinued. Another six month later the patient presented with a flare of AIH and decompensated liver cirrhosis to an external hospital. Whether the patient took his medication on a regular basis was unclear. Steroids were started (100 mg/day intravenously) and one day later he was transferred to our clinic. Liver enzymes (AST 210 U/l, ALT 221 U/l) and total IgG were elevated (50.8 g/l). Shortly after admission to our hospital the patient developed a status epilepticus for unknown reason and was admitted to our intensive care unit. In the following days he developed respiratory failure with the detection of Streptococcus pneumonia in bronchoscopic culture, PCR for M. tuberculosis was negative. Clinical condition further deteriorated (acute respiratory distress syndrome (ARDS), acidosis, intravascular hemolysis) and the patient subsequently died.\n\n\nDiscussion\n\nAIH is a differential diagnosis in every new onset hepatopathy. The diagnosis is based on several circulating autoantibodies, hypergammaglobulinemia, the exclusion of other causes of liver disease and liver biopsy showing typical histological findings. Two scores are used in clinical practice to determine the likelihood of AIH. While the revised AIH score includes female gender in the scoring system, the simplified AIH score does not consider gender at all.2,5 In addition, the prevalence of AIH is higher in western Europe and north America and significantly lower in Asia and Africa.1,3 Therefore, AIH is often not considered as a likely differential diagnosis in African patients with elevated liver enzymes. However, at first presentation African American patients have more advanced stages of liver fibrosis than white American patients.6 In line with this observation, data from the UK found that Black patients presented at younger age and with higher IgG levels than white patients.7 A retrospective study from a hospital in the US which serves indigent and under-resourced communities identified race/ethnicity as an independent risk factor for AIH.8 Taken together, AIH needs to be considered as a differential diagnosis not only in White women but also in patients of African origin.\n\nIn this context, D’Souza et al. published a case series that analyzed the clinical, histological and immunological features of AIH in young Somalian men.3 The authors identified six patients (all male) from Somalia (all immigrants who had lived in the UK for the last six years) by scanning their histopathology database. Similar to the aforementioned studies and our three individuals, these patients were younger at presentation (median age 37 years) than the European control group (median age 55 years). There was a trend toward more advanced liver disease at presentation in Somalian patients (median ISHAK fibrosis 2.5 compared to 2 in Europeans). Biochemical cholestasis (AP greater than twice the upper normal limit) was observed in 66% of the Somalian patients and histopathological findings consistent with cholestasis were detected in 50% of patients, in contrast there was only one European patient with evidence of biochemical cholestasis. While initial therapy with prednisolone and azathioprine was effective in 8/10 European AIH patients, only 1/6 Somalian patients had a treatment response. HLA typing in this study revealed classical autoimmune associated allotypes in the European patients (HLA A1, B8, Cw7, DR3 or DR4).1,3 In contrast, Somalian patients shared different HLA allotypes (HLA B7, DR8, DQ2 and DQ4).\n\nAnother study by Zolfino et al. identified twelve patients from Africa (six patients), Asia (five patients) and Arabia (one patient) with AIH from an AIH-patient database with a median age of 30 years at presentation.4 Of those nine (75%) had a cholestatic serum biochemistry and three had histological findings comparable to PBC or a cholangiographic evidence of PSC. Complete biochemical response to standard immunosuppressive therapy was detectable in only four patients (33%), while five patients (42%) had no response to standard therapy. Overall, four of the 12 patients underwent liver transplantation for intractable disease. Zolfino et al. compared the twelve patients to a group of 130 European patients with AIH. In contrast to Yang et al.1 the non-European patients were younger at presentation, presented with cholestatic biochemistry and morphological biliary features more frequently. In addition, they showed poorer response to standard immunosuppressive therapy.\n\nThe patients that were identified in our tertiary care hospital are comparable to the cases series mentioned before. Our Somalian patients also suffered from advanced liver disease (one required liver transplantation, another patient had progression towards decompensated liver cirrhosis in less than two years) at a young age (median age of 37). No Somalian women with AIH were identified in our tertiary care center and no relevant overlap syndrome was observed in our patients. In line with the previous report by D`Souza et al, one of our patients (no 2) showed also elevated cholestatic enzymes. The typical HLA genotypes were not detected in our cohort. The treatment response in our patients was different. Although patient 1 had a biochemical response, he subsequently developed hepatic decompensation with variceal bleeding and ascites requiring TIPS insertion and subsequently liver transplantation. Both, patients 2 and 3 had a biochemical response to standard immunosuppressive therapy. However, patient 3 was not compliant resulting in several flares of AIH with progression to liver cirrhosis in less than two years. While all three patients had possible AIH according to the revised/simplified AIH score, autoimmune hepatitis can be also be associated with the intake of certain drugs or herbal medicine.9 In this context, there are reports that Khat chewing is associated with liver disease in Somalian men,10 while others question this observation.11 Khat is a herbal product, and a study from Ethiopia observed a significant association between chewing khat and the risk for developing chronic liver disease. Unfortunately, our retrospective study could not rule out khat intake by all three patients.\n\nAn obvious limitation of this retrospective study is that there is no systematic follow up and that some patients may have been missed when the country of birth was not documented.\n\nIn summary, AIH should be considered in every new onset hepatopathy, especially when viral hepatitis is excluded. AIH in non-European patients is different. Somalian patients with AIH are younger at presentation and show a severe disease that may poorly respond to standard immunosuppressive therapy. AIH treatment of non-European patients requires a more aggressive and maybe alternative treatment. The different clinical features and treatment regimens should be considered in our multicultural society.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and histological images was obtained from the patients.",
"appendix": "Data availability\n\nAll relevant data is presented in the manuscript without restrictions. De-identified data cannot be publicly shared because it contains potentially identifying and sensitive patient information. De-identified data is only available on reasonable request after an approval process involving the Ethics committee at our hospital and the corresponding author. The corresponding author can be contacted through: mederacke.ingmar@mh-hannover.de.\n\nFigshare: Autoimmune hepatitis in young Somalian men – experience from a German tertiary care center (Case reports), https://doi.org/10.6084/m9.figshare.21547887.v4. 12\n\nThis project contains the following underlying data:\n\n- Raw histological images.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nYang F, Wang Q, Bian Z, et al.: Autoimmune hepatitis: East meets west. J. Gastroenterol. Hepatol. 2015; 30(8): 1230–1236. PubMed Abstract | Publisher Full Text\n\nHennes EM, Zeniya M, Czaja AJ, et al.: International Autoimmune Hepatitis Group. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008; 48(1): 169–176. Publisher Full Text\n\nD'Souza R, Sinnott P, Glynn MJ, et al.: An unusual form of autoimmune hepatitis in young somalian men. Liver Int. 2005; 25(2): 325–330. PubMed Abstract | Publisher Full Text\n\nZolfino T, Heneghan MA, Norris S, et al.: Characteristics of autoimmune hepatitis in patients who are not of european caucasoid ethnic origin. Gut. 2002; 50(5): 713–717. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlvarez F, Berg PA, Bianchi FB, et al.: International autoimmune hepatitis group report: Review of criteria for diagnosis of autoimmune hepatitis. J. Hepatol. 1999; 31(5): 929–938. PubMed Abstract | Publisher Full Text\n\nVerma S, Torbenson M, Thuluvath PJ: The impact of ethnicity on the natural history of autoimmune hepatitis. Hepatology. 2007; 46(6): 1828–1835. Publisher Full Text\n\nde Boer YS , Gerussi A, van den Brand FF , et al.: Association between black race and presentation and Liver-related outcomes of patients with Autoimmune Hepatitis. Clin. Gastroenterol. Hepatol. 2019; 17(8): 1616–1624.e2. PubMed Abstract | Publisher Full Text\n\nLee B, Holt EW, Wong RJ, et al.: Race/ethnicity is an independent risk factor for autoimmune hepatitis among the san francisco underserved. Autoimmunity. 2018; 51(5): 258–264. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCastiella A, Zapata E, Lucena MI, et al.: 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\nPeevers CG, Moorghen M, Collins PL, et al.: Liver disease and cirrhosis because of khat chewing in UK somali men: A case series. Liver Int. 2010; 30(8): 1242–1243. PubMed Abstract | Publisher Full Text\n\nCoton T, Simon F, Oliver M, et al.: Hepatotoxicity of khat chewing. Liver Int. 2011; 31(3): 434. PubMed Abstract | Publisher Full Text\n\nKirchner T, Hartleben B, Koehler S, et al.:Autoimmune hepatitis in young Somalian men – experience from a German tertiary care center (Case reports). figshare. [Dataset]. Figure. 2022. Publisher Full Text"
}
|
[
{
"id": "197209",
"date": "25 Aug 2023",
"name": "Alessandro Granito",
"expertise": [
"Reviewer Expertise Autoimmune liver diseases"
],
"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 this study, the authors aimed to identify additional Somalian patients with an unusual form of autoimmune hepatitis (AIH) as previously described in Somalian patients. They describe three patients with AIH. Of interest, all three patients were male, and two presented with acute onset. The study is of interest and of clinical impact. However, to further improve the clinical relevance of the manuscript, some points should be addressed:\nThe authors properly highlighted the importance of considering AIH in the differential diagnosis of hepatopathy. However, in this regard, they should recall the importance of the diagnostic process based on the diagnostic scoring systems because AIH does not have a single diagnostic test: According to literature data, there are two different diagnostic scoring systems for the AIH diagnosis: the original (1999) that considers several parameters and the more recently proposed simplified AIH scoring system (2008) more simple and easy to use in clinical practice, as previously well described and compared1. Both scoring systems are accurate as the simplified score has been validated in clinical practice as previously demonstrated2.\n\nAnother important point worth mentioning is the age of AIH onset as geographical differences have been reported worldwide. In this regard, it is important to highlight that AIH may onset also in the elderly as previously described3, thus requiring to take into account AIH also in the differential diagnosis in elderly.\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? Partly\n\nIs the conclusion balanced and justified on the basis of the findings? Partly",
"responses": []
},
{
"id": "220075",
"date": "22 Nov 2023",
"name": "Paul Manka",
"expertise": [
"Reviewer Expertise Liver Transplantation and metabolic liver 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\nThank you for giving me the opportunity to review the paper by Kirchner and colleagues.\n\nIn their paper, they present the clinical course of three Somali patients in Germany with autoimmune hepatitis. This is of particular interest as these patients do not fit the risk profile for AIH in Europe. The cases are well presented and clearly explained. The paper sensitises the reader to consider AIH even in such cases with an unusual laboratory constellation for AIH. Therefore, I see no objection to its indexing.\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": []
}
] | 1
|
https://f1000research.com/articles/12-178
|
https://f1000research.com/articles/9-1212/v1
|
08 Oct 20
|
{
"type": "Research Article",
"title": "First report on molecular identification of Fusarium species causing fruit rot of mandarin (Citrus reticulata) in Bangladesh",
"authors": [
"Mohammed Faruk Hasan",
"Mohammed Asadul Islam",
"Biswanath Sikdar",
"Mohammed Faruk Hasan",
"Mohammed Asadul Islam"
],
"abstract": "Background: Fusarium rot is a newly introduced, devastating disease of citrus fruits. The current investigation was undertaken to characterize the microbes responsible for fruit rot in Citrus reticulata. Methods: Pathogens were isolated from infected citrus fruits using morphological and molecular approaches. For confirmation of the isolated fungi, polymerase chain reaction (PCR) amplification and internal transcribed spacer gene sequencing techniques were used. Results: The isolated fungus was grown on potato dextrose agar for three days and it produced clamydospores, hyphae and macroconidia. PCR amplification of isolated fungal DNA gave a 650 bp product. The sequence obtained from isolated fungi had 99.42% similarity with the reference Fusarium concentricum sequence in NCBI GenBank. The obtained sequence was deposited in GenBank (Accession No. MT856371). Two isolates showed virulence capability on fresh guava, sweet orange and tomato fruits, which confirmed species identification and Koch’s postulates. Artificially inoculated fungal species grown on tested fruits showed typical Fusarium species symptoms. Conclusions: Outcomes of the present study are beneficial for the detection of this detrimental disease in postharvest Citrus reticulata fruits. Further research is needed for the control of this economically important disease. This is the first study of fruit rot in Citrus reticulata caused by Fusarium in Bangladesh.",
"keywords": [
"Citrus reticulata",
"Fruit Rot",
"Fusarium sp.",
"PCR",
"ITS rRNA gene"
],
"content": "Introduction\n\nCitrus reticulata Blanco, commonly known as mandarin, is an oblate fruit resembling other oranges, belonging to the family of Rutaceae (Ahmed et al., 2014) and originating from hybridization with Citrus maxima (Wang et al., 2018). Citrus fruits contain different vitamins, minerals and trace elements. Citrus aurantifolia fruits are usually eaten fresh or used in salads and also used as flavoring in some liqueurs (Morton, 1987). In traditional medicine, they are also used for the treatment of rheumatoid arthritis and obesity (Srinivasan et al., 2008).\n\nFusarium species can cause superficial infections in plants and animals with high mortality in persistently and severely neutropenic patients (Dignani & Anaissie, 2004). Fusarium species are highly competent at contamination, possessing several mycotoxins (O’Donnell et al., 2009) and different fruits decay in different storage and postharvest conditions (Whiteside et al., 1988). Citrus fruits lose their market value due to damage incurred by different pathogens, including fungi and bacteria. Fusarium fruit rot is a very common and destructive problem for mandarin after harvesting and marketing in Bangladesh (Ahmed et al., 2014).\n\nThe novel Fusarium fungi were isolated and identified through applying advanced methods on different crops from different countries (Aktaruzzaman et al., 2018; Al-Najada & Gherbawy, 2015; Geiser et al., 2004; Sun et al., 2018). To develop biosafety and biosecurity management strategies, isolation, identification and characterization of fruit rot causing microbes are needed. The objectives of the study were to identify the microbes responsible for fruit rot of mandarins in Bangladesh using morphological and molecular approaches.\n\n\nMethods\n\nIn 2018, 10 rotten Citrus reticulata fruits (Figure 1A) were collected from fruit market stores in Rajshahi, Bangladesh. Out of 10 fruits, three showed symptoms of rot. Collected fruits were cleaned under running tap water to remove foreign agents and kept in a Biosafety Cabinet (Esco, Singapore). Moreover, the fruits were disinfested with 1% sodium hypochlorite (NaOCl) for 30 seconds, followed by five rinses in autoclave distilled water. Disinfested tissue was excised and plated on potato dextrose agar (PDA) (Hi-Media, India) at 35°C in the dark for three days. The colonies showing typical morphological characteristics including, colony color, pigmentation, growth rate and size of macroconidia of Fusarium species were selected (Hafizi et al., 2013) and isolated using the single spore technique (Chowdhury et al., 2019). Isolated colonies were transferred onto a Petri plate with PDA and incubated for seven days at 35°C in dark conditions. Isolates were grouped into two on the basis of morphological color (blackish color in the first group and whitish in the second group). Finally, one isolate from each of the two groups was selected for morphological analysis.\n\n(A) Infected mandarin fruit; (B) fungus growth; (C) clamydospores, hyphae, appressoria; and (D) conidia under the microscope from seven-day-old culture at 35°C on potato dextrose agar.\n\nThe selected fungal colony was characterized by macromorphological and micromorphological investigation (Al-Najada & Gherbawy, 2015). The isolate was sub-cultured in fresh PDA medium and three-day-old cultures were mounted using the lacto-phenol cotton blue (LPCB) staining method (Sathya et al., 2017). The mounted microscope slide was covered with a cover slip and conidia were observed under a light microscope (LABOMED LX400, USA) at 40X magnification.\n\nGenomic DNA was extracted from 15 gm of mycelia, collected from day three-day-old PDA cultures. DNA was extracted using a MaxMaxwell® 16 LEV Plant DNA Kit (Cat No. AS1420, Promega, USA) and DNA quantity and quality were checked using a NanoDrop 2000 Spectrophotometer (Thermo Scientific, USA).\n\nTo amplify the internal transcribed spacer (ITS) gene, primer pairs ITS4 (5′-TCCTCCGCTTATTGATATGC-3′) and ITS5 (5′-GGAAGTAAAAGTCGTAACAAGG-3′) were used (Gardes & Bruns, 1993; White et al., 1990). The PCR reaction was performed using the method described by Hassan et al. (2018) using hot start green master mix (dNTPs, Buffer, MgCl2, Taq Pol) (Cat # M7432, Promega, USA). A total of 25 µl reaction volume containing 2 µl genomic DNA, 2.5 µl 1X PCR buffer, 1.0 µl MgCl2, 1.5 µl dNTPs, 0.5 µl of each primer, 0.5 µl of Taq polymerase and 16.5 µl of deionized water was used. The PCR was programmed with an initialization step at 95°C for 2 min, followed by 32 cycles of denaturation at 95°C for 30 seconds, primer annealing at 48°C for 30 seconds, and extension at 72°C for 45 seconds and a final extension at 72°C for 10 minutes using a G02 GeneAtlas PCR machine (Astec, Japan). PCR products were run by horizontal electrophoresis (Mini-Gel, CBS Scientific, USA) on 1% agarose (Cat # V3125, Promega, USA) gel with 0.5% ethidium bromide solution (Cat # H5041, Promega, USA) in 1x TAE buffer (Cat # V4251, Promega, USA) using a 1kb DNA ladder (Cat # G5711, Promega, USA) as marker and visualized under alpha imager UV trans-illumination (Mini, Protein Simple, USA). PCR products were purified from the agarose gel, using the Wizard SV Gel and PCR Clean-Up System (Cat # A9281, Promega, USA).\n\nPurified PCR products were sequenced commercially by Sanger sequencing (Apical Scientific, Malaysia). Sequences were used in a search using the NCBI BLAST tool. Sequences were submitted to GenBank and compared with the GenBank database. A phylogenetic tree was constructed using MEGA 10 software using the neighbor joining method (Kumar et al., 2016; Tamura et al., 2004).\n\nVirulence competency of the isolate was carried out using the method described by Tafinta et al. (2013). The surfaces of mature, fresh guava, lemon and tomato were sterilized using water and 70% ethanol. The fruits were holed using a 2 mm sized cork borer and selected fungal inoculums were aseptically placed in the holes. The inoculated samples and the control were placed in sterile polythene bags and incubated at 35°C for seven days in dark. Isolates from the fruits and colonies from the diseased lesions were sub-cultured in PDA. The isolated fungal stains were identified based on colony features, growth rates and pigmentation. For confirmation, genomic DNA was isolated from subcultured colonies, which were isolated from artificially infected fruits. PCR amplification was performed using same procedure described in our previous article (Hasan et al., 2020) for virulence potency test through ITS rDNA gene amplification.\n\n\nResults\n\nCollected samples were incubated on PDA medium following the single spore technique, and after seven days, white colored fungal colonies appeared (Figure 1B).\n\nIsolated fungus was whitish in color and produced clamydospores, hyphae, appressoria and macroconidia (Figure 1C–D) at day three on PDA medium. Isolates produced microconidia that were 0-septate, oval, obovoid with a truncate base, elliptical or reniform. Macroconidia were sporodochia and fusiform. Chlamydospores were monophialides.\n\nDNA amplification through PCR produced a bright band at approximately 650 bp where a 1kb DNA ladder was used as marker. No band was found in the negative control where water was used instead of template DNA (Figure 2).\n\n1kb DNA marker is used for size determination, M - marker, I - isolate, N - negative control.\n\nThe dendrogram tree showed a close relationship with Fusarium concentricum and dissimilarity with Fusarium begoniae (Figure 3). Therefore, molecular identification confirmed the isolates as Fusarium sp. The sequence of the total isolate was compared to Fusarium sequences in GenBank using BLASTN, which revealed closely related sequences and 99.42% homology with the reference sequence for F. concentricum (Accession No. NR_111886.1).\n\nThe tree was constructed by neighbor joining method. The scale bar on the rooted tree indicates a 0.20 substitution per nucleotide position.\n\nThe virulence test was conducted to characterize the fungus as pathogenic or saprophytic on mature, fresh and healthy guava, lemon and tomato. All fruits showed similar morphological characteristics of Fusarium symptoms (Figure 4A–C). Isolated ribosomal DNA (rDNA) of fungus from artificially inoculated guava, lemon and tomato showed clear bands of approximately 650bp in length (Figure 5).\n\n(A) Guava, (B) lemon and (C) tomato, the image was taken 10 days after inoculation.\n\n1kb DNA marker is used for size determination of inoculated fungus in different fruit samples. M - marker, G - guava, C - lemon, T - tomato, N - negative control.\n\n\nDiscussion\n\nTraditionally identification based on colony morphology, conidial morphology and other phenotypic characteristics has been used previously for different fungi of citrus fruits (Leslie & Summerell, 2006; Tafinta et al., 2013). Further confirmation of the isolated fungi using advanced morphological and molecular approaches is required for characterization and differentiation of closely related Fusarium species (Geiser et al., 2004). rDNA sequences of Fusarium, isolated from eggplant, lemon and onion (frequencies of occurrence ranging from 40% to 100%) were reported by Al-Najada & Gherbawy (2015).\n\nThe present Fusarium sp. responsible for mandarin fruit rot was identified using morpho- molecular approaches. Fusarium appeared as white or blackish-white and showed chlamydospores and macroconidia on PDA after seven days of culture. Huda-Shakirah et al. (2020) found 3-5 long, thin walled, septate macroconidia on a F. concentricum fugal stain under microscopic observation, which supports our present findings. Zhu et al. (2014) also found similar morphological characteristics for Fusarium isolated from Eleocharis dulcis. Phylogenetic analysis was done using comparative analysis with different ITS-rDNA regions of sequences published in NCBI databases. The sequence of the fungal ITS-rDNA region was 546bp in size and matched the sequence of Fusarium concentricum in the database with 99.42% similarity. Huda-Shakirah et al. (2020) reported 99.53% similarity with Fusarium concentricum isolated from Hibiscus sabdariffa. The results of PCR and ITS sequencing confirm the isolated fungus as F. concentricum, which is supported by some other researcher’s findings (Chowdhury et al., 2019; Hasan et al., 2020; Hyun et al., 2000).\n\n\nConclusions\n\nFusarium fruit rot is a big problem for the citrus fruit industry in Bangladesh. In this study, Fusarium species was found to cause citrus fruit rot in Bangladesh. Moreover, pathogenicity was confirmed according to Koch’s postulates using three different types of fresh fruits. Fusarium species fruit rot leads to declines in the Bangladeshi fruit industry as well as fruit markets. Therefore, the current study may help the development of control measures for postharvest mandarin rot.\n\n\nData availability\n\nFusarium sp. pure cultured isolate containing small subunit ribosomal RNA, internal transcribed spacer 1 and 5.8S ribosomal RNA on GenBank. Accession number, MT856371: https://www.ncbi.nlm.nih.gov/nuccore/MT856371.1?report=genbank.\n\nFigshare: PCR amplification of ITS region yielded ~650 bp product. https://doi.org/10.6084/m9.figshare.13014209.v1 (Hasan, 2020a).\n\nThis project contains the following underlying data:\n\n- Figure 2.jpg (original, unedited gel image from Figure 2)\n\nFigshare: PCR amplification of ITS region for virulence test. https://doi.org/10.6084/m9.figshare.13008458.v1 (Hasan, 2020b).\n\nThis project contains the following underlying data:\n\n- Gel doc.2.jpg (original, unedited gel image from Figure 5)\n\nFigshare: Molecular identification of Fusarium species causing fruit rot. https://doi.org/10.6084/m9.figshare.12990746.v1 (Hasan, 2020c).\n\nThis project contains the following underlying data:\n\n- Micro.imag.1.jpg (original, unedited microscopy image showing clamydospores, hyphae and appressoria from Figure 1C)\n\n- Micro.imag.2.jpg (original, unedited microscopy image showing conidia from Figure 1D)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nAhmed HU, Latif MA, Haq MF, et al.: Pest Risk Analysis (PRA) of Citrus in Bangladesh. SPCB project report, DAE, Farmgate, Dhaka-1215. 2014; 1–104. Reference Source\n\nAktaruzzaman M, Afroz T, Lee Y, et al.: Morphological and molecular characterization of Fusarium tricinctum. causing postharvest fruit rot of pumpkin in Korea. J General Plant Pathol. 2018; 84: 407–13. Publisher Full Text\n\nAl-Najada AR, Gherbawy YA: Molecular Identification of Spoilage Fungi Isolated from Fruit and Vegetables and Their Control with Chitosan. Food Biotechnol. 2015; 29(2): 166–184. Publisher Full Text\n\nChowdhury MEK, Jahan MS, Akhtar S, et al.: Characterization of fungal pathogens causing diseases in bitter gourd and establishment of their eco-friendly control measure. Int J Multidis Res Develop. 2019; 6(1): 109–15. Reference Source\n\nDignani MC, Anaissie EJ: Human fusariosis. Clin Microbiol Infect. 2004; 10(Suppl. 1): 67–75. PubMed Abstract | Publisher Full Text\n\nGardes M, Bruns TD: ITS primers with enhanced specificity for basidiomycetes application to the identification of mycorrhizae and rusts. Mol Ecol. 1993; 2(2): 113–118. PubMed Abstract | Publisher Full Text\n\nGeiser DM, Jiménez-Gasco MM, Kang S, et al.: FUSARIUM-ID v. 1.0: a DNA sequence database for identifying Fusarium. Eur J Plant Pathol. 2004; 110: 473–9. Publisher Full Text\n\nHafizi R, Salleh B, Latiffah Z: Morphological and molecular characterization of Fusarium. solani and F. oxysporum associated with crown disease of oil palm. Braz J Microbiol. 2013; 44(3): 959–968. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHasan Md: PCR amplification of ITS region yielded ~650 bp product. figshare. Figure. 2020a. http://www.doi.org/10.6084/m9.figshare.13014209.v1\n\nHasan Md: PCR amplification of ITS region for virulence test. figshare. Figure. 2020b. http://www.doi.org/10.6084/m9.figshare.13008458.v1\n\nHasan Md: Molecular identification of Fusarium species causing fruit rot.figshare. Figure. 2020c. http://www.doi.org/10.6084/m9.figshare.12990746.v1\n\nHasan MF, Islam MA, Sikdar B: PCR and Sequencing Base Detection of Gummosis Disease on Citrus aurantifolia Caused by Lasiodiplodia theobromae and Evaluation of Its Antagonisms. Journal of Advances in Microbiology. 2020; 20(3): 77–90. Publisher Full Text\n\nHassan O, Jeon JY, Chang T, et al.: Molecular and morphological characterization of Colletotrichum species in the Colletotrichum gloeosporioides complex associated with persimmon anthracnose in South Korea. Plant Dis. 2018; 102(5): 1015–24. PubMed Abstract | Publisher Full Text\n\nHuda-Shakirah AR, Nur-Salsabila K, Mohd MH: First report of Fusarium concentricum causing fruit blotch on roselle (Hibiscus sabdariffa). Australasian Plant Disease Notes. 2020; 15: 15. Publisher Full Text\n\nHyun JW, Seong CL, Dong HK, et al.: Fusarium Fruit Rot of Citrus in Jeju Island. Mycobiology. 2000; 28(3): 158–62. Publisher Full Text\n\nKumar S, Stecher G, Tamura K: MEGA7: molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol Biol Evol. 2016; 33(7): 1870–74. PubMed Abstract | Publisher Full Text\n\nLeslie JF, Summerell BA: The Fusarium laboratory manual. Blackwell Publishing, Ames. 2006; 388. Publisher Full Text\n\nMorton JF: Mandarin orange. In: Fruits of Warm Climates. 1987; 142–145.\n\nO’Donnell K, Sutton DA, Rinaldi MG, et al.: Novel multilocus sequence typing scheme reveals high genetic diversity of human pathogenic members of the Fusarium incarnatum-F. equiseti and F. chlamydosporum species complexes within the United States. J Clin Microbiol. 2009; 47(12): 3851–61. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSathya K, Parthasarathy S, Thiribhuvanamala G, et al.: Morphological and molecular variability of Lasiodiplodia theobromae. causing stem end rot of mango in Tamil Nadu, India. Int J Pure App Biosci. 2017; 5(6): 1024– 31. Publisher Full Text\n\nSrinivasan D, Ramasamy S, Sengottuvelu S: Protective effect of polyherbal formulation on experimentally induced ulcer in rats. Pharmacology online. 2008; 1: 331–50. Reference Source\n\nSun S, Lui Q, Han L, et al.: Identification and Characterization of Fusarium proliferatum, a New Species of Fungi that Cause Fungal Keratitis. Sci Rep. 2018; 8(1): 4859. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTafinta IY, Shehu K, Abdulganiyyu H, et al.: Isolation and Identification of Fungi Associated with the Spoilage of Sweet Orange (Citrus Sinensis) Fruits In Sokoto State. Nigerian Journal of Basic and Applied Science. 2013; 21(3): 193–6. Publisher Full Text\n\nTamura K, Nei M, Kumar S: Prospects for inferring very large phylogenies by using the neighbor-joining method. Proc Natl Acad Sci U S A. 2004; 101(30): 11030–35. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang L, He F, Huang Y, et al.: Genome of wild mandarin and domestication history of mandarin. Mol Plant. 2018; 11(8): 1024–1037. PubMed Abstract | Publisher Full Text\n\nWhite TJ, Bruns T, Lee SJWT, et al.: Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics. PCR protocols: A guide to methods and applications. 1990; 18(1): 315–22. Publisher Full Text\n\nWhiteside J, Bennett J, Holtzblatt K: Usability engineering: our experience and evolution. In: M. Helander (Ed.), Handbook of human-computer interaction. New York, North Holland, 1988; 791–817. Publisher Full Text\n\nZhu Z, Zheng L, Pan L, et al.: Identification and characterization of Fusarium species associated with wilt of Eleocharis dulcis. (Chinese water chestnut) in China. Plant Dis. 2014; 98(7): 977–987. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "73841",
"date": "07 Jan 2021",
"name": "Shuvra Kanti Dey",
"expertise": [
"Reviewer Expertise I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard."
],
"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 comment: I found the article well-written and cohesive. I was happy to read about the whole article and I am glad to recommend for indexing with minor corrections.\nSpecific comments:\nTitle and abstract: Title is very informative and abstract gives good insight into the study.\nIntroduction: Author describe the introduction very well. Importance of the study, background and objectives are very clear. It provided important information. Need to add some recent references.\nMethods: I think this section was clearly describe with relevant references.\nResults: This study describes the isolation and identification of a proposed new species of Fusarium. The isolate has been characterized using molecular approaches. The obtained sequence was deposited in GenBank (Accession No. MT856371). PCR and sequencing confirm the isolated stain. At the genomic level, the proposed new species was 99.42% similarity with the reference Fusarium concentricum sequence. Virulence test showed the fungus as pathogenic on healthy guava, lemon and tomato. Therefore, the proposed species meets the molecular and morphological requirements of being designated as a new species. Need to add outgroup in the phylogenetic tree.\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": "158099",
"date": "19 Dec 2022",
"name": "Barbara Sawicka",
"expertise": [
"Reviewer Expertise agriculture",
"agronomy",
"commodity sciences",
"food safety",
"plant protection"
],
"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 work entitled: \"The first report on the molecular identification of Fusarium species causing mandarin fruit rot (Citrus reticulata) in Bangladesh\" is an important contribution to the research on identifying the causes of mandarin fruit rot. However, the authors made several mistakes that need to be corrected before the work is published.\nDetailed notes: 1) The abstract is properly structured.\n2) The introduction should introduce the reader to the subject of the work and end with a clear purpose of the work.\n3) The purpose of the research should be clearly explained. The authors should also put forward an alternative research hypothesis to the null hypothesis in order to verify it later in the work.\n4) The methodology of work should be extended to the methodology of sampling for testing (the number of samples and isolates should be sufficient to make statistical calculations) and the methodology of statistical calculations.\n5) Research results should be thoroughly discussed with statistical justification.\n6) The \"Discussion\" section needs to be expanded. It should include references to the latest literature in the field.\n7) The application should be general and summative and should include a clear indication for the manufacturing practice. In addition, it should contain an indication (proposal) for the future.\n8) The list of literature should be enriched with the latest items in the researched area.\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?\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": [
{
"c_id": "9180",
"date": "04 Jan 2023",
"name": "Md. Faruk Hasan",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for your valuable comments and suggestions about our manuscript. We make some correction according to your comments in different parts of our manuscript which are marked as red color. We are submitting the new version of our MS. Regards Authors"
}
]
}
] | 1
|
https://f1000research.com/articles/9-1212
|
https://f1000research.com/articles/12-174/v1
|
14 Feb 23
|
{
"type": "Research Article",
"title": "Pesticide use behavior, cognitive impairment and the model of safety standard of pesticide use among farmworkers in Indonesia",
"authors": [
"Isa Ma'rufi",
"Erwin Nur Rif’ah",
"Syubbanul Wathon",
"Khaidar Ali",
"Erwin Nur Rif’ah",
"Syubbanul Wathon"
],
"abstract": "Background: The objective of this study was to identify pesticide residue, and to analyze associations between characteristics and pesticide use behavior with cognitive impairment among farmworkers. Additionally, a model of safety standard of pesticide use was constructed. Methods: This observational study was conducted in Jember Regency, Indonesia using a cross-sectional design. Cluster random sampling was performed, whereby 500 farmworkers were selected as participants. Characteristics, pesticide use behavior and cognitive impairment data were collected using questionnaires. Bivariate and multivariate analyses were performed using chi-squared and logistic regression tests, respectively. The model was created by comparative analysis between theoretical concepts and empirical findings. Results: This study found 10/15 agricultural products contain Chlorpyrifos class of Organochlorin. Based on Montreal Cognitive Assessment, 70% of participants were in the category indicating cognitive impairment. Pesticide use behavior among farmworkers showed that 92.4% of participants were in the favorable category. The chi-squared test presented the significance of the type of commodity and pesticide storage associated with cognitive impairment among farmworkers (p<0.05). According to logistic regression analysis, other commodities (tobacco) (AOR: 0.21 (CI: 0.09–0.46)), pesticide exposure duration (AOR: 0.52 (CI:0.27–0.99)), pesticide dissemination at night (AOR:5.77 (CI:1.12-29.85)) and pesticide storage outdoors (AOR: 1.81 (CI:1.13–2.90)) were associated with cognitive impairment (p<0.05). The model of safety standard of pesticide use is constructed by four variables: farmworker behavior, personal protection equipment (PPE) utilization, implementing Integrated Pest Management (IPM) principal, and waste control. Conclusions: High numbers of agricultural products still contain pesticide residue. Although, pesticide use behavior was mainly within the favorable category, there were issues with excessive dose use, pesticide storage and disseminating time. The combination of favorable farmworker behavior, PPE utilization, implementing IPM principal, and waste control may protect farmworkers during pesticide use. The Agriculture District Office should conduct training workshops to farmworkers and provide waste management systems.",
"keywords": [
"pesticide",
"cognitive impairment",
"behavior",
"model"
],
"content": "Introduction\n\nCurrently, the main issue among farmworkers is the excessive use of pesticide doses and poor safety behavior, hence the risk of adverse health effects, including poisoning, is life-threatening. Pesticides are a toxic substance used to eliminate living organisms that cause harm to plants and livestock.1 Specifically, pesticides used in the agriculture sector are called crop protection products, which distinguishes them from other products.2 Nonetheless, pesticides are also commonly used to control vector-borne disease, such as dengue, chikungunya, and malaria.3\n\nAccording to the type of pesticide, pesticides are divided into several groups, namely insecticides, fungicides, bactericides, nematicides, acaricides, rodenticides, molluscicides, and herbicides.4 The World Health Organization estimated 25 million cases of reported pesticide poisoning annually, which was highly distributed in developing countries, particularly Asia.5 Based on the Indonesian Ministry of Health (MoH) in Raini,6 820 cases and 125 deaths due to pesticide poisoning were recorded in Indonesia from 1996-1998, which increased during 1999-2001, with 868 cases and 134 deaths. Furthermore, the incidence of acute poisoning caused by pesticides from 2001-2005 was recorded to be approximately five times higher than 1996 with 4,867 cases and 3,789 deaths.6 In 2016, 771 cases of pesticide poisoning were recorded in Indonesia.7\n\nAs a recommended pesticide for the agriculture sector, organophosphate is commonly used as it is decomposable by nature. Nevertheless, the excessive use of this substance still leads to residues in the environment, including agricultural products, and can be harmful if consumed. The organophosphate affects nerve function by inhibiting the acetyl cholinesterase enzyme. This condition is exacerbated by long term exposure of organophosphates. Pesticide poisoning causes abnormalities in the blood profile. The chemical substances disrupt the process of forming blood cells and the immune system, which results in anemia.8 Anemia among farmworkers leads to reductions in productivity, where farmworkers experience more frequent fatigue and exhaustion. Dewi9 reported that pesticide exposure is causing mild cognitive impairment. Organochlorin and carbamate induce the health issues related to neuro impairment such as tremor, convulsion, and death. Therefore, the chemical substances of pesticides have neurotoxic attributes. Mostafalou et al.,10 mentioned that the exposure of pesticide elevates chronic disease rate, such as diabetes, cancer, neurodegenerative disorders, Alzheimer’s disease, birth defects, reproductive disorders, and amyotrophic lateral sclerosis.\n\nA pilot study was conducted in Jember by the authors using observational methods, in which pesticide use among farmworkers in Jember was found to be inappropriate. The use of pesticides was considerably out of standardized doses, where cover blanket systems of pesticide use have been implemented. The cover blanket system meant that the pesticide was being frequently disseminated without re-evaluating the number of pests or weeds in the agricultural field.\n\nThe objectives of this study were as follows: a) to identify pesticide residue in agricultural products, b) to assess the associations between characteristics and pesticide use behavior with cognitive impairment among farmworkers, and c) to generate a model of safety standard for the use of pesticides among farmworkers.\n\n\nMethods\n\nThis observational analytics study was conducted in Jember Regency, Indonesia. Jember is the third largest area in East Java Province and has 28 sub-districts. Jember was selected due to the high distribution of farmworkers in the population and diverse agricultural products (vegetable, crop, fruit, and other commodities). Based on The Bureau of Statistics of Jember, it was noted that 374,766 individuals within the population, which is approximately 15% of the total population, are farmworkers, and 157,596 Hectare (Ha) of harvesting area was reported with 961,977 tons of total production in 2021.11 Figure 1 presents the maps of Jember, Indonesia.\n\nThis study was approved by the Ethical Committee of Medical Research at The University of Jember on 4 November 2022, with No. Registration: 1769/UN25.8/KEPK/DL/2022.\n\nThis study used a cross-sectional design, in which the authors were eager to understand and assess the association of outcome- and predictor-variables at the same time. In this study, cluster random sampling was used. The study area was divided into five locations, namely west, east, north, south, and center area, in which the total sample included 500 farmworkers distributed in each location. Table 1 recorded the distribution of samples. In this study, 10 out of 28 sub-districts were selected as study areas, namely: Ambulu, bangsalsari, kalisat, pakusari, Puger, semboro, sukowono, sumberbaru, tanggul, Umbulsari. All participants were proportionately distributed in each sub-district.\n\nThe outcome- and predictor-variables include cognitive impairment and pesticide use behavior, respectively. Cognitive impairment was measured using the Montreal Cognitive Assessment Indonesian version (MoCa-Ina) that was previously validated.12 The MoCa has been widely used to assess cognitive impairment among populations.13–15 The MoCa-Ina assesses diverse cognitive domains, namely: attention and concentration, executive functions, language, memory, conceptual thinking, calculations, visuoconstructional skills and orientation. The maximum score of MoCA-Ina is 30 points, and the main categories are divided into two groups, namely normal (score: ≥26 points) and cognitive impairment (score: <26). In addition, one point is given to participants with formal education that lasted approximately 12 years with a total score of less than 30 points.\n\nThe variable of pesticide use behavior referred to the Integrated Pest Management Principal by Directorate General of Horticulture Production, Indonesian Ministry of Agriculture including quality, target, type, time, doses, utilization of pesticide (6T).16 There were 18 questions in which each question has one point. This variable is categorized into three group: a) favorable (13-18 points), b) moderate (7-12 points), and c) worse (0-6 points).\n\nData on farmworker characteristics were also collected, including sex, age, working duration (years), type of commodity, pesticide exposure (hours), pesticide dissemination, time of pesticide dissemination, pesticide storage. All participants provided written informed consent and agreed to participate in this study.\n\nData on characteristics and pesticide use behavior among farmworkers were collected using a quantitative questionnaire whereby a trained surveyor read/asked listed-questions in the questionnaire to help the participant, in which the answers of the participant were noted in the questionnaire by the surveyor. The role of the trained surveyor was to assist the respondent by describing the question and filling the respondent’s answer in the questionnaire. The questionnaire was generated based on literature study, a review of the relevant literature, as reported by Yaddanapudi and Yaddanapudi.17 The questionnaire consisted of characteristics on farmworkers and pesticide use behavior that referred to the Principal of Integrated Pest Management of Directorate General of Horticulture Production - Indonesian Ministry of Agriculture Moekasan.16 The questionnaire can be found as Extended data.47\n\nThe validity and reliability of the questionnaire were tested in a pilot study using 20 participants. Validity and reliability were measured using Product Moment Pearson and Alpha Cronbach, respectively, as performed in previous studies (Dewi and Sudaryanto18 and Binus19). Based on Pearson’s r test, the r score of the questionnaire ranged from 0.413 to 0.831 (p<0.05), Sugiyono20 noted that questionnaires with r score > 0.3 and p value <0.05 are valid. In addition, the Cronbach’s Alpha score of the questionnaire is 0.710, Putri et al.,21 reported that the questionnaire is reliable if the Alpha Cronbach score >0.6. The validity and reliability tests were assessed in IBM SPSS Statistics (RRID:SCR_016479) version 25.\n\nFollowing the administration of this questionnaire, participants were administered the MoCa-Ina instrument12 to collect the data regarding cognitive impairment. The data were collected after ethical clearance was established (data collection was from 5 November to 1 December 2022).\n\nIn order to achieve the objectives, several analyses have been conducted in this study, namely:\n\na) Pesticide residue in agricultural products: The availability of pesticide residue in agricultural products was measured for 15 samples collected in conventional markets. The author used Pesticide Detection Card to assess the pesticide residue. This technique was performed in accordance with a previous method.22 The examination of pesticide residue was conducted in Balai Besar Teknik Kesehatan Lingkungan dan Pengendalian Penyakit Surabaya (Centre for Environmental Health Engineering and Disease Control) - Indonesian Ministry of Health. The finding was reported descriptively.\n\nb) Associations between characteristics and pesticide use behavior with cognitive impairment among farmworkers: The data were primarily collected from participants by a trained surveyor using a questionnaire. The dataset was input into Microsoft Excel (RRID:SCR_016137), and then transferred to STATA. As the data of predictor and outcome variables were categorical, the associations were examined using a chi-squared test. The author also analyzed the association between farmworker’s characteristics and cognitive impairment by using chi-squared test. In addition, a logistic regression model was also used in the analysis. All statistical analysis was conducted in Stata (RRID:SCR_012763) ver 12 (Tx College, USA).\n\nc) Model of safety standard for pesticide use: The model was generated to provide information to farmworkers regarding safety standards for pesticide use. Several stages have been performed to create the model, including: 1) implementing the comparative analysis between theoretical concept and empirical findings based on the survey, 2) developing model concerns (such as policy, objective, scope, system and strategy, resources, monitoring), and 3) generating the model design.\n\n\nResults\n\nTable 247 presents the traces of pesticide residue in 15 samples of agricultural products in a local market in Jember. Based on Table 2, 10 out of 15 samples confirmed positive traces of pesticide residue of chlorpyriphos class of organochlorin.\n\nTable 3 reported the cognitive impairment score among farmworkers. Based on Table 3, 70% of participants (350 farmworkers) showed impaired cognitive ability with a MoCa-Ina score less than 26 points. On the other hand, 30% of participants showed a normal score.\n\nTable 4 presents the pesticide use behavior based on Integrated Pest Management Principal among farmworkers. Based on Table 4, the quality, dose, type and utilization of pesticide, targeted pest of pesticide, and time of pesticide dissemination is favorable among farmworkers (approximately 82% to 99%). However, 29% of participants did not use PPE during pesticide dissemination. Further explanatory analysis showed that farmworkers did not always follow the IPM criteria, they did not use appropriate pesticides for the specific type of plant (16.4%), they used unstandardized doses not following the label instructions (17.4%), and they used excessive doses of pesticide (18.2%).\n\nTable 5 presents the tiers of pesticide use behavior among farmworkers. Based on Table 5, 92.4% of participants (462 farmworkers) showed favorable pesticide use behavior. Meanwhile, 7.6% of participants showed moderate use behavior.\n\nTable 6 noted the association between characteristics and pesticide use behavior of farmworkers in terms of cognitive impairment. Based on Table 6, participants >50 years old (71.4%), male (70.6%), working duration >10 years (71.7%), planting tobacco (89.9%), >2 hour of pesticide exposure (70.9%), performing pesticide dissemination 3-4 time per month (72.6%), time of pesticide dissemination of 15.00-17.00 (81.6%), and pesticide storage indoors (80.2%) were highly distributed in the cognitive impairment category. In the variable of pesticide use behavior, moderate level behavior (65.7%) was associated with cognitive impairment.\n\nN: total participant; AOR: Adjusted Odd Ratio; CI: Confidence Interval.\n\n* Significant p value <0.05.\n\n** Significant p value <0.00).\n\n+ : Chi-squared test.\n\n++ : Logistic regression.\n\nBivariate analysis by chi-squared test presents the significance of the type of commodity and pesticide storage in terms of cognitive impairment among farmworkers (p<0.05). According to logistic regression analysis, other commodities (tobacco), pesticide exposure >2 hour, pesticide dissemination at night and pesticide storage outdoors were associated with cognitive impairment (p<0.05).\n\nThe model of safety standard of pesticide use is shown in Figure 2. As visualized in Figure 2, four factors are suggested to influence pesticide use among farmworkers, namely: the behavior of farmworkers (knowledge, attitude, and personal hygiene), implementation of integrated pest management principal (quality, doses, type, targeted pest, time of disseminating, utilization of pesticide), PPE utilization (head and face protection, goggles, mask, body protection, safety boots, and gloves), and pesticide waste control (waste control in water, land, and air).\n\nPPE, personal protection equipment.\n\n\nDiscussion\n\nPesticides are chemical compounds or substances used to eliminate pests (rodents, insects, fungi) and unwanted plants that are widely used to protect agriculture plants and to increase crop/yield production (weed).23,24 Kim et al.,25 reported that pesticide type insecticide is also used to control pests that carry diseases such as mosquitoes and tick. Despite the many beneficial uses of the utilization of pesticides in agriculture that have been reported, there are still a number of health issues associated with pesticide use as it is toxic to other organisms, particularly humans.26\n\nThe unsafe pesticide use behavior among farmworkers such as excessive dose of pesticide use not using protection during pesticide dissemination and pesticide use not following its label leads to adverse effects on health in both farmworkers and consumer populations. The chemical substances of pesticides may directly impact farmworkers, causing either acute or chronic diseases. Fucic et al.,27 noted that various pesticide types elevate the risk of diabetes, cancer, and neurodegeneration, including cognitive impairment. Health issues among consumers or populations is associated with the consumption of agricultural products containing pesticide residue. Furthermore, pesticide waste also pollutes the environment.28\n\nTable 2 reports the availability of pesticide residue in agricultural products. According to Table 2, 66.67% (10 out of 15 samples) contain the pesticide of chlorpyriphos, as found by using Pesticide Detection Card analysis. The presence of the chemical substances of pesticides in agricultural products is well documented.29 Ardiwinata30 and Hendriadi31 reported that pesticide residue of insecticide (organochlorine, organophosphate, carbamate, pyrethroid) and fungicide (dimethomorph, fenobucarb, propineb, benomyl) exists in agricultural products.30,31 The presence of organochlorine substances in the environment is high due to its persistence. In addition, based on observations of farmworker behavior in this study, it was found that cover blanket systems in pesticide use have been implemented, which lead to increases in the amount of pesticide residue among agricultural products.\n\nAs mentioned in Table 3, cognitive impairment, as assessed using the MoCa-Ina, among farmworkers is highly distributed (70% participants) in the impaired category (total score <26 points). Pesticide exposure and mild cognitive impairment is associated with neurotoxic dysfunction. High exposure to pesticides stimulates the inhibitor of cholinesterase enzyme. The impairment of cholinesterase enzyme leads to failure in hydrolysis of acetylcholine that has a critical role in passing stimulation from nerves to muscle cells and gland organs, consequently pesticide exposure can cause cognitive impairment, involuntary tremors in muscles, convulsion, and death.9 This finding is consistent with studies by Marucci et al.,32 and Mutia et al.,33 which found that the inhibition of brain acetylcholine catabolic enzymes, acetylcholinesterase, and butyrylcholinesterase elevate brain acetylcholine levels that cause cognitive dysfunction such as Alzheimer’s disease. Furthermore, Aloizou et al.,34 also reported that low dose exposure of pesticides and other chemical substances trigger hormetic neurobehavioral effects, and this effect is exacerbated by vitamin deficiency among farmworkers.\n\nTables 4 and 5 show pesticide use behavior based on the integrated pest management principals among farmworkers. Based on Table 3, the quality-, dose-, type- and utilization- of pesticides, targeted pest of pesticide, and time of pesticide dissemination is favorable among farmworkers, in which 92.4% of participant were in the favorable category and only 7.6% of participants were in the moderate category. In accordance with the behavior of pesticide use among farmworkers, Damalas and Koutroubas35 reported that pesticide use behavior is critical for accurate risk assessment, whereas perception, attitude and self-efficacy drive safety behavior among farmworkers.\n\nThis study found that a high number of participants have good or favorable pesticide use behavior, in which Endalew et al.,36 noted that 61.3% showed good practice of pesticide use in Ethiopia. Nevertheless, there were still high numbers of farmworkers that did not use PPE and use unfit pesticides for the specific type of plant and unstandardized doses that lead to increased risks of negative health effects among farmworkers. This finding is in agreement with Gesesew et al.,37 whereas only 42% of farmers in Rural Irrigation Villages in Southwest Ethiopia rarely used PPE. Struelens et al.,38 also mentioned that high percentages of farmers in Bolivia were incorrectly following pesticide dose recommendation. PPE use during pesticide dissemination is recommended among farmworkers for protection as the chemical substances of pesticides can enter the human body through inhalation, as well as oral and skin routes. Chittrakul et al.,39 found that inappropriate use of PPE may elevate urinary organophosphate metabolite levels.\n\nTable 6 reports the association between characteristics and pesticide use behavior with cognitive impairment among farmworkers, being >50 years old (71.4%), with a working duration >10 years (71.7%), male (70.6%), planting tobacco (89.9%), with >2 hour of pesticide exposure (70.9%), performing pesticide dissemination 3-4 times per month (72.6%), with a time of pesticide dissemination between 15.00 and 17.00 (81.6%), and storing pesticides indoors (80.2%) were highly distributed in participants with cognitive impairment. In the variable of pesticide use behavior, 65.7% of those in the moderate category had cognitive impairment. Yet, the chi-squared test showed significant associations between the type of commodity and pesticide storage with cognitive impairment (p<0.05). Furthermore, logistic regression analysis showed that other commodity (tobacco) (AOR: 0.21 (CI: 0.09 – 0.46)), pesticide exposure duration >2 hours (AOR: 0.52 (CI:0.27 – 0.10)), time of pesticide dissemination between 16.00-22.00 (AOR: 5.77 (CI: 1.12 – 29.85)), and pesticide storage outdoors (AOR: 1.81 (CI:1.13 – 2.90)) were associated with cognitive impairment (p<0.05).\n\nThe findings of this study showed that pesticide storage outdoors had an AOR>1 toward cognitive impairment, which indicates that pesticide storage outdoors is a risk factor. Based on observations, farmworkers often stored pesticides close to the main house building, where the chemical substance still enters the house toward their ventilation. The AOR of pesticide exposure duration >2 hours was less than 1. Based on theoretical concept, farmworkers are susceptible to long-term exposure of pesticides, which leads to adverse health outcomes. However, there are several rational as to why the AOR pesticide exposure duration is less than 1, namely: a) information of pesticide exposure duration is based on recall from farmworkers that led to misinformation, b) the pesticide disseminating process is often conducted in the morning, which is the recommended time. Therefore, the authors hypothesize that low or no exposure dose may appear, c) the high level of favorable pesticide use among farmworkers reduces the risks of pesticides. This study found that the AOR of time of pesticide dissemination between 16.00-22.00 is >1. It indicates that farmworkers spraying pesticide over that time are at risk for cognitive impairment. Several rationales correspond to this issue, including unfavorable conditions (temperature and humidity) for pesticide spraying and farmworkers being unable to detect wind duration during that time. In addition, a noteworthy finding has been found in this study that the AOR of type of commodity (tobacco) is less than 1. The authors hypothesize that the utilization of pesticides among farmworkers of tobacco is less than other farmworkers, and has favorable pesticide use behavior. However, further study is necessary.\n\nAll populations are vulnerable to the adverse effects of pesticides, in which children, pregnant women and older adults are more susceptible. The cognitive impairment or decline among participants >50 years old, working duration >10 years, spraying pesticide 3-4 times per month and >2 hour of pesticide exposure may be due to chronic exposure of the chemical substances of pesticides. The low dose of chemical substance is absorbed by the body and leads to several responses, particularly inhibiting the cholinesterase enzyme.9 Ganie et al.,40 reported that organophosphates, one of the pesticide types, is causing cholinergic crisis, intermediate syndrome, organophosphate-induced delayed neuropathy and chronic organophosphate-induced neuropsychiatric disorder. A study by Jallow et al.,41 found that pesticide application among farmworkers in Kuwait is also approximately two times a month.\n\nThis study found that most participants conducted an unstandardized protocol toward pesticide, including pesticide dissemination between 16.00 and 22.00 and indoor storage that stimulate cognitive impairment. The application of pesticides should be appropriate. Disseminating during the cooler part of the day (mild temperature: 27°C and high humidity: >45%) is recommended, in which the morning hours are the best conditions for spraying.42 In addition, EPA Australia42 also noted that pesticides should be stored in either an isolated, stand-alone building or a cupboard within multipurpose buildings. This study found a noteworthy finding. Although the AOR <1, the explanatory analysis showed that cognitive impairment was highly distributed among tobacco farmers. Therefore, further study is necessary to assess the pesticide use among tobacco farmers and its association with cognitive impairment.\n\nAs shown by Figure 2, the model of safety standard of pesticide use contains four main factors, namely: a) farmworker behavior, b) PPE utilization, c) application of integrated pest management, and d) waste control. Farmworker behavior plays an important role in pesticide use, in which appropriate behavior toward pesticide use may reduce the negative effects of pesticides. In order to improve farmworker behavior, increasing knowledge, attitude, and personal hygiene are necessary, in which continuing training from District Agriculture Office (DAO) among farmworkers is important. Ngah et al.,43 found that positive attitude influences safe practices among workers, in which attitude was influenced by knowledge. Therefore, increasing knowledge should improve behavior among farmworkers. The habits of good personal hygiene should be implemented, including washing hands with soap, nail hygiene, and body cleanliness.44\n\nThe factor of PPE utilization is reasonable to protect farmworkers. Farmworkers should be warned about the adverse health effects of pesticides and be urged to use PPE to protect their health, such as head or face protection, goggles, mask, body protection, safety boots, and gloves.42 The DAO is not only disseminating information about PPE but also provides the PPE tool kits. However, the authors suggest social approaches such as farmer-group donations to initiate the PPE procurement. EPA Australia42 also reported that PPE should be stored close to pesticides. In addition, minimum PPE should be printed on pesticide labels, in which pesticide manufacturers should consider the special conditions of farmers, including education level and age of farmer.45\n\nThe implementation of Integrated Pest Management (IPM) principal is prominent. Using pesticides with appropriate quality, type and target is necessary, including specific pesticides for targeting particular pests or weeds. The proper time of dissemination and utilization of pesticides should be considered. The perception of risk of loss by the reduction of pesticide use remains an issue among farmworkers. Hence, unstandardized pesticide use and not implementing IPM principals are common, including excessive dose usage. The excessive dose of pesticide use was found in this study. This finding corroborates to Damalas,46 who found that only 15.2% of the farmers in their study population were willing to reduce pesticide use. Therefore, implementing the IPM principal among farmworkers may reduce negative health effects due to exposure to the chemical substances of pesticides.\n\nThe waste control factor is important to reduce the concentration of chemical substances of pesticides in the environment. Waste control can be conducted by bioremediation, phytoremediation, and other methods. Physical waste such as the pesticide container or expired pesticide should be collected and stored in an isolated building, then transferred to an official waste management office to eliminate the waste. In addition, the awareness of farmworkers regarding waste control is necessary.\n\nThere are several limitations needed to be mentioned in this study, including: 1) only 15 types of agricultural products were used for the assessment of pesticide residue, 2) the questionnaire used to measure IPM principal in this study was limited to only 18 questions, which does not provide detailed enough information, and 3) the model is not yet implemented in the population hence the author cannot monitor and evaluate the model. The authors suggest further research to assess the pesticide residue among the agriculture products distributed in each local market in Indonesia, thus it would be useful for future studies to identify and detect the pesticide residue within processed food products (agriculture and fish products). The development of an IPM principal questionnaire is necessary to provide more detailed information among farmworkers, particular in Indonesia. The model of safety standard of pesticide use should be assessed with further studies by using a mixed method approach (quantitative and qualitative study).\n\n\nConclusions\n\nA high number of agricultural products still contain pesticide residue. Although, pesticide use behavior in this study generally fell within the favorable category, there were issues regarding particular aspects, namely excessive dose use, pesticide exposure duration and pesticide storage that have negative health impacts, particularly on cognitive impairment. The model of safety standard of pesticide use among farmworker was constructed by four factors, namely farmworker behavior, PPE utilization, implementing IPM principal, and waste control. The authors recommend continuing socialization and workshops among farmworkers to increase and sustain knowledge. In addition, the DAO of Indonesia should provide pesticide eliminate tools or systems to manage pesticide waste.",
"appendix": "Data availability\n\nMendeley Data: Pesticide Use Behavior, Cognitive Dysfunction and The Model of Safety Standard of Pesticide Use among farmworker in Indonesia. https://doi.org/10.17632/8kmksy24rg.4. 47\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nDadang: Inroduction of pesticide and application technic (Pengenalan Pestisida dan Teknik Aplikasi). In Workshop Pest and Jatropha curcas Unn ‘s disease: destruction potency and its control (Workshop Hama dan Penyakit Tanaman Jarak (Jatropha curcas Unn.): Potensi Kerusakan dan Teknik Pengendaliannya): Bogor, 5-6 Desember 2006.2006.\n\nDjojosumarto P: The comprehensive guide to pesticide and their application (Panduan Lengkap Pestisida & Aplikasinya). Agromedia.2008; pp. 13–31.\n\nWHO: Global insecticide use for vector-borne disease control. Geneva:World Health Organization;2021.\n\nWudianto R: The instructions of pesticide use (Petunjuk Penggunaan Pestisida). Jakarta:Penebar Swadaya;2010.\n\nMayasari D: The safety behavior among farmer toward pesticide use in Gisting Atas Village as risk factor for pesticide intoxication (Gambaran Perilaku Kerja Aman pada Petani Hortikultura Pengguna Pestisida Di Desa Gisting Atas sebagai Faktor Risiko Intoksikasi Pestisida). J. Kedokt. Univ. Lampung. 2017; 1(3): 530–535.\n\nRaini.: The toxicology of pesticide and its treatment toward pesticide poisioning (Toksikologi pestisida dan penanganan akibat keracunan pestisida). Media Litbang Kesehatan. 2007; 17(3).\n\nAmin NR: (Determinan Keracunan pada Petani Sayur Pengguna Pestisida di Desa Kanreapia Kecamatan Tombolo Pao Kab. Goa). Undergraduate Thesis. 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Jom FEKON. 2015; 2(2): 1–15.\n\nDuniaji AS, Suter IK: The assessment of pesticide residue within horticultural plant with Pesticide Detection Card- and Chromatography Mass Spectrophotometry- approach in Bandung (Pengujian Kandungan Residu Pestisida Pada Tanaman Sayuran Di Kabupaten Badung Dengan Kartu Pendeteksi Pestisida (Pesticide Detection Cards) Dan Gas Chromatography Mass Spectrophotometry). Itepa: Jurnal Ilmu dan Teknologi Pangan. 2021; 10(4): 746–752. Publisher Full Text\n\nCDC: Pesticide.2019.Reference Source\n\nWHO: Chemical safety: pesticide.2020.Reference Source\n\nKim K-H, et al.: Exposure to pesticides and the associated human health effects. Sci. Total Environ. 2017;1–11.\n\nTudi M, et al.: Agriculture development, pesticide application and its impanct on the environment. Int. Environm. Res. Public Health. 2021; 18: 1112. 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Publisher Full Text\n\nMarucci G, et al.: Efficacy of acetylcholinesterase inhibitors in Alzheimer’s Disease. Neuropharmacology. 2021; 190: 108352. Publisher Full Text\n\nMutia V, Oktarlina RZ: The chronic pesticide poisioning among farmwer (Keracunan Pestisida Kronik Pada Petani). JIMKI: Jurnal Ilmiah Mahasiswa Kedokteran Indonesia. 2020; 7(2): 130–139. Publisher Full Text\n\nAloizou A-M, et al.: Pesticides, cognitive function and dementia: a review. Toxicol. Lett. 2020; 326: 31–51. PubMed Abstract | Publisher Full Text\n\nDamalas CA, Koutroubas SD: Farmers’behaviour in pesticide use: a key concept for improving environmental safety. Curr. Opin. Environ. Sci. Health. 2018; 4: 27–30. Publisher Full Text\n\nEndalew, et al.: Pestice use knowledge, attitude, practices and practices associated factors among floriculture worker in bahirdar citu, North West, Ethiopia, 2022. Environ. Health Insights. 2022; 16: 1–10. Publisher Full Text\n\nGesesew HA, et al.: Farmers knowledge, attituted, practices and health problems associated with pesticide use in rural irrigation villages, southwest ethiopia. PLoS One. 2016; 11(9): e0162527. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStruelens QF, et al.: Pestice misuse among small Andean farmers stems from pervasive misinformation by retailers. PLOS Sustain. Transform. 2022; 1(6): e0000017. Publisher Full Text\n\nChittrakul J, et al.: Exposure to organophosphate insecticides, inappropriate personal protective equipment use, and cognitive performance among pesticide applicators. Front. Public Health. 2022; 17(10): 1060284.\n\nGanies SY, et al.: Mechanisms and treatment strategies of organophosphate pesticide induced neurotoxicity in humans: A critical appraisal. Toxicology. 2022; 472(472): 153181. Publisher Full Text\n\nJallow MFA, et al.: Pesticide risk behaviors and factors influencing pesticide use among farmers in Kuwait. Sci. Total Environ. 2017; 574: 490–498. PubMed Abstract | Publisher Full Text\n\nEPA South Australia: Safety and Effective Pesticide Use: A handbook for commercial spray operators. Australia:Government of South Australia.\n\nNgah H, et al.: Assessment of Knowledge, Attitude, and Practice on Safe Working in Confined Space among Male Water Services Workers in the Central Region of Malaysia. Int. J. Environ. Res. Public Health. 2022; 19: 7416. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCDC: Personal Hygiene.Reference Source\n\nBagheri, et al.: Farmers’ behavior in reading and using risk information displayed on pestice labels: a test with the theory of planned behaviour. Pest Manag. Sci. 2022; 77(6): 2903–2913.\n\nDamalas CA: Farmers’ intention to reduce pesticide use: the role of perceived risk of loss in the model of the planned behavior theory. Environ. Sci. Pollut. Res. Int. 2021; 28(26): 35278–35285. PubMed Abstract | Publisher Full Text\n\nMa’rufi I, et al.:Pesticide Use Behavior, Cognitive Dysfunction and The Model of Safety Standard of Pesticide Use among farmworker in Indonesia. [Dataset]. Mendeley Data. 2023; V4. Publisher Full Text"
}
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[
{
"id": "170997",
"date": "03 May 2023",
"name": "Donald Cole",
"expertise": [
"Reviewer Expertise Environmental and occupational medicine",
"epidemiology",
"public health"
],
"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\nImportant work, colleagues. You also provide a pathway to a substantial body of Indonesian work on pesticides and health in your References, very important to add to the global literature. Good luck with additional analyses and revisions.\nComments:\nTitle – needs some English editing as unclear meaning e.g. a model safety standard (an ideal), or a model of usual safety practices (empirically informed)?\nAbstract\nResults - If the first sentence is about residues on products, need to indicate product sampling and lab analysis in methods.\n\nChlorpyrifos is classified as an organophosphate pesticide, not organochlorine. Perhaps organophosphates or organochlorines? Massive impacts on cognitive status!\n\nNot sure what 'favourable pesticide use behaviour' means?\n\nPesticide application at night (dissemination refers more to information or communications).\n\nModel safety standard has four domains? Or Model predicting cognitive impairment?\n\nConclusions – IPM principles. May protect – well said. Is education the main feasible intervention, rather than regulations and import controls at the national level?\nIntroduction\nGood information on Indonesian burden of pesticide illness. Less general information about pesticides and more international literature relevant to this particular study needed.\nMethods\nSetting and population. Are these farmers as well as farmworkers? i.e. the economically active population engaged in agriculture?\n\nX-sectional design with independent and dependent variables the same time. Reserve predictor for longitudinal studies.\n\nCan you use table 1 to provide more characteristics of the participants e.g. age, gender, literacy?\n\nVariables – best to clearly separate those variables you consider dependent e.g. cognitive impairment, and those independent e.g. practices.\n\nRationale for the MoCa – Ina vs elements of the WHO Neurobehavioural battery – see Anger K and colleagues work – which has been used in pesticide using populations globally? < 26 is mild cognitive impairment.\n\nFor non-Indonesians, please say how the pesticide use behaviour items relate to others in use in the international literature. Appreciate having a copy of the questionnaire in the extended data on the Mendeley repository.\n\nFarmworker – farmer pesticide dissemination better to use the term application method.\n\nPesticide storage and commodity are more farm characteristics than person characteristics. I would re-categorize.\n\nQuestionnaire measurement characteristics are best thought of as part of analysis. Coefficients chosen are fair enough for versions of reliability (Cronbach Alpha is usually equated with internal consistency, whereas Pearson correlation coefficient is strongly associated with test–retest reliability) but not the varieties of validity. Any other approaches taken e.g. a couple of observers vs questionnaire responses?\n\nRationale for choice of order independent variables first, and then dependent variable? Same data collector or different?\n\nAgricultural product sampling should be in data collection, not analysis. How did you decide on which 15 samples, across how many products? If present, what kinds of concentrations are implied?\n\nStatistical analysis in b) makes sense but did you check relationships across independent variables as well? Currently, I worry that some are spurious e.g. outdoor pesticide storage, perhaps indicator of something else in Table 6.\n\nModel development seems a kind of knowledge synthesis – translation tool. Not sure how this was done, by whom. More elaboration would be helpful\nResults\nTable 3. Seems like you have a big enough sample to split the abnormals into the usual MoCA score categories i.e. 18–25 points, Mild cognitive impairment; 10–17 points, Moderate cognitive impairment; Fewer than 10 points, Severe cognitive impairment. Severe was likely rare (otherwise would not be able to farm). With Normal, Mild and Moderate-Severe, you could use ordinal logistic regression. Did you try this? If not, why not?\n\nTable 5. Not sure how the cut points between worse, moderate and better were chosen, seems very skewed distribution to higher scores. How about tercile cut points, so that the variable has more power to distinguish among groups and hence increase power of associations?\n\nTable 6. Your lower age category acting as referent is too small. Suggest aggregating so <30 yrs old. May then have more power to detect difference by age. 2 hr cutpoint reduces power. Poor categorization of pesticide use behaviour reduces power to detect differences, given zero in worse.\n\nFigure 2 model needs additional clarification on valence of pathways e.g. increasing or decreasing pesticide use. Not sure what the bidirectional arrows between blue domains signifies.\nDiscussion\nNeeds to have less general information and repetition of results, leaving room for more analysis of results in relation to global literature. The focus on personal farmer – farmworker behaviour versus contextual factors is less than helpful in many LMICs.\nReferences\nGood on Indonesian work, very limited on relevant international work. Need to do an up to date search on PubMed or Google Scholar. Particularly relevant that I am aware of would be:\n- For practices - Orozco et al., (2009)1.\n- For relationship with neurocognitive function, Cole et al., (2011)2.\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": []
}
] | 1
|
https://f1000research.com/articles/12-174
|
https://f1000research.com/articles/11-505/v1
|
09 May 22
|
{
"type": "Research Article",
"title": "Evaluation of additive manufacturing processes in the production of oculo-palpebral prosthesis",
"authors": [
"Diego Eyzaguirre",
"Rodrigo Salazar-Gamarra",
"Salvatore Binasco Lengua",
"Luciano Lauria Dib",
"Diego Eyzaguirre",
"Salvatore Binasco Lengua",
"Luciano Lauria Dib"
],
"abstract": "Background: Prosthetic restorations are made to adapt or attach missing human parts in order to restore function and appearance. Maxillofacial defects connote a greater impact on patients, since the face cannot be concealed, and all the senses of the human body are expressed in it. Therefore, in order to restore the patient’s quality of life, they are the ones that require the best possible adaptation to the characteristics of the patients. Methods: For the maxillofacial prostheses to fit patients, they must be personalized for each patient. The NGO “Mais Identidade” is a multidisciplinary team that specializes in the rehabilitation of patients with maxillofacial trauma. They use digital manufacturing as a tool to manufacture personalized maxillofacial prostheses for patients. With the help of the NGO, the following research is conducted with the purpose of evaluating different methods of additive manufacturing, 3D printing, in order to select the equipment that suits the needs of the method used in the manufacture of maxillofacial prostheses. To this end, eyelid models will be manufactured in different additive manufacturing equipment, and these will be evaluated according to their economic, physical, and aesthetic characteristics.",
"keywords": [
"Maxillofacial prosthesis",
"anaplastology",
"Digital Models",
"Additive Manufacturing",
"3D-Printing"
],
"content": "1. Introduction\n\nProsthesis encompasses a wide range of mechanisms for the replacement of body parts, in order to rehabilitate the characteristics of the missing part in function or appearance. Within them, there is a branch known as “maxillofacial prostheses”, among which are nasal, ear, oculo-palpebral prostheses, etc.1 They are generally used by patients who have suffered cancer (52%), deformities due to accidents (17%) and/or congenital diseases (19%), among others.2\n\nMost of the prostheses, being systems that simulate missing body parts, must be personalized for each patient, which tends to raise their costs. Traditional manufacturing methods require a lot of professional and patient time. In addition, in the public health system, when the service exists and is covered, there are patients who wait between 6 months and 2 years for their rehabilitations. Once the appointment is obtained, they can only be served between 30 minutes to 2 hours per appointment due to the shortage of time and high demand. With the method proposed by the NGO “Mais Identidade”, global work times can be reduced by half.3\n\nWith the aim of optimizing the process and making prostheses more accessible and of good quality,4 both data collection and manufacturing, a digital manufacturing process is chosen. Which consists of: data collection, such as digitization through 3D scanning or photogrammetry; prosthesis design (reverse engineering software) and rapid prototyping (3D printing).5,6\n\nIn the manufacturing process of these prostheses, the patient’s self-perception, emotional stability, personality characteristics and social circumstances are the most important factors when treating maxillofacial defects, as well as the rehabilitation process.7,8\n\nIn this sense, the purpose of this research is to compare additive manufacturing mechanisms, from a 3D model of the oculo-palpebral model for a future maxillofacial prosthesis, obtained from the “Mais Identidade” Method. It will be evaluated which of the additive manufacturing mechanisms achieves the best reproduction of the leather details and maintains the desired dimensional properties, according to the original file. To select the manufacturing method, the oculo-palpebral models manufactured in 7 different 3D printing mechanisms were evaluated, according to their economic, physical and aesthetic characteristics.\n\nThe structure of this paper is the following: section 2 briefly details the printing techniques used for the testing; section 3 describes the procedure of the experiments; section 4 presents and evaluates the results; section 5 discusses the evaluations and the context in which they were made; section 6 proposes suggestions for future work and research conclusions.\n\n\n2. Resin 3D printing comparison\n\nIt is the process by which physical objects are generated from 3D digital files. These files, prior to being printed, go through software in which they are divided into thin layers, with the desired printing characteristics (speed, layer thickness, etc.).9 For the “Mais Identidade” method, layer levels in the range of 100 μ to 16 μ are used to obtain a high level of detail.\n\nIt is the most used method of 3D printing. This method uses a thermoplastic filament that goes through a heating system where it is heated to a temperature at which it is moldable and extruded to take the desired shape.10 For the present investigation, PLA filament will be used as a material for printing the prototypes due to its printing practicality, low cost and because it is the most used material in this technology.\n\nThis method covers liquid resins that go through a photopolymerization process, which exposes them to a specific range of light, with which they undergo a chemical reaction that solidifies them.10 This technology is usually faster and has a higher level of finish than FDM. Within stereolithography, there are variants such as11:\n\n(1) SLA: A UV laser cures the resin point by point in the resin tank using a projector and a set of mirrors.\n\n(2) LCD: An LCD screen projects the UV light and passes through a filter that allows the exposure of light in the necessary points.\n\n(3) DLP: A projector emits light and through a mirror generates the shapes to be printed layer by layer.\n\nThe resins used, both in SLA and LCD and DLP, go through the photopolymerization process when interacting with a light range of 405 nm. Generally, each equipment uses its own resin, so basic light curing resins will be used for prototypes.\n\nThis method is based on the injection of polymers that are cured by ultraviolet light. This technology stands out for its high speed and high print resolution, as well as being able to reproduce functional models without the need to assemble them.12 For this research, Vero black was used to print the model, and Sup706 was used for the support.\n\n\n3. Methods\n\nThe selection of the ideal additive manufacturing equipment for printing models that are used in the manufacturing process of maxillofacial prostheses by the “Mais Identidade” method is detailed in Figure 1.\n\nThe following technologies were used for the tests: FDM, SLA, LCD, DLP and POLYJET. Table 1 specifies the characteristics of the equipment selected for its good resolution and precision.\n\nFor the tests, the model to be printed was a clinical case of a 75-year-old patient with an oculo-palpebral trauma. For the input parameters, the best printing options were selected: per layer, material to be used, printing temperature (FDM), exposure times (SLA, LCD, DLP), etc.\n\nFor the tests, three impressions per equipment were made, to make an average with the data, based on the Design of Experiments theory. The printed models, as they require supports, must go through a post process that eliminates them to obtain the final model.\n\nFor each impression, the data of the printing parameters were taken, to register them and carry out the economic and physical evaluations.\n\n3.4.1 Economic data collection\n\nTo carry out the economic evaluations of each equipment, the data shown in Table 2, must be collected from each impression.\n\nUsing the previous data, the cost was calculated using the following equations:\n\n1. Cost of material used\n\nWhere:\n\n• MC:Material Cost$\n\n• C:Costperliter or kilogramS/liter or kilogram\n\n• V:Print VolumemLogr\n\n2. Cost hours machine worked\n\nWhere:\n\n• MHC:Machine Hour Cost$\n\n• T:Printing TimeHr\n\n• MH:Machine Hours$/hr\n\nTaking into consideration that the Machine Hour is calculated as follows:\n\nWhere:\n\n• EV:Equipment Value$\n\n• RV:Rescue Value$\n\n• UL:Useful Lifeyears\n\n• D:DaysperYeardays/year\n\n• Hr:Hoursperdayhours/day\n\n3. Cost man-hour worked\n\nWhere:\n\n• CMH:CostperManHour$\n\n• D:DesignHr\n\n• E:EspecificationsHr\n\n• C:ControlHr\n\n• PP:Post PrintingHr\n\n• MH:ManHour$/hr\n\n• Taking into consideration that the cost of Man Hour is a fixed cost of $15/hr\n\n4. Printing cost\n\n3.4.2 Physical data collection\n\nFor physical evaluations, each printed model is digitized and compared to the original digital file. To do this, each model is covered with developer spray to obtain better scans; reference points are placed on the back face of the model; in the ZEISS software it is scanned with the COMET 8M model; the rotary option is selected, with 10 stops and the back and front of the model are scanned, obtaining the results shown in Figure 2.\n\nWith help of the reference points, the two shots are coupled to turn it into a single digitized model. Finally, the digitized model is compared with the original digital model and the deviation between both is obtained for each case, as shown in Figure 3.\n\nAfter registering the necessary data, economic, physical and aesthetic evaluations are made. Each evaluation has a score from 1 to 5, where 5 (five) is the model with the best features and 1 (one) the one with the lowest.\n\nIn the economic evaluation, the manufacturing cost for each prototype was considered for the score. In the physical evaluation, the precision was obtained according to the mean deviation for the models printed by each device. The aesthetic evaluation was carried out by Dr. Rodrigo Salazar, a specialist in the maxillofacial rehabilitation, according to his appreciation of the prototypes.\n\nAfter evaluating the prototypes by the established parameters, the final scores were multiplied equally, 33.33% per evaluation. Once the scores were multiplied by the weights of each factor, the totals were added.\n\n\n4. Results\n\n4.1.1 Mini L\n\nFor printing on the MINI L, with FDM technology, the 3DTALK slicer was used and parameters are shown in Table 3. The model is shown in Figure 4.\n\nThe model was not reproduced correctly, since it has complex parts that cannot be reproduced by FDM printers. For this reason, it was decided to leave aside the FDM technology in the evaluation.\n\n4.1.2 Photon S\n\nFor printing on the Photon S, with LCD technology, the CHITUBOX slicer was used and parameters are shown in Table 4. The model is shown in Figure 4.\n\n4.1.3 DS-200\n\nFor printing on the DS-200, with LCD technology, the 3DTALK slicer was used and parameters are shown in Table 5. The model is shown in Figure 4.\n\n4.1.4 Phrozen Shuffle XL\n\nFor printing on the Phrozen Shuffle XL, with LCD technology, the CHITUBOX slicer was used and parameters are shown in Table 6. The model is shown in Figure 4.\n\n4.1.5 MoonRay S\n\nFor printing on the MoonRay S, with DLP technology, the RayWare slicer was used and parameters are shown in Table 7. The model is shown in Figure 4.\n\n4.1.6 PRO95\n\nFor printing on the PRO95, with DLP technology, the RayWare slicer was used and parameters are shown in Table 8. The model is shown in Figure 4.\n\n4.1.7 Objet500 Connex3\n\nFor printing on the Objet500 Connex3, with Polyjet technology, a proprietary slicer was used the parameters are shown in Table 9. The model is shown in Figure 4.\n\nThe printing data per piece are shown in Table 10. Values such as: Days per year (Ds), Hours per day (Hr), Design, Specifications, Control and Post Printing Man-Hours are specified in Section 3.4.1.\n\nUsing the data obtained and equation 3.1 – 3.5, the printing cost was obtained as shown in Table 11.\n\nAs a result of the alignment and boolean cut of the digitized models with the originals, as shown in Figure 5, the deviation between them and the corresponding physical data in Table 12 is obtained.\n\n4.3.1 Economic evaluation\n\nAs shown in Table 13, the equipment with the best score and the lowest printing cost is the Photon S. While the equipment with the lowest score and the highest printing cost is the Objet500 Connex3.\n\n4.3.2 Physical evaluation\n\nAs shown in Table 14, the devices that are in the range of deviation with the best score are: Photon S, Phrozen Shuffle XL and PRO95, while the devices with the highest deviation are: DS-200 and Objet500 Connex3.\n\n4.3.3 Aesthetic evaluation\n\nAs shown in Table 15, the prints of the PRO95 and Objet500 Connex 3 obtained the best score, while the equipment with the least score was the DS-200 printer.\n\n4.3.4 Multicriteria evaluation\n\nFinally, as shown in Table 16, the equipment with the best combined score were the Photon S and the PRO95, with 4.67 out of 5.\n\nThe Photon S, due to its LCD technology, is an economical equipment, with a high level of precision and suitable for using a wide range of resins. The disadvantages of the equipment are its printing volume, 11.5×6.5×16.5 cm, in addition to having components with a short useful life, LCD screen, FEP film, etc.\n\nThe PRO95, due to its DLP technology, has an excellent level of precision, its large printing volume, as well as being one of the fastest stereolithography equipment on the market. The disadvantages of the equipment are its high cost, which exceeds $10,000 and its manufacturing cost is almost four times that of the Photon S.\n\nFor the choice of equipment to be used in the “Mais Identidade” methodology, the volume of work, acquisition capacity, reliability of the equipment, among other parameters, must be considered.\n\n\n5. Discussion\n\nIn the investigation, a standardized methodology was proposed in order to minimize the variation between tests. As in the printing process in LCD and DLP equipment, both in the steps in the use of the slicer and in post printing. In the same way, this must be done in the digitization process with the Comet 8M scanner, since it has labor requirements for optimal results.\n\nPrevious research on additive manufacturing (3D printing) demonstrates the feasibility of its use for manufacturing processes of maxillofacial prostheses. Unlike these investigations, this one focuses on the equipment within the Peruvian market for the selection of the ideal team for the “Mais Identidade” process, evaluated based on the investigation of the Mais Identidade Institute, in conjunction with Dr. Rodrigo Salazar. Likewise, it was decided to use these seven pieces of equipment in the investigation due to time limits and accessibility to them.\n\n\n6. Conclusions and future work\n\nIn the economic evaluation the Photon S printer obtained the best score with 9.72 dollars, unlike the Objet500 Connex3 which obtained the lowest score with 32.95 dollars. In the physical evaluation, the Photon S, Phrozen Shuffle XL and PRO95 obtained the best score, within the deviation range of 0–2%. While the DS-200 and Objet500 Connex3 equipment obtained the lowest score, within the deviation range of 4–6%. In the aesthetic evaluation, the doctor gave his appreciation for the printed models, highlighting those printed on the PRO95 equipment, while the equipment with the lowest results were the DS-200 and Objet500 Connex3.\n\nWhen obtaining the final results, there are two teams with equal scores in the Multicriteria Analysis (Photon S and PRO95), both scored 4.67 points out of 5. The characteristics of each team should be taken into consideration: printing volume, printing speed, volume of work; as well as organizational factors: budget, conditions or workflow.\n\nIn this way, it is recommended in future research to broaden the spectrum of evaluation with criteria such as: printing capacity of each equipment, reliability of the equipment, volume of work, etc. As well as expanding the range of technologies and equipment to be evaluated, since with technological advances, equipment may arise that is more suited to the needs of each organization.",
"appendix": "References\n\nAndrades DP: Trauma Maxilofacial, Santiago de Chile.2004.\n\nNemil CAHYBTYKSK: Quality of life of patients with implantretained Caxillofacial prostheses: A prospective and retrospective study. J. Prosthet. Dent. 2013; 109(1): 44–52. PubMed Abstract | Publisher Full Text\n\nSalazar R: Interviewee, Entrevista Método Masa Identidad. [Intreview].29-09-2019.\n\nMéndez-Ruiz HIM-C y V: Diseño y fabricación de prótesis faciales utilizando técnicas modernas de la ingeniería. Revista de aplicaciones de la Ingeniería, Tangamanga. 2016.\n\nMazher Iqbal Mohammed JTBCGP a IG: Advanced Auricular Prosthesis Development by 3D Modelling and Multi-Material Printing. Knowledge E. 2017; 1: 7.\n\nMaj Al Mardini CEGNG: A technique to reproduce a mirror-image wax pattern of an ear using rapid prototyping technology.2005; 94(2): 195–198.\n\nMuhanad JWDS, Hatamleh M: Closed-eye orbital prosthesis: A clinical report. The Journal of Prosthetic Dentistry, United Kingdom. 2015.\n\nJani NGSRM: An Evaluation of Facial Prostheses. J. Prosthet. Dent. 1978; 39(5); 546–550. Publisher Full Text\n\nKVP: Keene Village Plastics. [Last Access: 07-06-2019]. Reference Source\n\nRedwood B: 3D Hubs. [Last Access: 07-06-2019]. Reference Source\n\nCherdo L: Aniwaa. [Last Access: 07-06-2019]. Reference Source\n\nGreguric L: ALL3DP.29 Junio 2019. [Last Access: 11 Noviembre 2019]. Reference Source"
}
|
[
{
"id": "150243",
"date": "23 Sep 2022",
"name": "Dinesh Rokaya",
"expertise": [
"Reviewer Expertise Dentistry",
"Prosthodontics",
"Maxillofacial Prosthetics",
"Dental Biomaterials"
],
"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 an interesting study but needs significant corrections and editing of the manuscript.\nAbstract:\n“Prosthetic restorations are made to adapt or attach missing human parts in order to restore function and appearance.” Please remove this line as this is generally for intraoral prostheses. And add one line on the role of the maxillofacial prosthesis in the restoration of the maxillofacial defect.\n\nAdd objectives of this research.\n\nIt is better to add some results.\n\nIntroduction:\nPlease add some common biomaterials that can be printed for medical applications.1\n\nIn the introduction, it will be useful to add a paragraph on the ocular prosthesis in the restoration of the ocular defect.1,2\n\nMaterials and Methods:\nPlease add references for the data in Table 1, and Tables 4-9.\n\nAdd references for the equations used.\n\nPlease describe more on the statistical analysis.\n\nResults:\nFigure 1 should be edited to make it better fitting in the manuscript.\n\nDiscussion:\nMore discussion needs to be done comparing with other studies.\n\nPlease add the limitations of this research.\n\nConclusion:\nIt is long. Present the conclusion in a better way and make it concise.\n\nOverall:\nRevision is required.\n\nRe-access is needed after the revision.\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? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "9304",
"date": "14 Feb 2023",
"name": "Salvatore Binasco Lengua",
"role": "Author Response",
"response": "Thank you for the feedback. A new version of the manuscript was uploaded. We did the changes in the abstract for a better preview of the paper and added the topics you recommended in the introduction. The Data in Table1 and 4-9 was made by us, based on the printing parameters on the printers used. We also correct the discussion and conclusion. Just a question: What exactly do you mean by Figure 1 best fitting the manuscript?"
}
]
},
{
"id": "150240",
"date": "03 Oct 2022",
"name": "Rodrigo de Faria Valle Dornelles",
"expertise": [
"Reviewer Expertise Plastic Surgery",
"Cranio-Maxillo-Facial Surgery",
"3D researcher"
],
"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 study proposes to quantitatively evaluate the quality and cost results of different methods of producing oculo-palpebral prostheses by means of 3D printing. The authors have background and experience for the production of the piece and summarize the workflow. The additive manufacturing methods used and the calculation methods used to define costs are described. Quality was assessed objectively by Boolean principles and subjectively by one of the authors. The conclusion was based on findings with the formulas described and on a subjective assessment of the most appropriate method.\nIs the study design appropriate and is the work technically sound?\nThe subjective assessment would be more appropriate if it were performed by more than one professional not connected to the study\n\nAre sufficient details of methods and analysis provided to allow replication by others?\nIt was not clear the parameters used for printing, especially with regard to FDM\n\nAre all the source data underlying the results available to ensure full reproducibility?\nSame reason as before, and not clear why the FDM method was discarded\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? No\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? Yes",
"responses": [
{
"c_id": "9305",
"date": "14 Feb 2023",
"name": "Salvatore Binasco Lengua",
"role": "Author Response",
"response": "Thank you for the feedback. In a new version of the manuscript we have clarified the points you mentioned about printing parameters and ruling out FDM technology. We will also take into account the comment about an evaluator not linked to the study for future work."
}
]
}
] | 1
|
https://f1000research.com/articles/11-505
|
https://f1000research.com/articles/12-173/v1
|
13 Feb 23
|
{
"type": "Research Article",
"title": "Uncovering culinary medicine research themes: Current status and future direction",
"authors": [
"Jyothi Mallya",
"K Thirugnanasambantham",
"Pallavi Shettigar",
"Jyothi Mallya",
"K Thirugnanasambantham"
],
"abstract": "Background: Culinary medicine (CM), an emerging discipline, is a novel approach that focuses on the art of food and cooking to prevent or improve health outcomes among chronic patients suffering from lifestyle diseases. The concept originated in the USA, gaining interest from scholars in medicine, nutrition, nursing, and the gastronomic discipline. Notably, in the last five years, there has been exponential growth in CM literature. In this regard, this study sought to examine the growth, performance and distinct research themes of CM literature over time.\nMethods: To achieve the study’s objectives, this study employs descriptive, performance and bibliometric analysis. The descriptive analysis was applied to examine the growth of the CM literature since its emergence. The performance analysis was used to identify the most influential journals, articles, and authors in the CM domain. The bibliographic coupling analysis was adopted to discover the various research themes of the CM knowledge base.\nResults: This study identifies three stages of literature development: Early stage, modest growth stage, and emerging stage. Further, the results indicate that most of the studies on CM had been conducted in developed countries. Our findings reveal a clear interest in integrating the CM curriculum into medical/nutrition education programs in recent years. Additionally, the study discovers four distinct main research themes: knowledge assessment, impact measurement, acceptance and efficacy, and implementation of CM.\nConclusions: These findings are helpful for scholars in medicine, nutrition, nursing, and gastronomy as they provide an overview of CM’s development and research focus. Future studies could focus on expanding the geographical distribution of research on CM and further exploring the identified research themes to gain a deeper understanding of the potential of this approach for improving health outcomes among chronic disease patients.",
"keywords": [
"culinary medicine",
"nutrition",
"gastronomy",
"research themes",
"knowledge assessment",
"impact measurement",
"acceptance and efficacy",
"implementation"
],
"content": "Introduction\n\nLifestyle diseases kill almost 41 million people annually; around 71% of deaths globally1 primarily result from lifestyle habits. Chronic diseases such as heart disease, stroke, diabetes, obesity, and some types of cancer are lifestyle diseases resulting from three modifiable lifestyle behaviors: smoking, eating poorly and being inactive.1 According to a World Health Organization report,2 chronic diseases accounted for 61% and 49% of all deaths and global disease burden, respectively. By 2030, it is projected that 56% of the world’s population will be afflicted with chronic diseases, accounting for 70% of all global deaths. However, healthier lifestyles and eating behaviors can prevent approximately 80% of chronic diseases because unhealthy dietary patterns are key drivers of inflammation and disease development.3 A poor-quality diet has been linked to one in five deaths globally.4,5 One of the fundamental rights of patients with chronic diseases is the timely administration of an appropriate diet to accelerate recovery and improve their quality of life.6 It also underlines the necessity of offering an appropriate diet outside the hospital for the rapid recovery of chronic patients.7\n\nIn his seminal text,8 Brillat-Savarin defines Gastronomy as “the reasoned comprehension of everything connected with the nourishment of man” (1970, p. 52). He contends that gastronomy relates to history, physics, chemistry, cookery, commerce, and political economy and “[…] governs man’s whole life”. Later, other academics recognized the development of this discipline as crucial for sustainable and functional food.9 Notably, the learning and training in gastronomy are also applied in the healthcare field to cultivate dietary recommendations for patients suffering from chronic diseases.10 However, poor integration programs (For example, culinary nutrition, also known as culinary medicine) in medical curricula inhibit medical practitioners from playing the role of nutrition advisors and lifestyle models.11\n\nCulinary medicine (CM) is “a practice that incorporates the science of medicine and the art of food and cooking to create an individualized approach to food choices (p.1)”.12 Regarding disease prevention and treatment, CM also considers social and cultural aspects of food consumption.13 The primary purpose of CM is to spread awareness of the significant impact of food on health and disease. Additionally, it offers practical culinary training to impart knowledge on preparing foods with nutritional benefits to prevent, manage, and cure chronic diseases.3 Robust evidence has shown that simple dietary changes can prevent or improve many chronic diseases.14–16 Furthermore, a recent review study recommended the integration of nutrition competencies, such as skill-based nutrition training, into medical education.17 Moreover, many medical schools in developed countries (USA, UK, and Australia) integrate the culinary medicine curriculum (CMC) into their clinical nutrition curriculum.3,18\n\nOver the last three decades, many studies on CM have suggested a growing interest among medical, social science, nursing, and gastronomy scholars. There were review19 and scoping reviews evaluating the impact of nutritional interventions,20 CM programs,13 and CM interventions.21 However, despite being a multidisciplinary and popular research field, there are no comprehensive bibliometric analyses of the CM knowledge base. Therefore, this study sought to answer three research questions. First, how has the CM knowledge base evolved since its beginning? Second, what are the most influential research constituents in the CM domain? Third, what are the research themes in the CM knowledge base? Our study also offers future research opportunities in the CM domain. Forty-seven documents from the Scopus database were analyzed to achieve these objectives. Specifically, the study findings will help future medical/nutrition/gastronomy education researchers identify challenges and opportunities in the CM domain. Our study findings are also helpful for CM chefs targeting chronic disease patients.\n\n\nMethods\n\nData for this study were retrieved from the Scopus database. The journals indexed in Scopus were peer-reviewed. The indexing is based on four numerical quality measures: H-Index, CiteScore, SCImago journal rank and source normalized impact per paper.22 Data for this study were selected using the keywords “culinary” and “medicine” in the article title. The search yielded a total of 69 records. Next, articles published in English journals were selected. Thus, a total of 47 documents were included. For the analyses, we used the VOSviewer software. This software is a freely available computer program developed to construct and view bibliometric maps. VOSviewer was used because of its more remarkable ability to represent the bibliographical map than other software visually. Specifically, VOSviewer helps to demonstrate large bibliometric maps that are easily interpretive.23 Three types of analyses were conducted:1) descriptive analyses, 2) performance analyses, and 3) scientific mapping. Descriptive analyses deal with the growth of the CM literature and the subject-wise distribution of documents. We included the most influential research constituents in the performance analyses, such as journals, articles, and authors. Further, two scientific mapping analyses were conducted to uncover the research themes of the CM literature: Bibliographical Coupling Analysis (BCA).\n\n\nResults\n\nRegarding the first question of the study, we outlined the advancement of the scientific production of the CM knowledge base. Figure 1 shows the development and trends, suggesting that the CM knowledge base is still emerging. Nevertheless, the growth rate over the years has not been equally dispersed. Between 1992-2016 (24 years), only 10% of the total contributions were published. Therefore, this period can be described as the “Early stage” of the CMs’ scientific production. During this period, there were early discussions on the importance of CM as a healthy eating habit. Between 2017-2019 (three years), there were 13 publications (28%). This period witnessed substantial growth in the number of publications. Thus, it can be described as a “modest growth stage” in the CM knowledge domain. During this period, a CMC was developed and integrated into the medical education curriculum to improve chronic disease management and prevention. Between 2020-2022, 29 articles were published. Thus, this period can be named as “Emerging stage” of the CM knowledge domain. Intervention studies were conducted during this period, and it was found that integrating CMC into medical and nutrition curricula affected students’ knowledge, attitudes, and behaviors.\n\nA few countries involved in the scientific production of CM literature indicate that this domain is still not conceptualized in developing countries (Figure 2). According to the following figure, 74% of the total scientific production is from the USA.\n\nOur second query identified the most prominent constituents of the CM domain. Tables (Tables 1–3) represent the most influential journals, articles, and authors, respectively. While the count of publications denotes a journal’s productivity, the count of citations illustrates the academic influence and impact.24 Therefore, based on the two-fold measures, the “American Journal of Lifestyle Medicine” was at the top, with 11 publications and 60 citations, followed by Medical Science Educator, with six documents and nine citations (Table 1). However, in terms of citations, the articles published in the “Journal of Alternative and Complementary Medicine” and “Journal of Nutrition Education and Behaviour” had more citations than the journal “Medical Science Educator”. Notably, all these journals were in the Q1 or Q2 quartile of the Scopus journal index. This finding offered a comprehensive assessment of the journal quality of the CM studies. The results suggest that much of this field’s research meets a good quality standard. Further, it is also found that articles have been published in interdisciplinary subject domains such as medicine, nutrition, and alternative and complementary medicine.\n\nArticle-wise citation resulted in eight documents with a minimum of five citations per document (Table 2). The top eight articles are listed in Table 2. The article “Culinary medicine and community partnership: hands-on culinary skills training to empower medical students to provide patient-centred nutrition education” has had 20 citations since its publication in 2019. Therefore, it is safe to consider this article one of the seminal works in the CM domain. Next, we conduct an author-wise analysis. We identified six authors with at least three documents and five citations. Table 3 presents the six authors of this domain.\n\nThe third query identified the intellectual structure and thematic trends of the CM knowledge base. For this purpose, we adopted bibliographical coupling analysis (BCA) using VOSviewer software.25 Bibliographical coupling is the similarity of an article’s references.25 In the BCA, the unit of analysis can be a document, source, or country. In our study, we used documents as the unit of analysis. Thus, BCA was conducted for articles with a minimum of two citations. This analysis resulted in 24 documents across the four clusters. Figure 3 shows the results of the analysis. A larger circle represents a superior connotation for a document.26\n\nCluster one has eight articles. Of these, three articles were commentaries on providing a robust CM for health professionals to support patients’ health outcomes,27 home cooking prescriptions by clinicians,28 and the mechanism of how food and beverages work in the body.29 The remaining four articles assessed participants’ pre- and post-nutrition knowledge, attitudes, and counselling confidence.30–33 The findings of these studies provide empirical evidence for significant improvement in knowledge, attitude, and healthy cooking behaviors among the respondents. However, scholars recommend further inclusion of resources in CM courses to meet participants’ demands.30 Most of the studies in the clusters have adopted the questionnaire method to assess respondents’ pre- and post-nutrition knowledge, attitudes, and counselling confidence.30,32,34 The last document was a Master’s thesis34 that assessed first-year medical students’ knowledge, attitudes, behaviors, and confidence based on a mixed-method research approach.\n\nCluster two contained six articles. Studies in this cluster have assessed the impact of CM education on lifestyle medicine counselling,35 existing nutrition intervention,36 counselling confidence,5 dietary knowledge and behaviours,35 and outcome of CM education.37 The findings suggest that hands-on cooking-based nutrition education, such as Cooking for Health Optimization with Patients (CHOP), significantly impacts Mediterranean diet intake more than traditional nutrition education versus traditional curricula.35 Additionally, participants participating in the CM program were more confident discussing nutrition intake with their patients.5 More importantly, hands-on culinary education courses were positively associated with adherence to the Mediterranean diet and improved knowledge of healthy eating.35 Thus, such interventions are cost-effective for addressing lifestyle diseases, such as obesity and chronic illness.35 Specifically, a study conducted among 1031 Heart failure (HF) admissions found that medication and dietary noncompliance were two significant contributing factors for readmissions (34.62% and 16.92%, respectively). Other factors included comorbidity, HF exacerbation, iatrogenic factors, and drug abuse. In contrast to conventional care, providing CM education to patients with HF would have avoided 93 HF readmissions and saved $3.9 million over an expected 4-year timeframe.38\n\nIn cluster three, there are six studies. Of six, four studies measure the impact of the CM course on nutrition.39–42 The other two studies were commentary papers on integration43 and CM’s importance of CM44 in the medical curriculum. The findings of the studies included in this cluster suggest that the CM elective is highly acceptable40 and valuable to the medical school curriculum.42 These findings also provide evidence for the successful integration of the CM elective course in the nutrition program to combat the rising rates of obesity, diabetes, and preventable diseases related to nutrition.40\n\nCluster four comprised four articles. The studies in this cluster discuss the implementation of CM training,45 the integration of CMC as an interprofessional competency,46 the impact of CMC on biometric and psychological factors,47 and barriers to implementing CMC.48 Studies have adopted research approaches, such as intervention,49 quasi-experimental design,47 and focus groups.48 An experimental study47 also established a substantial decline in HbA1c levels among participants. Furthermore, this study demonstrated a significant increase in the consumption of fruits and vegetables. In other words, the findings of this study suggest a potentially positive impact on health outcomes among patients with type 2 diabetes.47\n\n\nDiscussion and recommendations for future studies\n\nThis first bibliometric study aimed to advance understanding of current research trends and streams in the CM knowledge domain. Our findings suggest a clear interest in integrating CMC into medical/nutrition education programs in recent years. In 2022, 14 new publications evaluated the viability of using CMC in medical/nutritional education.13,21,41,50–52 Studies have also evaluated knowledge and confidence in counselling.31,35\n\nBased on the years of growth of the CM literature, we have identified three stages of literature development: Early stage (1992-2016), modest growth stage (2017-2019) and emerging stage (2020-2022). During the early stage, studies focused mainly on understanding the culinary metaphor.53,54 During the modest growth (2017-2020), most studies were on the feasibility, training, integration, and efficacy of CMC.28,30,33,36,39,40,42,43,49,55–57 A study on formulating a natural medicine based on three culinary herbs for a skin infection58 was also published during the early stage. However, the emerging stage (2020-2022) witnessed prolific growth in literature. Of 47, 29 articles were published during this period. Researchers advanced the CM knowledge base by studying the impact of CM education,50,51,59 barriers to implementing CMC,48,60 remote learning of CM,41,47,52 and the impact of CM training on patients’ health.61 Our findings also revealed that most of these studies had been published over the last five years. Of 47, 40 were published between 2018-2022. Studies have also achieved statistically significant outcomes regarding the promotion of hands-on CM methods over traditional didactic methods to train and assist chronic patients as future physicians.\n\nOur findings also revealed that most published studies were from the United States of America (36 out of 47). This outcome suggests that increasing interest in CM is geographically concentrated and limited. However, this emphasis on North America suggests the need for greater international participation to validate CMC as an effective strategy for nutrition instruction in medical education. It also emphasizes the significance of considering cultural relevance and the probable need for adjustment when implementing international norms.21 CM is an evidence-based field that blends the art of food and cooking with the science of medicine.29 It is considered to help individuals make personal medical decisions regarding healthy eating habits, which helps them to prevent lifestyle diseases and restore well-being. Furthermore, CM attempts to improve a patient’s condition with what she or he regularly eats and drinks.12 Therefore, we recommend that researchers in developing countries focus on integrating CM programs into medical/nutrition programs to benefit individuals’ overall well-being.\n\nOur findings also revealed that most articles were published in medical journals. A healthy diet is one of the four factors that appear to be linked to an 80% risk reduction in deadly chronic diseases.1 In 2020, the World Health Assembly called for developing a national public health policy framework to establish programs for the prevention and control of chronic diseases, emphasizing developing countries. However, there is minimal public awareness regarding the association between health and lifestyle. Modest but achievable lifestyle changes are likely to considerably impact individual and population levels. Therefore, we recommend that future studies in the CM domain focus on these aspects.\n\nThe performance analyses of research constituents identified the most prolific journals, articles, and authors. The “American Journal of Lifestyle Medicine” emerged as the most influential journal, with 11 documents and 60 citations. The second most influential journals in documents and citations were “Medical Science Educator” and “Journal of Alternative and Complementary Medicine”. Further, the two documents from the “Journal of Nutrition Education and Behaviour” had 20 citations. This indicates that the CM is an interdisciplinary discipline.\n\nGiven the recency of this domain, our study identified four major research themes in the CM domain. The identified domains were knowledge assessment, impact measurement, acceptance and efficacy, and CMC implementation. There is a lack of studies on program costs.21 The additional costs involved in personnel, facilities, consumables, and types of equipment remain understudied. Furthermore, these costs may differ significantly between programmes and locations.21 Moreover, although food prescription and CM programs are gaining popularity, there are not enough studies on how physicians/nutritionists can provide evidence-based nutritional information tailored for culturally diverse low-income populations.62 Therefore, this could be another area of research interest in designing a CM program targeted at low-income, food-insecure people. Therefore, we recommend that future studies address this gap.\n\nCM’s beneficial role in improving health and reducing healthcare costs must be integrated beyond medical/nutritional education.3 Focusing more on healthy eating habits and understanding the nuances of the scientific cooking method is critical to reducing chronic disease burden and healthcare expenses. Empowering and teaching individuals about healthy eating habits is cheaper than prescriptions and aggressive treatments to manage chronic diseases.3 Therefore, we recommend that future research should focus on this literature gap. The integration and efficacy of CM programs should be conducted with a different set of samples, such as public and community health professionals. Similarly, although medical/nutrition education professionals are well-trained to deliver nutrition education to students, this could also be offered to school communities.63\n\nGastronomy, a new interdisciplinary approach to food, has been recognized as a vital yet underexplored area of academia.9 In developed countries, such as the USA and the UK, CM chefs prepare a diet for chronic patients. These CM chefs prepare food based on recipes provided by dietitians.64 Furthermore, because of the popularity of healthy nutrition, culinary services with special menus, such as gluten-free, are extended to chronic patients by chefs without sufficient knowledge.3 Previous studies also revealed that a vegan diet is associated with a lower risk of diabetes,65 CVD, and IHD.66 However, our study did not find any studies on other popular diets, such as the vegetarian diet, and their impact on chronic patients. This gap can be addressed by the collaborative efforts of gastronomists12 and dietitians to improve performance in the health sector. Therefore, we recommend that future studies in the domain of CM focus on these research gaps in the literature. Future studies should also consider integrating vegetarians and other popular diets into CMC. The findings of these studies can offer concrete and robust ways for healthcare solutions to improve the quality of life of chronic patients.\n\nThis study adds to the body of the CM knowledge base in several ways. This study was the first to demonstrate the thematic evolution of critical research themes in the CM domain. By doing so, this study advances CM’s learning and comprehension of CM. This paper also explains the future direction of this field of study. Second, this study advances the field’s theoretical advancement by assisting researchers in identifying prospective avenues for CM. Given recent findings, this study encourages medical/nutritional educators to innovate and integrate CM initiatives into medical/nutritional education. This study identified a subtle but noteworthy body of literature describing the evolution of the CM knowledge base over time since its emergence. This study also empirically identified the most influential research constituents in the CM domain. Our study also adds to the body of knowledge by scientifically identifying different clusters in the CM domain. The four clusters that emerged were knowledge assessment, Impact Measurement, acceptance and efficacy, and implementation of the CM program. Our study is helpful for future researchers in the domain of CM, as they can visualize the evolution and development of the CM knowledge base concerning the assessment, measurement, acceptance, and implementation of the CM. Further, our study is valuable to practitioners and policymakers who wish to implement, measure, and assess CM programs.\n\nIrrespective of its contribution to the body of CM knowledge, this study has a few limitations. First, the documents for this study were included only from the Scopus database. Though the Scopus database is one of the reputed databases, the studies from the other databases could enrich the study. Therefore, we recommend that papers from other databases be used in future research. Second, this study only included articles in English. Thus, it is advised that future studies should include non-English articles. Third, software such as VOS viewer places the same threshold value for documents at different points when performing bibliometric analysis.\n\n\nConclusion\n\nFor the last five years, there has been a scholarly interest in CM among scholars across different domains of literature. Many medical schools have successfully integrated CMC into their programs in developed countries, such as the USA and Australia. However, developing countries are yet to attempt to include CMC in their programs. The inclusion of CMC is essential for several reasons. First, teaching culinary skills to children and youth will likely prevent lifestyle diseases such as obesity, diabetes, and heart disease. Second, culinary skills and competencies are associated with an increased intake of fruits and vegetables. Third, most studies included in this review found that culinary skills in medical/nutrition education enhance knowledge, attitude, self-efficacy, and health-promoting behaviours among physicians and dieticians. Fourth, CMC offers a unique opportunity for experiential learning, further encouraging nutrition-led behaviour among the youth. Most importantly, CM interventions appear logical in targeting chronic diseases because unhealthy eating habits are considered attributing factors, such as lifestyle diseases. Fifth, properly integrating CMC in medicine and nutrition curricula helps reduce healthcare costs. Finally, given the significance of healthy cooking and eating habits in preventing chronic diseases, if adopted scientifically and successfully, CM plays a vital role in overall well-being and reduction in healthcare costs. Capitalizing CM as a tool to improve dietary patterns is the most significant step in incorporating lifestyle into medicine. To be successful in community outreach efforts, enhanced CM education is imparted in medical, nutritional, and culinary programs. CM programs should be expanded and promoted in developing countries. This expansion and inclusion may further impact chronic patients and overall community well-being.\n\n\nAuthor contributions\n\nMs Pallavi Mahesh Shettigar: conceptualization, writing - original draft; writing - review & editing, validation\n\nDr Chef K. Thirugnanasambantham: conceptualization, methodology, resources, supervision, validation, visualization\n\nMs Jyothi Mallya: conceptualization, data curation, formal analysis, methodology, software, writing the original draft",
"appendix": "Data availability\n\nFigshare. Culinary Medicine. DOI: https://doi.org/10.6084/m9.figshare.21973925.v1. 67\n\nThis project contains the following data:\n\nThis is bibliographic data of articles on culinary medicine\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAl-Maskari F: Lifestyle diseases: An Economic Burden on the Health Services|United Nations. United Nations.2021.\n\nWorld Health Organization: Preventing chronic diseases: a vital investment: WHO global report. World Health;2005.\n\nMauriello LM, Artz K: Culinary Medicine: Bringing Healthcare Into the Kitchen. Am. J. Health Promot. 2019; 33: 825–829. SAGE Publications Inc. PubMed Abstract | Publisher Full Text\n\nWood NI, Gleit RD, Levine DL: Culinary nutrition course equips future physicians to educate patients on a healthy diet: an interventional pilot study. BMC Med. Educ. 2021 Dec 1; 21(1): 280. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nD’Adamo CR, Workman K, Barnabic C, et al.: Culinary Medicine Training in Core Medical School Curriculum Improved Medical Student Nutrition Knowledge and Confidence in Providing Nutrition Counseling. Am. J. Lifestyle Med. 2022 Jun 21; 16(6): 740–752. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAsano S, Jasperse AE, Schaper DC, et al.: A Culinary Medicine Elective Course Incorporating Lifestyle Medicine for Medical Students. Med. Sci. Educ. 2021 Aug 1; 31(4): 1343–1349. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDreibelbis TD, George DR: “Low-Hanging Fruit”: Enhancing Culinary Medicine Curricula by Building Intuitive Community Partnerships. Med. Sci. Educ. 2018 Sep 13; 28(4): 813–814. Publisher Full Text\n\nVanderpool LE, Trilk JL, Griffin SF, et al.: Culinary medicine an evaluation to assess the knowledge, attitudes, behaviors, and confidence of first-year medical students in a culinary medicine teaching kitchen. Top. Clin. Nutr. 2020; 35(4): 351–360. Publisher Full Text\n\nRazavi AC, Monlezun DJ, Sapin A, et al.: Multisite Culinary Medicine Curriculum Is Associated With Cardioprotective Dietary Patterns and Lifestyle Medicine Competencies Among Medical Trainees. Am. J. Lifestyle Med. 2020 Jan 24; 14(2): 225–233. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIrl BH, Evert A, Fleming A, et al.: Culinary Medicine: Advancing a Framework for Healthier Eating to Improve Chronic Disease Management and Prevention. Clin. Ther. 2019 Oct 1; 41(10): 2184–2198. PubMed Abstract | Publisher Full Text\n\nRothman JM, Bilici N, Mergler B, et al.: A Culinary Medicine Elective for Clinically Experienced Medical Students: A Pilot Study. J. Altern. Complement. Med. 2020 Jul 14; 26(7): 636–644. PubMed Abstract | Publisher Full Text\n\nRazavi AC, Monlezun DJ, Sapin A, et al.: Etiological Role of Diet in 30-Day Readmissions for Heart Failure: Implications for Reducing Heart Failure–Associated Costs via Culinary Medicine. Am. J. Lifestyle Med. 2020 Jul 1; 14(4): 351–360. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPang B, Memel Z, Diamant C, et al.: Culinary medicine and community partnership: hands-on culinary skills training to empower medical students to provide patient-centered nutrition education. Med. Educ. Online. 2019 Jan 1; 24(1). PubMed Abstract | Publisher Full Text | Free Full Text\n\nRing M, Cheung E, Mahadevan R, et al.: Cooking Up Health: A Novel Culinary Medicine and Service Learning Elective for Health Professional Students. J. Altern. Complement. Med. 2019 Jan 18; 25(1): 61–72. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nSicker K, Habash D, Hamilton L, et al.: Implementing Culinary Medicine Training: Collaboratively Learning the Way Forward. J. Nutr. Educ. Behav. 2020; 52(7): 742–746. PubMed Abstract | Publisher Full Text\n\nLawrence JC, Knol LL, Clem J, et al.: Integration of Interprofessional Education (IPE) Core Competencies Into Health Care Education: IPE Meets Culinary Medicine. J. Nutr. Educ. Behav. 2019; 51(4): 510–512. PubMed Abstract | Publisher Full Text\n\nSharma SV, McWhorter JW, Chow J, et al.: Impact of a virtual culinary medicine curriculum on biometric outcomes, dietary habits, and related psychosocial factors among patients with diabetes participating in a food prescription program. Nutrients. 2021 Dec 15; 13(12): 4492. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcWhorter JW, Danho MP, LaRue DM, et al.: Barriers and Facilitators of Implementing a Clinic-Integrated Food Prescription Plus Culinary Medicine Program in a Low-Income Food Insecure Population: A Qualitative Study. J. Acad. Nutr. Diet. 2022 Aug 1; 122(8): 1499–1513. PubMed Abstract | Publisher Full Text\n\nLawrence JC, Knol LL, Clem J, et al.: Integration of Interprofessional Education (IPE) Core Competencies Into Health Care Education: IPE Meets Culinary Medicine. J. Nutr. Educ. Behav. 2019 Apr 1; 51(4): 510–512. PubMed Abstract | Publisher Full Text\n\nHynicka LM, Piedrahita G, Barnabic C, et al.: Interprofessional Culinary Medicine Training Enhanced Nutrition Knowledge, Nutrition Counseling Confidence, and Interprofessional Experience. J. Integr. Complement. Med. 2022 Oct 1; 28(10): 811–820. PubMed Abstract | Publisher Full Text\n\nWattick RA, Saurborn EG, Olfert MD: Impact of a Brief Culinary Medicine Elective on Medical Students’ Nutrition Knowledge, Self-efficacy, and Attitudes. Med. Sci. Educ. 2022 Aug 1; 32(4): 785–792. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYousef NM, Wallace RJ, Harlan GA, et al.: Bringing the “Joy of Healthy Eating” to Advanced Medical Students: Utilizing a Remote Learning Platform to Teach Culinary Medicine: Findings from the First Online Course Based on the ACLM’s Whole-Food Plant-Based Culinary Medicine Curriculum. Am. J. Lifestyle Med. 2022 Jul 1; 16(4): 447–459. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAhmed H, Ogala WN, Ibrahim M: Culinary metaphors in Western medicine: a dilemma of medical students in Africa. Med. Educ. 1992; 26(5): 423–424. Publisher Full Text\n\nWynia MK: Culinary metaphors in medicine. Infect. Dis. Clin. Pract. 1995; 4(6): 437–440. Publisher Full Text\n\nLang RD, Jennings MC, Lam C, et al.: Community Culinary Workshops as a Nutrition Curriculum in a Preventive Medicine Residency Program. MedEdPORTAL J. Teach. Learn. Resour. 2019 Dec 13; 15: 10859. Publisher Full Text\n\nDreibelbis TD, George DR: Integrating Intergenerational Mentoring into a Culinary Medicine Curriculum. Med. Sci. Educ. 2017 Dec 1; 27(4): 575–576. Publisher Full Text\n\nDreibelbis TD, George DR: An Intergenerational Teaching Kitchen: Reimagining a Senior Center as a Shared Site for Medical Students and Elders Enrolled in a Culinary Medicine Course. J. Intergener. Relatsh. 2017 Apr 3; 15(2): 174–180. Publisher Full Text\n\nAparna M, Gayathri V: Formulation of culinary plant medicine against bacterial skin infections caused by Staphylococcus sps. and Streptococcus sps. J. Pure Appl. Microbiol. 2018; 12(3): 1607–1615. Publisher Full Text\n\nD’Adamo CR, Workman K, Barnabic C, et al.: Culinary Medicine Training in Core Medical School Curriculum Improved Medical Student Nutrition Knowledge and Confidence in Providing Nutrition Counseling. Am. J. Lifestyle Med. 2022 Nov 1; 16(6): 740–752. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAsher RC, Bucher T, Shrewsbury VA, et al.: Facilitators and barriers to providing culinary nutrition, culinary medicine and behaviour change support: An online cross-sectional survey of Australian health and education professionals. J. Hum. Nutr. Diet. 2022; 36: 252–265. Publisher Full Text\n\nStauber Z, Razavi AC, Sarris L, et al.: Multisite Medical Student–Led Community Culinary Medicine Classes Improve Patients’ Diets: Machine Learning–Augmented Propensity Score–Adjusted Fixed Effects Cohort Analysis of 1381 Subjects. Am. J. Lifestyle Med. 2022 Mar 1; 16(2): 214–220. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcWhorter JW, Danho MP, LaRue DM, et al.: Barriers and Facilitators of Implementing a Clinic-Integrated Food Prescription Plus Culinary Medicine Program in a Low-Income Food Insecure Population: A Qualitative Study. J. Acad. Nutr. Diet. 2022 Aug 1; 122(8): 1499–1513. Publisher Full Text\n\nde Vlieger N , Riley N, Miller A, et al.: Nutrition education in the Australian New South Wales primary school curriculum: An exploration of time allocation, translation and attitudes in a sample of teachers. Heal. Promot. J. Aust. 2019 Jan 1; 30(1): 94–101. PubMed Abstract | Publisher Full Text\n\nEisenberg DM, Myrdal Miller A, McManus K, et al.: Enhancing medical education to address obesity: “See one. Taste one. Cook one. Teach one.”. JAMA Intern. Med. 2013; 173: 470–472. Publisher Full Text\n\nTuta-Quintero E, Coronado-Sarmiento J, Vega-Corredor MC, et al.: Vegetarian/vegan diets in the control of the glycemic profile in patients with type 2 diabetes mellitus: An scoping review. Med. Natur. 2021 Jan 1; 15(1): 8–15.\n\nDybvik JS, Svendsen M, Aune D: Vegetarian and vegan diets and the risk of cardiovascular disease, ischemic heart disease and stroke: a systematic review and meta-analysis of prospective cohort studies. Eur. J. Nutr. 2022; 62: 51–69. Publisher Full Text\n\nMallya J, Thirugyanasambatham K, Shettigar P:Culinary Medicine. Dataset. figshare. 2023. Publisher Full Text"
}
|
[
{
"id": "200890",
"date": "15 Nov 2023",
"name": "Ashish Dahiya",
"expertise": [
"Reviewer Expertise Hospitality & Tourism Education",
"Culinary Research",
"Indian Food",
"Hotel Operations",
"Housekeeping"
],
"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\nBrief: \"Uncovering Culinary Medicine Research Themes: Current Status and Future Direction\" is a well-presented and informative article that contributes to the understanding of the growth and research themes in culinary medicine literature. While it effectively supports its conclusions with data, providing more information about the sources of data would enhance the study's reproducibility. Overall, it is a valuable contribution to the field of culinary medicine and offers insights for future research directions. However, there is a question which must be answered that India has been observing Culinary Medicine through Ayurveda. This part is silent in the article. Similar contexts can also be observed in other parts of world.\n\nDetailed Report: The article titled \"Uncovering Culinary Medicine Research Themes: Current Status and Future Direction\" exhibits a well-organized structure and effectively communicates its research findings. It adeptly introduces the background, objectives, methods, and outcomes of the study, offering a comprehensive understanding of the subject matter. The article properly integrates current literature, discussing the emergence and significant growth of culinary medicine (CM) as a discipline over the past five years. This effectively contextualizes the research.\nThe study's design aligns appropriately with its research objectives. It employs descriptive, performance, and bibliometric analyses to scrutinize the growth, performance, and research themes within CM literature, which are technically sound approaches for fulfilling the study's aims. Descriptive analysis tracks CM literature's growth, performance analysis pinpoints influential journals, articles, and authors, and bibliographic coupling analysis unveils key research themes. These combined methods provide a holistic overview of CM's development.\nThe article generously offers methodological details, allowing readers to comprehend and potentially replicate the study. However, more information regarding specific bibliometric metrics and thresholds would bolster the methodological transparency.\nThe study heavily leans on bibliometric analysis, focusing on publication and citation data. While traditional statistical analysis is not applied, this method remains appropriate for discerning trends and research themes within CM literature. The interpretation of the findings is robust, successfully identifying research themes and stages of CM literature development.\nThe article does not explicitly address the availability of the source data underpinning the results, an aspect that is typically emphasized in bibliometric studies. Including references to the databases and data sources used for collection would enhance reproducibility.\nThe conclusions drawn are well substantiated by the results, with the study effectively identifying three stages of CM literature development, the geographic distribution of research, and four distinct research themes. These conclusions align with the presented data, offering valuable insights for scholars in various fields. The call for future research to explore CM's potential for enhancing health outcomes among individuals with chronic diseases is logically founded on the study's findings.\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": "215298",
"date": "30 Nov 2023",
"name": "Sanjeev Kumar Saxena",
"expertise": [
"Reviewer Expertise Hospitality & Tourism Management"
],
"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 text highlights the global impact of lifestyle diseases, attributing approximately 71% of deaths to modifiable behaviors such as smoking, poor diet, and inactivity. It introduces the concept of Gastronomy and emphasizes the integration of culinary medicine (CM) into healthcare for preventing and managing chronic diseases through personalized dietary approaches. The study conducts a bibliometric analysis, revealing the evolution of CM literature in three stages and the dominance of the United States in scientific production. It identifies major research themes, including knowledge assessment, impact measurement, acceptance and efficacy, and CM program implementation. The study underscores the need for future research to address gaps in program costs, the impact of CM on diverse populations, and the integration of popular diets into CM. Overall, the findings advocate for the expansion of CM programs, particularly in developing countries, to positively impact chronic patients and community well-being.\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/12-173
|
https://f1000research.com/articles/11-1218/v1
|
26 Oct 22
|
{
"type": "Research Article",
"title": "Gender, digital financial services and vulnerability in the era of pandemics: A cross-sectional analysis",
"authors": [
"Mohammed Amidu",
"Agnes Akpene Akakpo",
"James Kwame Mensah",
"Edward Asiedu",
"Agnes Akpene Akakpo",
"James Kwame Mensah",
"Edward Asiedu"
],
"abstract": "Background: The COVID-19 pandemic has rapidly spread across the world, infecting millions and causing economic disruption on an unprecedented scale. While everyone is affected by the COVID-19 pandemic, vulnerable communities are at the greatest risk. The objective of this study is to examine the relationship between digital financial services (DFS), gender, and the vulnerability of informal settlement dwellers to COVID-19. Methods: We sampled a total of 2,697 households from 101 informal settlements across eleven out of sixteen administrative regions of Ghana. The regions were selected based on the relative severity of the pandemic, and the associated national lockdown regulations. Results: Adopting the multiple regression analytical technique, the results reveal three main findings: First, we observe that males in informal settlements are more likely to be exposed to infected people or a person who died from COVID-19 than females. However, women are more likely to be vulnerable to the pandemic than men as vulnerable populations have a higher susceptibility to pandemics due to less capacity to implement preparedness and response strategies due to disparities in their societal status. Finally, we find that the vulnerability of informal dwellers is moderated by the use of digital financial services. Conclusions: Our results provide policy implications for authorities designing policies to address vulnerability to pandemics in poor informal settlements in Africa.",
"keywords": [
"Digital financial services",
"Gender",
"Vulnerability",
"Pandemics",
"COVID-19",
"Ghana"
],
"content": "Introduction\n\nThe outbreak of the COVID-19 pandemic has spread worldwide, affecting every aspect of life. Millions of people have been affected by COVID-19 and many more have lost their lives. To minimise the impact of COVID-19, governments all over the world instituted measures such as lockdowns, increased handwashing, social distancing, and travel bans. While these measures have helped in containing the spread of COVID-19, they have also led to some unintended consequences (Sumalatha et al., 2021). Indeed, the economy has suffered, jobs have been lost, debts are mounting, people are quarantined in their homes and most vulnerable people are likely to go below the poverty line. While COVID-19 poses a severe threat to all, vulnerable populations are severely affected and face even greater challenges. Indeed, many vulnerable populations are experiencing adverse consequences such as job loss, food insecurity, and the inability to manage existing medical conditions and maintain preventive measures such as social distancing and personal protective gear.\n\nPrevious research has found that vulnerable populations are at greater risk during pandemics because they usually don’t have the capability to implement preparedness and response plans or withstand its consequences due to the disparities in their economic status and other social factors including cultural, settlement, educational and linguistic barriers as well as the inability to access and use health facilities (Debruin et al., 2012 and Hutchins et al., 2009).\n\nThe COVID-19 pandemic and the requirement for social distancing have put a spotlight on digital financial services. Digital financial services are broadly defined as financial services offered through digital platforms such as mobile phones, internet, cards, point of sale (POS), among others (Alexander, 2017). In the case of this study, digital financial services refer to financial services offered/performed through the mobile phone because this was the most common form of technology available to the respondents of the study. Digital financial services (DFS) do not only allow for social distancing but also allow governments to disburse funds to those in need quickly and effectively. More importantly, digital financial services allow many households and firms to rapidly access online payments and financing (Agur et al., 2020). As noted by Arner et al. (2020), whereas digital financial services can be harnessed to respond to the COVID-19 pandemic, the pandemic also has the potential to accelerate their development and use. The point is that, for digital financial services, all transactions continue, and more importantly financial support reaches the vulnerable irrespective of COVID-19 restrictions and health guidelines (Auer et al., 2020).\n\nThe COVID-19 pandemic also poses questions about its effects on men and women. Indeed, the pandemic has affected women and men differently due to their distinct roles in society and national economies. According to the International Labour Organisation [ILO] (2021), while the COVID-19 pandemic led to unprecedented job losses, women have been disproportionately hit (4.2%) compared to men (3%). Research has also shown differences in COVID-19−related beliefs and behaviours. Thus, in their study, Galasso et al. (2020) found that women are more likely to perceive the pandemic as a very serious health problem and to agree and comply with restraining measures. This is partially the reason why more men than women are dying of COVID-19 (Grasselli et al., 2020). Aside from the evidence on perceived impacts, very little is known regarding the impact of the pandemic on various indicators of vulnerability.\n\nDespite the plethora of scholarly research on COVID-19, there appears to be a paucity of research examining how digital financial services have been harnessed as a pro-poor tool to minimise the impact of COVID-19 on vulnerability in the context of developing countries. Some studies have concentrated on the utilisation of digital financial services during the COVID-19 pandemic (Auer et al., 2020; Ting et al., 2020), the impact of the COVID-19 pandemic on vulnerable populations such as women (Nyashanu et al., 2020) as well as adoption and implementation of COVID-19 pandemic measures (Prempeh, 2021). This study differs from previous research to the extent that the focus is on the use of digital financial services to support vulnerable populations in a developing country during the COVID-19 pandemic whereas previous studies focused on the impact of COVID-19 on the vulnerable or the use of digital financial services during COVID-19. The issue of how digital financial services can serve as a catalyst to ameliorate the plight of the vulnerable especially women in developing contexts is worth perusing as this has implications for the achievement of several of the sustainable development goals [SDGs] (Bhatia and Singh, 2019).\n\nThe objective of this paper is to examine the relationship between gender, digital financial services, and vulnerability during COVID-19 in Ghana. This is important to the extent that most of the government policy measures announced in developing countries during the COVID-19 pandemic are in the form of cash assistance (Davidovic et al., 2020). The use of digital means helped in achieving the purpose of government policy by reaching the vulnerable while reducing contact and spread of the virus. This is significant because digital financial services allow for the disbursement of financial support to those in need quickly, effectively, and safely while preventing direct contact among individuals (Auer et al., 2020). Analysing the pandemic from a gender and digital financial inclusion perspective is significant as gender is a social category that shapes the pattern of the outbreak itself and people’s access to resources (Kim et al., 2020).\n\nThe results of the study revealed three main findings: First, we observe that men are more likely to be exposed to the COVID-19 pandemic than women living in slum populations. During pandemics, women are usually restricted to traditional roles including caregiving in their homes (Power, 2020). This acts as a movement restriction on the part of women which reduces their exposure to pandemics. Men, often charged with the responsibility of providing for their household are put in a very precarious position to go all out to work to fend for their families, hence increasing their exposure. Secondly, this study finds that women are more likely to be vulnerable than men during pandemics which confirms our hypothesis. The vulnerability to health for women during pandemics can be linked to contact between them and others who disregard preventive measures. Thirdly, vulnerable populations can insulate themselves from the harsh effects of pandemics when they make use of digital financial services. The use of digital financial services such as mobile money and M-Pesa helps to reduce disease transmission through human contact. Once the exposure levels of men are reduced, the vulnerability suffered by women is also reduced if not eliminated.\n\nThe next section provides a theoretical and empirical review of the literature. This is followed by the methodology employed in the study. The fourth section discusses the results of the study while the last section provides concluding remarks and practical implications of the paper.\n\n\nLiterature review\n\nDigital financial services are part of the financial inclusion movement that emphasises the provision of, and access to, financial services to all members of the population particularly the poor, vulnerable and several excluded members of the population (Ozili, 2018). Due to the importance of financial inclusion and its great promise, many governments especially in the emerging and developing economies have initiated policies and strategies to ensure financial inclusion (Allen et al., 2016). The literature on financial inclusion is replete with many theories of the concept – including public good theory, dissatisfaction theory, vulnerable group theory, systems theory, among others. In this paper, vulnerable group theory will be adopted to anchor this study. This theory suggests that financial inclusion initiatives should target the vulnerable in society as they are mostly at a disadvantage during economic hardships and crises. Thus, during pandemics and crises, the vulnerable are the most affected, and as such, it makes a lot of sense to bring these vulnerable people into the formal financial sector (Ozili, 2020). One way to achieve this is through the digital financial system. This includes the use of technology to deliver financial services to members of the society including the vulnerable such as poor people, young people, women, and elderly people. The crux of the vulnerable group theory is that financial inclusion efforts through means such as digital financial services should be targeted to vulnerable people in society (Ozili, 2020). During crises such as the COVID-19 pandemic, the use of digital financial services helps to provide support quickly and conveniently to the vulnerable population who need urgent support.\n\nThe COVID-19 pandemic started in 2019 in Wuhan China and resulted in immediate, serious human health issues around the world. The pandemic brought dire consequences to lives and livelihoods (Asante et al., 2021). The rapid spread of the pandemic across the world has continued to produce fear, panic and anxiety in people (Ahorsu et al., 2020). Thus, the alarming speed of the pandemic has overwhelmed even the most resilient health and social care systems (Guzman and Malik, 2020).\n\nIn such a situation, governments need to ensure public safety by prioritising the management of health crises. Also, a number of economic recovery strategies have been deliberately introduced across countries to support suffering economies affected by COVID-19. Key to these strategies is the need to protect the public health system as well as ameliorate the harmful impact of COVID-19 on the economy (Deloitte, 2020). The key COVID-19 control measures include border closures, lockdowns, social distancing, contact tracing, quarantine, and isolation (Asante et al., 2021).\n\nAccording to the Lancet (2020), the vulnerable are those that are disproportionally exposed to risk, but vulnerability can change dynamically. In this case, it is added that a person not considered vulnerable at the outset of a pandemic can become vulnerable depending on the policy response. The Lancet (2020) therefore expanded the definition of vulnerability in the context of COVID-19 beyond individuals with comorbidities and ill health, elderly persons, and homeless people to incorporate people from a range of economic backgrounds who may struggle to cope either physically, psychologically, or financially as a result of the COVID-19 crisis.\n\nThe current COVID-19 crisis has further exacerbated the gender gap in terms of quality of employment particularly for those women working in the informal sector and feminised occupations (ILO, 2021). As noted by Sen and Östlin (2008) gender is a crucial social element of health which intersects with several dimensions of society. Gender has implications for how different people cope with vulnerability, and their capacity and responsibilities during unexpected public health emergencies (Kim et al., 2020). Globally, the data has showed that more men are infected by COVID-19 than women (Global Health 50/50, 2020), which indicates that being a man is a risk factor for COVID-19 infection (Chen et al., 2020).\n\nThe issue of financial inclusion has received a lot of scholarly and practitioner attention because of its potential to contribute to inclusive economic and financial development as well as improve income equality (Bhatia and Singh, 2019). However, the use of traditional financial products and services for financial inclusion does not seem to reach the vulnerable including women. Indeed, the 2014 Global Findex data, showed that 47 per cent of women around the world have a financial account, compared to 53 per cent of men (Demirgüç-Kunt et al., 2015). In the current dispensation, technology can serve as a tool to pursue aggressive financial inclusion. According to Gammage et al. (2017), digital finance seems to offer innovative platforms for financial inclusion. This is because digital financial services have the potential to overcome restrictions brought on by geography, reduce the transaction costs of using financial services, and enhance transparency and therefore increase trust in financial systems (Gammage et al., 2017). Digital financial services have the potential to slow the spread of the COVID-19 pandemic as it allows for social distancing, quick and effective disbursement of financial services online (Agur et al., 2020). Indeed, Auer, Cornelli and Frost (2020) argued that digital financial resources support social distancing measures that were imposed in many countries to minimise the spread of the COVID-19 pandemic. So crucial is the fact that during lockdowns, digital financial services could still be used to deliver financial services to the vulnerable, and informal settlement dwellers when other forms become difficult (Auer, Cornelli, and Frost, 2020). Using digital financial technology like mobile money, people without bank accounts, especially women, vulnerable groups and informal sector workers can now have access to financial services which will help improve their economic situation during the pandemic (Agur et al., 2020). During pandemics, speed in the delivery of support is of the essence and digital financial technologies are obviously the game changer when it comes to speed and volumes of financial services (Auer et al., 2020).\n\n\nMethods\n\nA cross-sectional survey was conducted among residents of informal settlements in Ghana after obtaining ethical approval from the University of Ghana Ethics Committee for the Humanities (ECH). Data collection took place from August 2021 to November 2021 across informal settlements in Ghana.\n\nGhana was the area of study. The country has 16 administrative regions with each region containing several districts. There are currently 261 districts. Projections from the Ghana Statistical Service put the current population of Ghana at 30.07 million (Alhassan et al., 2021). This study was conducted in informal settlements in eleven of the sixteen regions in Ghana (Greater Accra, Central, Volta, Ashanti, Western, Northern, Savanna, Northeast, Bono East, Bono, and Ahafo). Peoples Dialogue, a Non-Governmental Organisation that focuses on informal settlements in Ghana provided the list of informal settlements for this study. Peoples Dialogue has enumerated informal settlements in Accra and throughout Ghana (Farouk and Owusu, 2012). As part of the Shack/Slum Dwellers International (SDI) network, Peoples Dialogue has become the most reliable organisation to obtain data on informal settlements in Ghana. Based on the data from Peoples Dialogue, the informal settlements were zoned to thirteen (13).\n\nData for this study was collected from 101 informal settlements in 11 of 16 regions in Ghana. Households were eligible if they were within informal settlements.\n\nSampling strategy\n\nThe study adopted the 2014 Ghana Demographic and Health Survey sampling frame. The frame is a complete list of all the census Enumeration Areas (EAs) created for the 2010 Population and Housing Census (PHC). An EA is a geographic area covering an average of 145 households. A three-stage sampling procedure was adopted. In the first stage, a total of 261 districts were selected from all 16 regions. In the second stage, EAs were selected across all the districts. The total number of EAs across the country is 37,641. We took a cue from the GDHS 2014 and selected a total of 854 EAs by implementing a simple random sampling technique across all 261 districts. After the selection of EAs and before the main survey, a household listing operation was carried out in all the selected EAs. The household listing operation consists of visiting each of the 780 selected EAs and compiling a list of members of the household. In the third and final stage, 8 households were selected from the list of households compiled in the EAs using the systematic sampling procedure to obtain a total of 2,697 households. We administered structured questionnaires to each of the selected households. This sampling strategy ensured that we captured indicators across the national level and as well as districts across the country. A copy of the questionnaire used can be found under Extended data (Amidu, 2022).\n\nA total of 2,697 households in informal settlements across Ghana were involved in this study through the use of a three-sampling procedure as described. This sample size is considered adequate and representative of informal settlements in the country.\n\nWe acquired tablets for the 23 enumerators and engaged the services of a Data Manager to coordinate the transmission of interviewee responses from various sites to a station at Accra, the national capital. The use of tablets to collect the data enhanced the quality of the data collected by prompting and disallowing some responses which were not consistent per checks in the survey instrument. The instant synchronization of the data at the end of the interview helped the survey management team to follow what was happening at all survey sites with ease. However, interviews conducted in areas where internet connection was poor could only be synchronized in the evening when the team returned to the district capitals where they lodged. The data manager run the field check tables to assess the quality of data received through Dropbox on a daily basis, whilst the fieldwork was ongoing. Observations from the field check tables were then shared with the enumerators and the team members through a WhatsApp group. Meetings were then held regularly with the field enumerators to ensure that all queries raised were addressed and if clarification was required, the project team responded before the teams proceeded to the next survey areas. These protocols were put in place to provide assurance of data quality.\n\nSurvey instruments\n\nThere are four main variables under investigation in this study: vulnerable populations, digital financial services, gender, and COVID-19 exposure. These variables are discussed below with their measures.\n\nSex/Gender: We limit the measurement of sex and gender to binary measurement. Participants could indicate whether they were male or female using a tick box.\n\nCOVID-19 exposure: exposure to COVID-19 is defined as the state of being exposed to someone with COVID-19 (Kazak et al., 2021). Three questions namely personal knowledge of COVID-19 infected persons, having heard or associated with a known COVID-19 infected person, and being exposed to a COVID-19 related deceased person were used to measure exposure to COVID-19 in this study. The use of these measures led to the creation of the COVID-19 exposure index, with one being the lowest and three the highest.\n\nVulnerable population: the vulnerability index questionnaire by Acharya and Porwal (2020) was adopted in this study. This index was built on the social vulnerability index by Flanagan et al. (2011) with the addition of the COVID-19 pandemic. The questionnaire consists of five dimensions - (1) socio-economic condition; (2) demographic composition; (3) housing and hygiene condition; (4) availability of health-care facilities, and (5) COVID-19-related epidemiological factors. First, the socio-economic vulnerability of populations was measured with four indicator variables as follows: (1) attaining some level of education with primary level being the least, (2) employment status of respondents, (3) monthly household income and (4) as a proxy for poverty is the proportion of the population who did not have any household assets. These assets include but are not limited to television, radio, bicycle, phone, and refrigerator. Similarly, demographic vulnerability was measured by the use of the elderly population (this includes persons aged 60 years and above), place of residence (be it urban or rural), and how well homes are suited. Concerning housing and hygiene conditions, the paper utilises four variables: number of people per room, availability of toilet facilities within a household, availability of hand hygiene facilities and household access to water. With regards to the availability of healthcare, the study uses four indicators - possessing of health insurance, access to health care, willingness to visit and access health facilities, and the number of health care facilities in a community. For epidemiological factors, the study took into consideration three main indicators as proxies. They include a person’s current health condition, a person with any current chronic morbidity, a person undergoing any long-term medical treatment. A respondent scores 1 when he demonstrates or finds himself in a vulnerable situation and scores 0 when otherwise is observed. A total score of 18 denotes high vulnerability.\n\nDigital financial services: In this paper, digital financial services inclusion was defined as the provision of financial services accessed and delivered through a mobile device. Therefore, mobile money was used as a proxy to measure digital financial inclusion. This study limits digital financial services to mobile money because this was the most common form of technology available to informal settlement dwellers. Indeed, in the advent of COVID-19, the government of Ghana increased the amount that could be transferred while lowering the charges on the mobile financial system. This served as an incentive for a lot of people to use the mobile financial system as a form of digital financial service. We construct an index of 1 to 9, with 9 being a person with more usage of financial technology and inclusion.\n\nWe employ a number of control variables that affect the relationship of interest. These include age, religion, marital status and region. The main and other control variables are presented in Table 1.\n\nThis study was approved by the University of Ghana Ethics Committee for The Humanities (ECH) (approval number: ech 342/21-22). In addition, we clearly indicated the purpose of the study to the respondents and participation in the study was voluntary. Participants were also debriefed, their consent sought and made aware the data was for academic publication purposes.\n\nIn this section, firstly, we estimate the effect of gender on COVID-19 exposure, controlling for a wide range of potential drivers of exposure and dummies for individual participant household characteristics. We specify the model below to estimate the impact gender has on COVID-19 exposure.\n\nIn the model above, COVID-19 exposure which is denoted as Y1j∗, is the dependent variable. COVID-19 exposure is measured using three indicator variables namely: personal exposure, exposure to an infected person, and contact with a COVID-19 related deceased person. Each indicator is scored one when a respondent answers in the affirmative with regards to exposure-related questions. The subscript j refers to the individual.Xj′ is a vector of individual household level characteristics such as age, marital status, geographical location, etc. R1j′β is the gender. It consists of two mutually exclusive and exhaustive categories that are men or women. It takes the value 1 when the respondent is a man and 0 when the respondent is a woman. εj is a normally distributed random error term with zero mean and constant variance.\n\nNext, we explore how gender influences the vulnerability of marginalised populations. In line with the vulnerability literature, we forecast that women are more likely to be vulnerable than men during the pandemic outbreaks. This can be attributed to the poor socio-economic status most women have which makes it difficult for them to adopt measures that will help insulate them from the risks of pandemics thus increasing their vulnerability. To help us examine the relationship between gender and vulnerability, we model the equation below:\n\nHere, Y2j∗ is the index score of vulnerability. Vulnerability in this study is constructed as an index comprising five main constructs: socioeconomic, demographic, housing and hygiene condition, availability of health care and epidemiological factors. A respondent scores 1 when they demonstrate or finds themself in a vulnerable situation on a dimension and scores 0 when otherwise is observed. A total score of 18 denotes high vulnerability. The subscript j refers to the individual.Xj′ is a vector of individual household level characteristics such as age, marital status, geographical location, etc. R2j′β is the gender. It consists of two mutually exclusive and exhaustive categories, that is men or women. It takes the value 1 when the respondent is a man and 0 when the respondent is a woman. εj is a normally distributed random error term with zero mean and constant variance.\n\nHaving estimated the relationship between gender and COVID-19 exposure on one hand and the vulnerability on the other hand, the next step is to evaluate the impact of digital financial services on vulnerable populations in the era of COVID-19. The rationale is that even in the face of expected support, when the right financial technology is not employed, the support may not achieve the intended outcomes.\n\nWhere,Y3j∗, is the dependent variable, vulnerability. Vulnerability in this study is constructed as an index comprising five main constructs: socioeconomic, demographic, housing and hygiene conditions, availability of health care and epidemiological factors. A respondent scores 1 when they demonstrate or find themself in a vulnerable situation and scores 0 when otherwise is observed. A total score of 18 denotes high vulnerability. The subscript j refers to the individual. Xj′ is a vector of individual household level characteristics such as age, marital status, geographical location etc.P3j′β represents the digital financial services with an index, 1-9 with 9 being a person with more usage of financial technology and inclusion. εj is a normally distributed random error term with zero mean and constant variance.\n\nFurthermore, we estimate the joint effect of gender, vulnerability and digital financial services has on COVID-19 exposure. Here, further analysis is conducted to examine the channel through which gender is exposed to the COVID-19 pandemic. That is, we analyse whether the amelioration of gender to COVID-19 is dependent on vulnerability or the adoption and use of financial technology. We use the model below:\n\nHere again,Y4j∗, the dependent variable is COVID-19 exposure. The subscript j refers to the individual. Xj′ is a vector of individual household level characteristics such as age, marital status, geographical location etc. R3j′β is the gender. Q3j′β is the vulnerability and is constructed as an index comprising five main constructs: socioeconomic, demographic, housing and hygiene condition, availability of health care and epidemiological factors. A respondent scores 1 when they demonstrate or find themself in a vulnerable situation and scores 0 when otherwise is observed. A total score of 18 denotes high vulnerability.P3j′ β represents the digital financial services with an index, 1-9 with 9 being a person with more usage of financial services and inclusion. In the equation (4) above,R3j′β∗P3j′β represents the interaction between gender and digital financial service, andQ3j′β∗R3j′β represents the interaction between vulnerability and gender. εj is a normally distributed random error term with zero mean and constant variance. All variables used in the models, their definitions, and measurements are shown in Table 1.\n\n\nResults\n\nIn this section, we provide the summary and descriptive statistics of our key variables of interest employed in the study. Given the gendered perspective of this study, we first present in Table 2a the data gathered on gender under two broad classifications. We collected data from men and women over the age of 18 who consented to be a part of the study. Men constitute 1,070 (40%) out of the 2,697 individuals sampled and women make up the remaining 1,627 (60%). The raw data can be found under Underlying data (Amidu, 2022).\n\nAnother characteristic feature of our sampled respondents is their marital status. We classified respondents into the various categories as single/never married, co-habiting, married, separated/divorced, and widowed. We find the majority of them were married. The second-largest cohort in terms of marital status classification is the single/never married. They make up approximately 33% of the study’s sample population. Those co-habiting, separated/divorced, and widowed made up approximately 17% of the sample.\n\nFurthermore, respondents were sampled across 11 out of the 16 regions of Ghana. The regional distribution of our sample reveals that persons from the Greater Accra region constituted about 38.75% of the sample thus ranking as the region with the highest representation in this study. The other regions included in this study were fairly represented with their sample size hovering above 1% but not more than 10%. Table 1a acts as a reference for the aforementioned statistics.\n\nIn order to explore the gender and vulnerability nexus, we again collected data across the five domain vulnerabilities and computed indices accordingly. The vulnerability scores of the regional slums under consideration are presented in Table 2b and each column denotes a specified vulnerability under the five domains. In the last column of the table, we find total vulnerability which happens to be the composite score of all five domain vulnerabilities per region. We observe from Table 2b that the total vulnerability score ranges between 4 and 6. Amongst the regions, we find the Western region recording the highest total vulnerability with a score of 5.439 whereas the Bono region scored the least with an index of 4.096. Again, the Western region suffers the highest socio-economic and demographic compared to the regional slums sampled by this study. In terms of housing and hygiene, health care and epidemiological vulnerability, we observe slums in the North-East, Central, and Volta regions suffering the most with vulnerability indices of 1.966, 2.151, and 0.961 respectively. On average, the domain vulnerability score for socioeconomic, demographic, housing and hygiene, health care vulnerability and epidemiological vulnerability are 0.856, 0.510, 1.342, 1.371, and 0.310 respectively.\n\nWe also collected data on the ownership of mobile accounts and usage of mobile-enabled digital financial services by our respondents as it forms part of our objective to examine the effect digital financial services have on the vulnerability of slum populations. In Table 2c, we present data on the usage of digital financial services as enabled by possessing a mobile account on a mobile device. We arrived at this by soliciting a Yes or No response from respondents. It comes to bare that the majority of respondents (95.81%) possess a mobile device whereas 86.87% of sampled respondents responded in the affirmative that they own an account on their mobile device. On the usage variables, withdrawal and savings were the most patronised mobile-enabled digital financial services. Payment using a mobile account ranked third with 17.50%. The least used service was lending the money using money account. The statistics show untapped mobile account usage gaps and also reflect to some extent the financial behaviour of Ghanaians.\n\nThis section of the study closes with data collected on the COVID-19 exposure status of respondents as shown in Table 2d. The exposure of respondents is scored as an index ranging from 0 to 3. We observe that the majority of respondents (constituting 91.36%) score 0 and 1 suggesting no to very low level of exposure. Respondents who scored 2 to 3 make up the remaining 8.64%. We can therefore infer from the exposure distribution of our sampled respondents that living in slums does not necessarily imply high exposure to COVID-19 despite overcrowding and insanitary conditions prevailing in such communities.\n\n1. The influence of gender on COVID-19 exposure\n\nIn Table 3, we present the results of the influence of gender on COVID-19 exposure. We arrive at this by regressing gender against COVID-19 exposure whilst controlling for possible drivers of exposure. The results suggest that men are more likely to be exposed to the COVID-19 pandemic than women. We observe a positive and a highly significant relationship between men and COVID-19 exposure. This occurrence can be attributed to ignorance of preventive measures by this gender group. More so, men have a perception of having a stronger immune system that will enable them to fight the virus more than women (Bwire, 2020). Galasso et al. (2020) found that women are more likely to perceive the pandemic as a very serious health problem and therefore are more likely to agree and comply with restraining measures. Grasselli et al. (2020) put forward similar sentiments. They opine that the disregard for restrictive measures is partially the reason why more men than women are dying from COVID-19.\n\nIndividuals’ age serves as a significant determinant in exploring COVID-19 exposure. The outbreak of the COVID-19 pandemic resulted in the death of the elderly population around the world. This is attributed to weak immune systems and various underlying health conditions suffered by this age class. However, in this study, we find a negative and highly significant relationship between age and exposure for persons living in slums. We also find that the marital status and religious affiliation of an individual have no significant bearing when it comes to exposure to pandemics like COVID-19. Although the co-efficient of these variables are positive, they do not show any statistical significance. We can therefore suggest that marital status and religion are not significant determinants of one’s exposure status.\n\nRegional slums including Central, Greater Accra, Ashanti, Bono and North-East regions showed statistical significance with exposure with variations in terms of direction and magnitude. The results suggest that among the above-mentioned regions, the North-East region is more likely to be exposed to COVID-19. We find a positive and a highly significant association between the region and exposure.\n\n2. The influence of gender on vulnerability\n\nIn this section, we explore the influence of gender on vulnerability. The results of this are displayed in Table 4. The results suggest that men are less likely to be vulnerable compared to women. This observation is true and falls in tandem with the vulnerability literature. Women around the world suffer an array of vulnerabilities not limited to social, economic and health vulnerabilities. From Table 3, we observe a negative and a highly significant relationship between men and four domain vulnerability measures together with their composite. Although men may suffer epidemiological vulnerability more than women, the magnitude of the other four vulnerabilities far outweighs the effect of their epidemiological vulnerabilities thus explaining the negative total vulnerability observed. The epidemiological vulnerability men may suffer can be associated with the neglect of preventive measures.\n\nAlso, we find the following controlling variables to be significant determinants of vulnerability: age, marital status, and one’s region of residence. For age, we observe a positive and highly significant total vulnerability relationship. This suggests that an individual’s age can increase their overall vulnerability whereas marriage status goes a long way to reduce vulnerability. We find the coefficient of the total vulnerability of the married to be negative. Marriage provides some form of synergy which makes it possible for couples to reduce their vulnerability. The total vulnerability across the sampled regions appears to be negative and highly significant despite some of its domain vulnerabilities being positive.\n\n3. The influence of digital financial service usage on the vulnerability of slum populations\n\nTable 5 shows how the usage of digital financial services influences vulnerable populations in the era of COVID-19. In this section we regress digital financial services usage index against individual domain vulnerabilities (socioeconomic, demographic, housing and hygiene condition, availability of health care and epidemiological factors) and their composite. In this instance, we control for the age, marital status, region of residence and religion of respondents. We observe from the table in reference, a negative and highly significant relationship between usage of digital financial services during the COVID-19 pandemic and vulnerability (domain and composite). This suggests that the usage of digital financial services reduces vulnerability thus confirming the importance of using digital financial services during and even beyond pandemics. Digital financial services reduce human contact hence reducing the risk of transmission of contagious diseases like COVID-19. The specific vulnerabilities are socio-economic, housing and hygiene, and health care. In terms of marital status, a negative and highly significant relationship is observed for all vulnerability measures except for housing and hygiene. This may be a result of the married sharing limited space with their spouse and children thus increasing their vulnerability along with that domain. Although age appears to be positive and highly significant, in terms of epidemiological vulnerability it shows a negative effect. This suggests that the age of a respondent can reduce this epidemiological vulnerability.\n\nOn the regional influence, we observe a negative and highly significant relationship for the total vulnerability of sampled regions given usage of digital financial services. A closer look at results on the Greater Accra Region suggests the high potency of digital financial services to reduce vulnerability in its slums given its status as the epicentre of the COVID-19 outbreak in the country. This can be attributed to the greater concentration of digital infrastructure in the region which promotes the usage of digital financial services. We observe that, given the usage of digital financial services, both domain vulnerabilities and their total are negative and highly significant except for epidemiological vulnerability which shows a positive and highly significant association. Generally, all the regions show at least a negative significant relationship with a domain vulnerability. The results also suggest that regional differences and dynamics should be factored in when policies are being formulated towards improving the living conditions of persons living in slums and considered vulnerable. This is at the backdrop of COVID-19 disproportionately affecting regions. For religion, we observe that, among the five domain vulnerabilities, only socio-economic vulnerability shows some statistical significance.\n\n4. The sensitivity of gender, vulnerability and digital financial services to COVID-19 exposure\n\nFinally, the study explores the sensitivities of gender, vulnerability and usage of digital financial services of respondents on their exposure to the COVID-19 pandemic. We observe from Table 6 that COVID-19 exposure is highly sensitive to the interaction among gender, vulnerability and usage of financial service. The results show a negative and highly significant relation. The results suggest that given the seemingly high exposure of men to the pandemic, men can take advantage of the opportunities offered by the usage of digital financial services to reduce their exposure to the COVID-19 pandemic.\n\n\nConclusion and policy implications\n\nIn this study, we examined the usage of digital financial services, vulnerability, and exposure of slum populations in the COVID-19 pandemic. We employed data from 101 informal settlements across 11 out of the 16 administrative regions of Ghana. By exploring these variables from a gendered perspective, our study makes the following contribution to literature: firstly, men are more likely to be exposed to the COVID-19 pandemic. Secondly, similarly to other findings, this study finds that women are more likely to be vulnerable than men even during pandemics. Thirdly, by making use of digital financial services vulnerable groups can reduce their exposure to the pandemic.\n\nWe therefore conclude that there exist gender disparities with regards to COVID-19 exposure and vulnerability. Also, there is a ripple effect of men’s exposure to COVID-19 on the vulnerability of women at large. Given that men are more likely to be exposed to the pandemic than women, there is a need to educate men more on the need to take preventive measures seriously since their negligence would affect women negatively thus increasing their vulnerability. Given that women perform more traditional homemaking roles during pandemics (Power, 2020), support should be given to women to ensure they do not lose their source of livelihood to be able to adequately provide for their needs and that of their families. Again, the labour department of organisations should not be quick in making women redundant during pandemics but should rather find innovative means by which women can contribute towards growth.\n\nLike several other studies, this paper has some limitations. First, the cross-sectional nature of the data means that we cannot assume causality in the findings, rather they should be interpreted as associations. Again, the data was limited to Ghana and residents of informal settlements. However, these limitations do not affect the validity of the findings which can be used in similar contexts especially for vulnerable populations across the world.\n\n\nData availability\n\nOSF: Gender, digital financial services and vulnerability in the era of pandemics. https://doi.org/10.17605/OSF.IO/US6AV (Amidu, 2022).\n\nThis project contains the following underlying data:\n\n- Gender DFS and Vulnerability CLEAN.xlsx [This file contains data collected from informal settlement dwellers in Ghana]\n\nOSF: Gender, digital financial services and vulnerability in the era of pandemics. https://doi.org/10.17605/OSF.IO/US6AV (Amidu, 2022).\n\nThis project contains the following extended data:\n\n- Questionnaire.pdf\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nAcharya R, Porwal A: A vulnerability index for the management of and response to the COVID-19 epidemic in India: an ecological study. Lancet Glob. Health. 2020; 8(9): e1142–e1151. PubMed Abstract | Publisher Full Text\n\nAgur I, Peria SM, Rochon C: Digital financial services and the pandemic: Opportunities and risks for emerging and developing economies. International Monetary Fund Special Series on COVID-19. Transactions. 2020; 1: 1–2.\n\nAhorsu DK, Imani V, Lin CY, et al.: Associations -between fear of COVID-19, mental health, and preventive behaviours across pregnant women and husbands: an actor-partner interdependence modelling. Int. J. Ment. Heal. Addict. 2020: 1–15.\n\nAlexander K: Financial Inclusion: The Role of Fintech and Digital Financial Services. UNCTAD, Multi-year Expert Meeting on Trade, Services and Development, 18-20 July 2017.2017.\n\nAllen F, Demirguc-Kunt A, Klapper L, et al.: The foundations of financial inclusion: Understanding ownership and use of formal accounts. J. Financ. Intermed. 2016; 27: 1–30. Publisher Full Text\n\nAlhassan RK, Aberese-Ako M, Doegah PT, et al.: COVID-19 vaccine hesitancy among the adult population in Ghana: evidence from a pre-vaccination rollout survey. Trop. Med. Health. 2021; 49(1): 1–13. Publisher Full Text\n\nAmidu M: Gender, digital financial services and vulnerability in the era of pandemics: A cross-sectional analysis.2022. Publisher Full Text\n\nArner DW, Barberis JN, Walker J, et al.: Digital Finance & the COVID-19 Crisis. University of Hong Kong Faculty of Law Research Paper No. 2020/017.2020.\n\nAsante D, Twumasi MA, Sakyi ASK, et al.: A socio-geographic perspective of health and economic impacts of COVID-19 on poor households in Ghana. GeoJournal. 2021: 1–13. Publisher Full Text\n\nAuer R, Comelli G, Frost J: COVID-19, Cash, and the Future of Payments. BIS Bulletin No. 3.2020.Reference Source\n\nBhatia S, Singh S: Empowering women through financial inclusion: a study of urban slum. Vikalpa. 2019; 44(4): 182–197. Publisher Full Text\n\nBwire GM: Coronavirus: why men are more vulnerable to Covid-19 than women? SN Compr. Clin. Med. 2020; 2(7): 874–876. PubMed Abstract | Publisher Full Text\n\nChen N, Zhou M, Dong X, et al.: Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet. 2020; 395(10223): 507–513. PubMed Abstract | Publisher Full Text\n\nDavidovic S, Prady D, Tourpe H: You’ve Got Money: Mobile Payments Help People during the Pandemic. IMF Blog online, 22 June. Accessed November 10, 2021.2020.\n\nDeBruin D, Liaschenko J, Marshall MF: Social justice in pandemic preparedness. Am. J. Public Health. 2012; 102(4): 586–591. Publisher Full Text\n\nDeloitte Access Economic: The social impacts of COVID-19; Reset or restart: taking advantage of crisis for social change.2020.Reference Source\n\nDemirgüç-Kunt A, Klapper LF, Singer D, et al.: The Global Findex Database 2014: Measuring Financial Inclusion Around the World (World Bank Policy Research Working Paper 7255). Washington, DC:World Bank;2015.\n\nFarouk BR, Owusu M: “If in doubt, count”: the role of community-driven enumerations in blocking eviction in Old Fadama, Accra. Environ. Urban. 2012; 24(1): 47–57. Publisher Full Text\n\nGalasso V, Pons V, Profeta P, et al.: Gender differences in COVID-19 attitudes and behavior: Panel evidence from eight countries. Proc. Natl. Acad. Sci. 2020; 117(44): 27285–27291. PubMed Abstract | Publisher Full Text\n\nGammage S, Kes A, Winograd L, et al.: Gender and digital financial inclusion: What do we know and what do we need to know? International Center for Research on Women (ICRW) October 2017.2017.\n\nGrasselli G, Pesenti A, Cecconi M: Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience and forecast during an emergency response. JAMA. 2020; 323(16): 1545–1546. Publisher Full Text\n\nGlobal Health 50/50: COVID-19 sex-disaggregated data tracker: Sex, gender, and COVID-19.2020. Retrieved November 9, 2021.Reference Source\n\nGuzman RD, Malik M: Dual Challenge of Cancer and COVID-19: impact on Health Care and Socioeconomic Systems in Asia Pacific. JCO Glob. Oncol. 2020; 6: 906–912. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHutchins S, Truman B, Merlin T, et al.: Protecting vulnerable populations from pandemic influenza in the United States: A strategic imperative. Am. J. Public Health. 2009; 99(S2): S243–S248. PubMed Abstract | Publisher Full Text\n\nILO: Building Forward Fairer: Women’s rights to work and at work at the core of the COVID-19 recovery. ILO Policy Brief;2021.\n\nKazak AE, Alderfer M, Enlow PT, et al.: COVID-19 exposure and family impact scales: factor structure and initial psychometrics. J. Pediatr. Psychol. 2021; 46(5): 504–513. PubMed Abstract | Publisher Full Text\n\nKim S, Kim JH, Park Y, et al.: Gender Analysis of COVID-19 Outbreak in South Korea: A Common Challenge and Call for Action. Health Educ. Behav. 2020; 47(4): 525–530. PubMed Abstract | Publisher Full Text\n\nNyashanu M, Simbanegavi P, Gibson L: Exploring the impact of COVID-19 pandemic lockdown on informal settlements in Tshwane Gauteng Province, South Africa. Global Public Health. 2020; 15: 1443–1453. Publisher Full Text\n\nOzili PK:Theories of financial inclusion. Uncertainty and Challenges in Contemporary Economic Behaviour. Emerald Publishing Limited;2020.\n\nOzili PK: Impact of digital finance on financial inclusion and stability. Borsa Istanbul Review.2018; 18(4): 329–340.\n\nPower K: The COVID-19 pandemic has increased the care burden of women and families. Sustain.: Sci. Pract. Policy. 2020; 16(1): 67–73.\n\nPrempeh C: Religion and the state in an episodic moment of COVID-19 in Ghana. Social Sciences & Humanities Open. 2021; 4(1): 100141. PubMed Abstract | Publisher Full Text\n\nSen G, Östlin P: Gender inequity in health: why it exists and how we can change it.2008; 3(Suppl. 1): 1–12.\n\nSumalatha BS, Bhat LD, Chitra KP: Impact of COVID-19 on informal sector: A study of women domestic workers in India. Indian J. Econ. 2021; 69(3): 441–461. Publisher Full Text\n\nThe Lancet: Redefining vulnerability in the era of COVID-19. Lancet (London, England). 2020; 395(10230): 1089. PubMed Abstract | Publisher Full Text\n\nTing DSW, Carin L, Dzau V, et al.: Digital technology and COVID-19. Nat. Med. 2020; 26(4): 459–461. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "155855",
"date": "05 Dec 2022",
"name": "Matthew Ocran",
"expertise": [
"Reviewer Expertise Econometrics",
"development finance",
"and development economics."
],
"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 is timely and well-motivated. But the authors have to pay attention to a few issues.\nThere are grammatical errors that need correction. They can do this with the services of a good copy editor.\n\nThe measure of COVID-19 exposure is problematic. The authors cite the work of Kazak et al 2021. However, the measure of exposure defined in the present study is inconsistent with that given by Kazak et al 2021 (pp.506). The cited study used 5 exposure items related to COVID-19. The present study does not account for most of the exposure items in Kazak's work and does not provide reasons for the adopted measurement approach. The least they can do is provide a disclaimer or caution in interpreting the results.\n\nThe authors have to provide information on the estimator used in the empirical analysis.\n\nThe regression estimates do not provide any robustness checks. I suspect that they might have used OLS estimators. If they did, then they have to indicate how they have dealt with the challenges associated with the estimator. Indeed, the practice is that whatever econometric tool or estimator one uses, one has to provide statistics to indicate the robustness of the estimations. This is missing.\nThe instrumental variable (IV) approach is often used to estimate causal relationships in studies such as the present one. The authors may want to consider IV as an estimator for the regression analysis.\n\nIn sum, the econometric approach is neither transparent nor persuasive.\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? No\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": "9194",
"date": "13 Feb 2023",
"name": "Mohammed Amidu",
"role": "Author Response",
"response": "Dear reviewer, we have reflected on the feedback, revised, and re-submitted a significantly improved manuscript. We have taken the reviewers’ comments seriously and did our possible best to address them. We have made changes leading to a significantly improved version of the manuscript. We have also copyedited the paper to remove redundancies and repetitions as well as any syntax and grammatical errors. We hope that the changes and additions satisfactorily address the reviewers’ concerns. We will now turn to the reviewers’ comments with an attached document. In the remainder of this document, we have copied the referee’s comments in bold and italics, and then described the manner in which we have addressed the comments There are grammatical errors that need correction. They can do this with the services of a good copy editor. The grammatical errors have been addressed in this manuscript with the support of a professional editor The measure of COVID-19 exposure is problematic. The authors cite the work of Kazak et al 2021. However, the measure of exposure defined in the present study is inconsistent with that given by Kazak et al 2021 (pp.506). The cited study used 5 exposure items related to COVID-19. The present study does not account for most of the exposure items in Kazak's work and does not provide reasons for the adopted measurement approach. The least they can do is provide a disclaimer or caution in interpreting the results. The study cited Kazak et al. 2021 for its definition of COVID-19 exposure. However, the measurement of the variable was conceptualised by the authors given the setting in which the study is being carried out. Data was collected at the time that there was high stigmatization of persons who had been exposed to the virus. Hence questions were carved such that respondents will be willing to provide such information since the questions did not relate to them personally. The authors have to provide information on the estimator used in the empirical analysis: The regression estimates do not provide any robustness checks. I suspect that they might have used OLS estimators. If they did, then they have to indicate how they have dealt with the challenges associated with the estimator. Indeed, the practice is that whatever econometric tool or estimator one uses, one has to provide statistics to indicate the robustness of the estimations. This is missing. The instrumental variable (IV) approach is often used to estimate causal relationships in studies such as the present one. The authors may want to consider IV as an estimator for the regression analysis. The estimator used in the analysis is the Ordinary Least Square (OLS) estimator. We performed multicollinearity tests and run the regressions by specifying the robust standard errors to take care of the issues of heteroskedasticity. We also used the link test to check that the model is correctly specified. Robustness checks statistics have now been added. The use of the instrumental variables (IV) technique helps to explicitly specify the instruments. In sum, the econometric approach is neither transparent nor persuasive. We believed that the econometric approach is transparent as we have provided enough data to support the replication of the study’s results"
}
]
},
{
"id": "156855",
"date": "15 Dec 2022",
"name": "Daniel Sakyi",
"expertise": [
"Reviewer Expertise 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\nREVIEW REPORT ON GENDER, DIGITAL FINANCIAL SERVICES AND VULNERABILITY IN THE ERA OF PANDEMICS: A CROSS-SECTIONAL ANALYSIS\nGENERAL COMMENT\nThe paper investigate the relationship between digital financial services (DFS), gender, and the vulnerability of informal settlement dwellers and COVID-19. The paper makes use of 2697 households from 101 informal settlement from 11 out the 16 regions of Ghana. The paper looks at an interesting topic and it is timely considering the enormity of the impact as a results of the pandemic - COVID 19. The comment on the paper are presented based on the various sections.\nABSTRACT\nThe abstract is generally good and reflects the tittle of the paper. However, the abstract needs improvement. For instance, the authors mention that they used the multiple regression analytical technique for the analysis, but the authors have to mention the exact estimation technique for the analysis. Multiple regression is not an estimation technique. Also, the authors should be specific on the policy implication in the abstract instead of just saying that they results provide policy implications for authorities ………. in Africa.\nINTRODUCTION\nThe introduction section is good and reflects the topic very well. The link between the pandemic and the key variables – gender, digital financial services and vulnerability have been highlighted. The motivation of the paper is generally good as the authors have highlighted the need for this present paper.\nHowever, the authors should address the following:\nThe authors should read through the whole paper and correct any error. For instance, the use of “reason why” is tautology. The authors have to use one of them and not both.\n\nThe authors mention in paragraph 5 that this present study is essential as it has implications for the achievement of several SDGs. It will be ideal for the authors to mention the specific SDGs referring to.\n\nIn the paragraph 6, the authors use the “digital financial inclusion” which is different from the term used earlier which is the “digital financial services”. The authors should note that the two are not the same therefore this must be reconciled. Financial services and financial inclusion are different concepts.\n\nThe authors should delete the findings added to the introduction section. This is because same results is presented in the results section and are highlighted in the conclusion as well as in the abstract, and so it will be more of repetition.\nLITERATURE REVIEW\nThe authors have provided some theoretical foundation for the paper and seem satisfactory.\nSome empirical review has also been provided. However, the authors should try and read through and correct some errors in the text. For example, the authors write “….data has showed that ….” Instead of “…data has shown that …..”.\nMETHODS\nThe authors have provided information regarding the methods adopted in this paper. The sampling technique has also been explained. How the data was collected has been highlighted as well. However, the authors should address the following concerns.\nIt will be ideal for the authors to explain or define what the informal settlement is. This is because the authors have stated that the data was collected from 2697 households from informal settlements in Ghana. The authors further stated that an individual becomes eligible if he or she is within informal settlement. So the question is, what constitute the informal settlements?\n\nThe authors have to really explain the key variable – Covid-19 exposure very well. The authors mentioned that they asked three questions in connection with this variable – having knowledge of Covid-19 infected person, having heard or associated with Covid-19 infected person and finally being exposed to Covid-19 related deceased person. The first question is what were the responses to these questions? Again, after obtaining these responses how was the index created and the range of the index – 1 (lowest) to 3 (highest) for instance. This has to be explained in detail because it is a key variable in the study and hence its reliability/appropriateness is very key. If this is not done, the analysis will not be well appreciated.\n\nThe authors also have to explain the digital financial service variable very well. What question was asked? What was the response? And how was the index created? The authors mentioned that they created an index of 1 to 9 with 9 being a person with more usage of financial technology and inclusion. The question is why 1 to 9 and not any other number like 1 to 10 or 1 to 15 etc.? How did the authors determine “more usage of financial technology?” This is because the authors rightly mentioned that they limited the DFS to the use of only mobile phone. So how then does the “more usage of technology” become the measure? This is not clear at all and needs to be elaborated. The same issue applies to the vulnerability variable. How did the authors come up with the score of 0 to 18 for the vulnerability variable? This is because the authors mentioned that they built the index based on five dimensions, so what went into the analysis and this index of 0 to 18 was arrived at. These have to be made clear in the study. In fact, the authors have to spend some time explaining properly how the key variables were obtained. Without this exercise, one will not be able to appreciate the results as well as the discussion.\n\nThe authors have to in fact explain very well to the readers the model specified in Equations 1, 2 and 3. Based on the measures of the various dependent variables mentioned the authors should tell readers the exact models that have been specified. The dependent variable for equations 2 and 3 is vulnerability population, which is a score – 0-18. So what model and estimation technique was employed to achieve this objective? Again, the dependent variable for equation 1 is Covid-19 exposure, which is also an index or score – 1 to 3. So what model and estimation technique was employed for this also?\nThese are very crucial issues that need to be addressed to validate the results of the study.\n\nThe authors should also justify some of the measurement of some variables. For instance, in Ghana, there are many religions so why did the authors decide to use binary dummy – 1 for Christian and 0 for otherwise? This needs to be justified, else the other religions in Ghana must be considered in the study. Same for marital status, education level (1 for primary and 0 for otherwise – but there are other educational levels, why are they not considered?), household income (what influenced the threshold of 313 for this variable? This must be explained) etc. Again, the variables definitions mentioned in Table 1 is fine but the most important thing is that how they were used to create the indexes and scores should be the focused as I have mentioned earlier. This is because most of these variables are used in creating the index and they are not used individually in the regression analysis.\n\nThe authors mentioned that the Covid-19 exposure has a score of 1 to 3 (see under the survey instrument, the third paragraph on covid-19 exposure), but when one observe Table 2d, the Covid-19 exposure variable has a “0” in there, making it 0-3. The authors need to reconcile this accordingly.\n\nThe authors should read through and correct all errors. For example, “with regards” instead of “with regard”.\nRESULTS\nIn fact, given the issues raised concerning the model specified and estimation technique, the authors have to reconsider the regression analysis all over again.\nFirst, the authors should have a table that reports all the key variables, especially the dependent variables, and then the explanatory variables. This will help the authors to explain the exact nature of the dependent variables and hence the estimation technique to be employed. Because this is not done it is clear that the right estimation has not been done and hence the results are not appropriate.\nFor instance, let’s consider the first analysis where the authors said they want to look at the effect of gender on Covid-19 exposure. The Covid-19 exposure variable per the authors’ definition under section 3 is a score – 1 to 3 / 0 to 3 (as mentioned earlier). Neither the questions that were used to measure the exposure nor the score itself is an ordered or multiple response and hence the question is what estimation was done? But the authors use expressions like “more likely” in explaining the results. See below:\n“In Table 3, we present the results of the influence of gender on COVID-19 exposure. We arrive at this by regressing gender against COVID-19 exposure whilst controlling for possible drivers of exposure. The results suggest that men are more likely to be exposed to the COVID-19 pandemic than women. We observe a positive and a highly significant relationship between men and COVID-19 exposure. This occurrence can be attributed to ignorance of preventive measures by this gender group. More so, men have a perception of having a stronger immune system that will enable them to fight the virus more than women (Bwire, 2020). Galasso et al. (2020) found that women are more likely to perceive the pandemic as a very serious health problem and therefore are more likely to agree and comply with restraining measures. Grasselli et al. (2020) put forward similar sentiments. They opine that the disregard for restrictive measures is partially the reason why more men than women are dying from COVID-19.”\n\nIt is clear from the above that the right estimation technique is not used and hence the need to revise the analyses throughout the paper.\nThe same applies to the second objective where the authors look at the effect of gender on vulnerability. The authors use expressions like “less likely” but one does not know the estimation technique used. See below:\n\"In this section, we explore the influence of gender on vulnerability. The results of this are displayed in Table 4. The results suggest that men are less likely to be vulnerable compared to women. This observation is true and falls in tandem with the vulnerability literature. Women around the world suffer an array of vulnerabilities not limited to social, economic and health vulnerabilities. From Table 3, we observe a negative and a highly significant relationship between men and four Domain vulnerability measures together with their composite. Although men may suffer epidemiological vulnerability more than women, the magnitude of the other four vulnerabilities far outweighs the effect of their epidemiological vulnerabilities thus explaining the negative total vulnerability observed. The epidemiological vulnerability men may suffer can be associated with the neglect of preventive measures.\"\nThe authors should note the expressions like “more likely / less likely” are used in probability models such binary probit/logit, ordered probit/logit, multinomial probit/logit etc. But in this present study, and as I have mentioned earlier one does not know the estimation techniques used. Again, the estimation techniques I have mentioned above are dependent on the nature of the dependent variable in question. Per the definition and measurement of the dependent variables in this study – the Covid -19 exposure and vulnerability –, these techniques (binary probit/logit, ordered probit/logit, multinomial probit/logit) are not even applicable. Therefore, the authors should spend some time and go through the literature and get the appropriate estimation technique the analyses.\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": "9195",
"date": "13 Feb 2023",
"name": "Mohammed Amidu",
"role": "Author Response",
"response": "Dear reviewer, we have reflected on the feedback, revised, and re-submitted a significantly improved manuscript. We have taken the reviewers’ comments seriously and did our possible best to address them. We have made changes leading to a significantly improved version of the manuscript. We have also copyedited the paper to remove redundancies and repetitions as well as any syntax and grammatical errors. We hope that the changes and additions satisfactorily address the reviewers’ concerns. We will now turn to the reviewers’ comments with an attached document. In the remainder of this document, we have copied the referee’s comments in bold and italics, and then described the manner in which we have addressed the comments ABSTRACT The abstract is generally good and reflects the title of the paper. However, the abstract needs improvement. For instance, the authors mention that they used the multiple regression analytical technique for the analysis, but the authors have to mention the exact estimation technique for the analysis. Multiple regression is not an estimation technique. Also, the authors should be specific on the policy implication in the abstract instead of just saying that the results provide policy implications for authorities ………. in Africa. The grammatical errors in the abstract have been addressed including a clear policy implication of the paper. The analytical technique for the analysis has been clearly stated as the ordinary least square (OLS) analytical technique. We employed 2sls Instrumental Variable technique for the robustness test. INTRODUCTION However, the authors should address the following: 1. The authors should read through the whole paper and correct any errors. For instance, the use of “reason why” is a tautology. The authors have to use one of them and not both. The grammatical errors have been addressed in this manuscript with the support of a professional editor These corrections have been made 2. The authors mention in paragraph 5 that this present study is essential as it has implications for the achievement of several SDGs. It will be ideal for the authors to mention the specific SDGs referring to. This has been corrected and specific SDGs have been mentioned – SDGs 3, 10, 11, 15 and 17 3. In the paragraph 6, the authors use the “digital financial inclusion” which is different from the term used earlier which is the “digital financial services”. The authors should note that the two are not the same therefore this must be reconciled. Financial services and financial inclusion are different concepts. This has been duly corrected to digital financial services 4. The authors should delete the findings added to the introduction section. This is because same results is presented in the results section and are highlighted in the conclusion as well as in the abstract, and so it will be more of repetition. Even though this sounds repetitive, we prefer to keep the summary of the findings in the introduction for three main reasons. First, most journals require that a summary of the findings is mentioned in the introduction. Second, some readers may only read the introduction, and this will help them get to know the findings of the paper. Third, this is a general practice LITERATURE REVIEW The authors have provided some theoretical foundation for the paper and seem satisfactory. Some empirical review has also been provided. However, the authors should try and read through and correct some errors in the text. For example, the authors write “….data has showed that ….” Instead of “…data has shown that …” The grammatical errors have been addressed in this manuscript with the support of a professional editor. METHODS However, the authors should address the following concerns: 1. It will be ideal for the authors to explain or define what the informal settlement is. This is because the authors have stated that the data was collected from 2697 households from informal settlements in Ghana. The authors further stated that an individual becomes eligible if he or she is within informal settlement. So the question is, what constitute the informal settlements? Informal settlements have been clearly defined in this paper. Consistent with the UN-Habitat (2016), informal settlements in this study are defined as residential areas where (a) inhabitants have no security of tenure vis-`a-vis the land or dwellings they inhabit, with modalities ranging from squatting to informal rental housing, (b) the neighbourhoods usually lack, or cut off from, basic services and city infrastructure and (c) the housing may not comply with current planning and building regulations and is often found in geographically and environmentally hazardous areas. 2. The authors have to really explain the key variable – Covid-19 exposure very well. The authors mentioned that they asked three questions in connection with this variable – having knowledge of Covid-19 infected person, having heard or associated with Covid-19 infected person and finally being exposed to Covid-19 related deceased person. The first question is what were the responses to these questions? Again, after obtaining these responses how was the index created and the range of the index – 1 (lowest) to 3 (highest) for instance. This has to be explained in detail because it is a key variable in the study and hence its reliability/appropriateness is very key. If this is not done, the analysis will not be well appreciated. Respondents were asked to indicate a YES/NO response to the questions posed. Thus, all respondents who answered yes to any one of the three questions scored 1. A respondent scores two when answers in the affirmative to two of any of the three questions and three when he /she indicates yes to all three covid exposure questions. 3. The authors also have to explain the digital financial service variable very well. What question was asked? What was the response? And how was the index created? The authors mentioned that they created an index of 1 to 9 with 9 being a person with more usage of financial technology and inclusion. The question is why 1 to 9 and not any other number like 1 to 10 or 1 to 15 etc.? How did the authors determine “more usage of financial technology?” This is because the authors rightly mentioned that they limited the DFS to the use of only mobile phone. So how then does the “more usage of technology” become the measure? This is not clear at all and needs to be elaborated. The same issue applies to the vulnerability variable. How did the authors come up with the score of 0 to 18 for the vulnerability variable? This is because the authors mentioned that they built the index based on five dimensions, so what went into the analysis and this index of 0 to 18 was arrived at. These have to be made clear in the study. In fact, the authors have to spend some time explaining properly how the key variables were obtained. Without this exercise, one will not be able to appreciate the results as well as the discussion. Digital financial service as used in this study captures the ownership and usage of mobile-enabled digital financial services including the ownership of a mobile account and having accessed financial services such as savings, withdrawal, tax payment etc on the mobile device. The financial services index of 0-9 is a factor of respondents’ responses of either Yes or No. So, the index increases with increased usage of any of the 9 financial services variables. Again, for each vulnerability variable respondents’ responses were coded as 1 (which indicated vulnerability or 0 when otherwise observed. For Demographic vulnerability, 3 questions were asked. Housing and hygiene, 4. For healthcare vulnerability, we posed 4 questions. Also, for Epidemiological factors, we had respondents answer 3 questions. For socio-economic vulnerability respondents had 4 questions to respond to. The sum of the scores for all five domain vulnerabilities gives a score of 18. 4. The authors have to in fact explain very well to the readers the model specified in Equations 1, 2 and 3. Based on the measures of the various dependent variables mentioned the authors should tell readers the exact models that have been specified. The dependent variable for equations 2 and 3 is vulnerability population, which is a score – 0-18. So what model and estimation technique was employed to achieve this objective? Again, the dependent variable for equation 1 is Covid-19 exposure, which is also an index or score – 1 to 3. So what model and estimation technique was employed for this also? These are very crucial issues that need to be addressed to validate the results of the study. The models used in the write-up have been defined to measure four main relationships. Hence in equation 1, the model is specified to explore the relationship between gender and COVID-19 exposure. In equation 2, we explore the influence of gender on the vulnerability of the sampled populations. In equation 3, we establish the relationship between digital financial services on COVID-19 exposure and vulnerability. For each domain vulnerability, the study found the averages of the score and based on the averages developed an index between 0 and 1. The OLS estimation technique was employed for all specified models. 5. The authors should also justify some of the measurement of some variables. For instance, in Ghana, there are many religions so why did the authors decide to use binary dummy – 1 for Christian and 0 for otherwise? This needs to be justified, else the other religions in Ghana must be considered in the study. Same for marital status, education level (1 for primary and 0 for otherwise – but there are other educational levels, why are they not considered?), household income (what influenced the threshold of 313 for this variable? This must be explained) etc. Again, the variables definitions mentioned in Table 1 is fine but the most important thing is that how they were used to create the indexes and scores should be the focused as I have mentioned earlier. This is because most of these variables are used in creating the index and they are not used individually in the regression analysis. Data was collected for other religions in Ghana as well. However, the others make up the minority as there are more Christians in Ghana than otherwise. We used married or otherwise as the classification as divorced, single, widowed etc suggests not staying in with a spousal equivalent. Moreso, we expect that spouses may be the source of the spread of the virus to their counterparts hence recording higher exposure levels. 6. The authors mentioned that the Covid-19 exposure has a score of 1 to 3 (see under the survey instrument, the third paragraph on covid-19 exposure), but when one observe Table 2d, the Covid-19 exposure variable has a “0” in there, making it 0-3. The authors need to reconcile this accordingly. The index score of 1 to 3 captures respondents who answered in the affirmative that they have been exposed to COVID. Persons who responded that they have by no means been exposed were scored zero. The three questions asked were: if the respondent knows a dead COVID patient if the respondent has heard or has been associated with a COVID-infected person. if the respondent personally knows a person infected with COVID-19. Thus, the index is such that a respondent score one if he answers in the affirmative to any of the above questions. As the positive responses increase the index also increases. RESULTS In fact, given the issues raised concerning the model specified and estimation technique, the authors have to reconsider the regression analysis all over again. 1. First, the authors should have a table that reports all the key variables, especially the dependent variables, and then the explanatory variables. This will help the authors to explain the exact nature of the dependent variables and hence the estimation technique to be employed. Because this is not done it is clear that the right estimation has not been done and hence the results are not appropriate. For instance, let’s consider the first analysis where the authors said they want to look at the effect of gender on Covid-19 exposure. The Covid-19 exposure variable per the authors’ definition under section 3 is a score – 1 to 3 / 0 to 3 (as mentioned earlier). Neither the questions that were used to measure the exposure nor the score itself is an ordered or multiple response and hence the question is what estimation was done? But the authors use expressions like “more likely” in explaining the results. See below: “In Table 3, we present the results of the influence of gender on COVID-19 exposure. We arrive at this by regressing gender against COVID-19 exposure whilst controlling for possible drivers of exposure. The results suggest that men are more likely to be exposed to the COVID-19 pandemic than women. We observe a positive and a highly significant relationship between men and COVID-19 exposure. This occurrence can be attributed to ignorance of preventive measures by this gender group. More so, men have a perception of having a stronger immune system that will enable them to fight the virus more than women (Bwire, 2020). Galasso et al. (2020) found that women are more likely to perceive the pandemic as a very serious health problem and therefore are more likely to agree and comply with restraining measures. Grasselli et al. (2020) put forward similar sentiments. They opine that the disregard for restrictive measures is partially the reason why more men than women are dying from COVID-19.” It is clear from the above that the right estimation technique is not used and hence the need to revise the analyses throughout the paper. We have provided a table that reports on the key variables now. We believe that the right estimator, i.e OLS was used and is appropriate for cross sectional data. The robustness test using the Instrumental variable provided the same result. It should also be noted that the data is cross-sectional and there is a limit to the type of estimators to be used The same applies to the second objective where the authors look at the effect of gender on vulnerability. The authors use expressions like “less likely” but one does not know the estimation technique used. See below: \"In this section, we explore the influence of gender on vulnerability. The results of this are displayed in Table 4. The results suggest that men are less likely to be vulnerable compared to women. This observation is true and falls in tandem with the vulnerability literature. Women around the world suffer an array of vulnerabilities not limited to social, economic and health vulnerabilities. From Table 3, we observe a negative and a highly significant relationship between men and four Domain vulnerability measures together with their composite. Although men may suffer epidemiological vulnerability more than women, the magnitude of the other four vulnerabilities far outweighs the effect of their epidemiological vulnerabilities thus explaining the negative total vulnerability observed. The epidemiological vulnerability men may suffer can be associated with the neglect of preventive measures.\" The OLS estimation technique was used for the purpose of exploring the relationship between gender and vulnerability. This is appropriate valid estimator for the use of cross-sectional data The authors should note the expressions like “more likely / less likely” are used in probability models such binary probit/logit, ordered probit/logit, multinomial probit/logit etc. But in this present study, and as I have mentioned earlier one does not know the estimation techniques used. Again, the estimation techniques I have mentioned above are dependent on the nature of the dependent variable in question. Per the definition and measurement of the dependent variables in this study – the Covid -19 exposure and vulnerability –, these techniques (binary probit/logit, ordered probit/logit, multinomial probit/logit) are not even applicable. Therefore, the authors should spend some time and go through the literature and get the appropriate estimation technique the analyses. The expressions mentioned were used to avoid over-generalisation and apply some nuances to the results. They have been corrected in the manuscript Yes, as the Reviewer suggested, we could not have used (binary probit/logit, ordered probit/logit, or multinomial probit/logit) as the dependent variables are not binary. For the robustness test, we employed Instrumental Variable."
}
]
}
] | 1
|
https://f1000research.com/articles/11-1218
|
https://f1000research.com/articles/12-171/v1
|
13 Feb 23
|
{
"type": "Review",
"title": "Biosensors for therapeutic drug monitoring: a review",
"authors": [
"Wervyan Shalannanda",
"Ardianto Satriawan",
"Muhammad Fairuziko Nurrajab",
"Anchelmia Chyntia Hanna Ayulestari",
"Diah Ayu Safitri",
"Finna Alivia Nabila",
"Casi Setianingsih",
"Isa Anshori",
"Wervyan Shalannanda",
"Muhammad Fairuziko Nurrajab",
"Anchelmia Chyntia Hanna Ayulestari",
"Diah Ayu Safitri",
"Finna Alivia Nabila",
"Isa Anshori"
],
"abstract": "Therapeutic drug monitoring (TDM) is a crucial and essential step for patient care when an accurate medication dosage is necessary. High-performance liquid chromatography (HPLC) and immunoassays are commonly used methods for TDM, but they are expensive and incapable of real-time monitoring. Biosensor technology is believed to have the potential to perform TDM effectively. Biosensors are flexible and can be tailored to individual patient needs. This article reviews the development of biosensors for TDM, including the types of biosensors that have been fabricated and the drugs they have successfully monitored. Biosensor technology is expected to have a bright future, particularly for real-time monitoring and integration with internet of things (IoT) systems.",
"keywords": [
"Therapeutic Drug Monitoring",
"Biosensor",
"Fabricated Biosensor"
],
"content": "Introduction\n\nAdministering the appropriate dosage of medication to patients is crucial. The correct dosage is crucial for effective treatment. Incorrect dosage can cause ineffective treatment or dangerous side effects. Therefore, monitoring drug levels in the body, known as therapeutic drug monitoring (TDM), is essential and necessary (Table 1).\n\nTDM is a process of monitoring the levels of drugs or chemicals in the body of patients to determine the appropriate dose and duration of treatment.1 This helps to minimize side effects and optimize treatment outcomes.2 TDM can also monitor substances produced in the body due to the treatment.\n\nTDM is typically conducted by analyzing a sample of a patient’s bodily fluids, most commonly blood. The patient’s blood is analyzed using several tools, with high-performance liquid chromatography (HPLC-MS) being considered the gold standard.3 An immunoassay method can also be used to analyze samples with various kits. However, both methods are costly and have limited access to laboratories.4 As a result, there is currently a trend to develop small and flexible biosensors for TDM.\n\nBiosensors are gaining attention as a cutting-edge technology for TDM. These sensors detect drugs and select optimal materials for the specific type of TDM being performed. Additionally, the trend in TDM is towards cost-effective solutions, which biosensors are well-suited to provide. Their compact size and flexibility also make them ideal for use in internet of things (IoT) based TDM systems. Furthermore, biosensors can potentially aid in the real-time monitoring of deadly diseases, greatly assisting medical experts in their treatment.5\n\nIn this paper, we review biosensor research for TDM. We explain the biosensors used for TDM, the types of drugs and chemicals detected using biosensors in the TDM process, and the future directions for developing biosensors for TDM. The review analyzes scientific articles from various research journals published in the last 15 years.\n\n\nBackground: overview of therapeutic drug monitoring\n\nIn this section, we explain the purpose of TDM in general, the considerations for using it in patients’ treatment, its history, and guidelines.\n\nThe purposes of TDM in the therapeutic process are the following1:\n\n1. Assessing compliance;\n\n2. Customizing treatment (during early therapy and/or dosage changes);\n\n3. Recognizing under-treatment;\n\n4. Preventing toxicity;\n\n5. Keeping track of and identifying drug interactions;\n\n6. Assisting with therapeutic discontinuation;\n\nAll the processes must be conducted from the start to the end of the treatment. Figure 1 shows the process details of determining the dose in treatment.\n\nThere are also several additional things to consider in applying TDM for patients. Some of these things are as follows:\n\n• Difficulty understanding clinical evidence of harmful or therapeutic effects;\n\n• A low toxic therapeutic ratio;\n\n• A strong correlation between the plasma drug concentration and the therapeutic, toxic, or both effects;\n\n• A significant active metabolite is not produced by the dose;\n\nEfforts by medical personnel to monitor therapy with drugs have been carried out since ancient times. However, the first recorded history of chemical substance or drug concentration calculation in a patient’s body was in 1932. Erik M.P. Widmark measures the concentration of alcohol in the human body to analyze the chemical components in the human body’s blood.6 Researchers have developed many technologies for therapeutic drug monitoring (TDM) since then.\n\nThe most rapid development period for TDM was in the mid-1950s to mid-1960s. Rosalyn Sussman Yalow developed a technique that uses radioactive materials to investigate the human body for small amounts of substances in 1959, called radioimmunoassay. She received the Nobel Prize in Physiology or Medicine for her discovery in 1977. Then, in the mid-1960s, Joseph Jack Kirkland discovered a method that would later become the gold standard of TDM, namely high-performance liquid chromatography (HPLC).6\n\nThe first time TDM was performed on treated patients was also in the mid-1960s. Frits Buchthal did a measure to find a clinical correlation between plasma concentrations of phenytoin in epileptic patients. In the following decades, researchers performed many TDM trials on various types of drugs. Carolyn Bertozzi introduced the term “biorthogonal chemistry”, which later became popular in determining drug dosages and the continuity of the TDM process in 2003, which led her to win the Nobel Prize in Chemistry in 2022. In 2019, TDM was used for the first time in a continuous treatment process. In recent years, there has been an increasing trend of producing cheap and flexible biosensors to assist the TDM process in patient care.7\n\nIn conducting TDM, there are guidelines that one needs to follow. These guidelines ensure drug concentrations in plasma or blood are within a desired range. Dealing with significant interpatient pharmacokinetic variability, therapeutic concentration-related effects, unclear therapeutic concentration ranges, and challenging-to-manage desirable therapeutic outcomes are a few things that must be considered when performing TDM.8\n\nSeveral things must be considered in conducting TDM to ensure it runs smoothly, which are6:\n\n1. Administering drugs to patients requires TDM: The psychiatry of the human body is complex, and the effects of drugs on patients can cause unexpected reactions. Clinical TDM currently targets a wide range of pharmaceuticals, including antineoplastic, anti-infective, immunosuppressive, cardioactive, respiratory-acting, neuropsychiatric, and mood-active agents.\n\n2. Matrix selection: After determining the type of drug to be monitored, the next step is to select the type of sample containing the molecule of interest, with common choices being blood, urine, and saliva.\n\n3. Interpretation of the results: The final step in TDM is to interpret the measurement results, which are monitored over a specific period based on the characteristics of the drug administered.\n\nAnalytical techniques are crucial for accurate TDM. Current standard practice for TDM involves separation, mass spectrometric analysis, and immunoassays on specialized equipment. A more recent advancement in chromatography, combining mass spectrometry and chromatography, has created a new potential instrument for TDM services. LC-tandem MS (LC-MS/MS) is currently the preferred technique among recently developed technologies for measuring therapeutic drugs in bodily fluids. This is due to its increased selectivity compared to single MS detection methods. Additionally, multi-component approaches can be used with LC-MS/MS, such as developing and successfully applying LC-MS/MS for simultaneous analysis of multiple immunosuppressive medications.9\n\nWhile immunoassays require several steps to quantify therapeutic medicines, the ELISA (Enzyme-Linked Immune Sorbent Assay) approach can run numerous tests simultaneously. The widely used ELISA, a double-antigen test, cannot assess antidrug antibodies (ADAs) in the presence of medicines because the drug competes with the detection antigen. Therefore, this assay is only useful when trough levels are undetectable.10 The ability to multiplex is an advantage of ELISA technology. High multiplexing has its benefits, but it can also necessitate big enough samples to guarantee an analysis’s cost-effectiveness. The homogeneous mobility shift assay (HMSA), based on high-pressure liquid chromatography, is more promising than ELISA. The fact that HMSA separates drug-ADA complexes allows it to quantify both medicines and ADAs independently. The widely used ELISA has been used to validate this method. There was a significant link between drug levels and ADA titers, and HMSA also found ELISA-based false-positive ADA results.11\n\nHowever, the infrastructure required for therapeutic drug monitoring using chromatographic, mass spectrometric, and immunoassay methods are expensive and often unavailable in smaller healthcare facilities and communities. When using separation techniques, the analysis is labor- and time-intensive because blood samples must be thoroughly prepared for analysis and the time required for separation on the device itself. Biosensors and nano biosensors are well suited to deliver a quick response for therapeutic drugs since they require less infrastructure and sample preparation.\n\n\nRecent types of biosensors for therapeutic drug monitoring\n\nOptical biosensors detect changes in light’s properties, such as refraction index, absorption, fluorescence, or scattering, when a receptor comes into contact with an analyte. These sensors are useful for identifying affinity or catalytic receptors and are more sensitive and versatile than other methods. They consist of an optical transducer system and a biorecognition element, such as surface plasmon resonance (SPR), localized SPR (LSPR), surface enhanced Raman spectroscopy (SERS), visual plasmonic colorimetric sensors, or SPR imaging (SPRI).8\n\nAn optical biosensor aims to provide a signal corresponding to the concentration of the studied analyte. It uses a variety of biological substances, such as enzymes, antibodies, antigens, receptors, nucleic acids, cells, or tissues, as biorecognition elements.12\n\nSurface plasmon resonance spectroscopy\n\nSPR utilizes the oscillations of free electrons at the interface of a metal and dielectric to detect changes in the refractive index at a surface. Light reflects off surfaces at different angles, each with a distinct refractive index. The absorbed light causes a reduction in the intensity of the reflected light. As the refractive index changes, the angle of minimum shifts, enabling monitoring.13\n\nSPR is widely used in biosensing applications due to its versatility and the ability to detect a wide range of molecules. However, detecting and measuring small molecules, such as most drugs, can be difficult as they do not significantly alter the refractive index. Secondary detection methods using antibodies or functionalized nanoparticles can be employed to overcome this limitation to enhance the SPR response. Many biosensors for therapeutic drug monitoring are based on competitive assays, but these methods can have lower sensitivity. SPR is susceptible to nonspecific binding in complex matrices like many universal detectors. This occurs when molecules from the matrix produce a signal by depositing on the sensor’s surface without being recognized by a specific receptor. This can mask the signal from the analyte, making detection impossible. To address this issue, researchers have developed various surface chemistries to protect the SPR sensors from fouling agents commonly found in complex biological matrices.4\n\nSPR has been used to find medicines in the past. One example is infliximab (IFX) detection employing fiber optic SPR with anti-IFX antibodies and AuNPs coupled to detection antibodies. Compared to ELISA, Pearson correlation coefficients of 0.997 were attained, demonstrating a substantially comparable outcome of SPR sensing technology with ELISA as TDM standard practice. This was demonstrated to be applicable in diluted whole blood, dried blood spots, and IFX-treated patients.14\n\nSPR is effective in multiplex measurements, for example, simultaneous detection of IFX and the anti-IFX antibody. This is achieved by attaching tumor necrosis factor, used for detecting IFX, and IFX, used for detecting the antibody, to the flow channels of a microfluidic device. The concentration of both analytes can then be determined by comparing the SPR shift from the ligand strips to the control strips.15\n\nLocalized surface plasmon resonance spectroscopy\n\nThe use of gold and silver metal nanoparticles as small, highly sensitive label-free optical sensors has gained attention in recent years. These nanoparticles act as transducers by translating changes in the local refractive index into shifts in the LSPR band. This general LSPR-shift assay technique can test any chemical’s binding affinity or rate that alters the local refractive index near the metallic nanostructures. By adding molecular recognition components, such as chemical or biological ligands, to the nanostructures, specificity and selectivity to the target analyte can be achieved. The main difference between LSPR and SPR is that, in LSPR, the molecular receptor is immobilized using noble metal nanoparticles rather than a thin gold film as in SPR.16\n\nIn contrast to SPR, LSPR’s electromagnetic field is much stronger and close to the nanoparticle. It decays 40–50 times faster as it moves away from the surface, making it less sensitive to bulk changes in the refractive index but more sensitive to the adsorption of small molecules. This high intensity near the surface enables direct detection of small molecules with LSPR, making it well-suited for therapeutic drug monitoring, but most of these investigations are conducted in buffer or diluted matrices before they can be used in a clinical setting for the study of drugs.4\n\nLSPR, using gold nanoparticles (GNP), has been used to detect therapeutic drugs with a limited therapeutic range, such as digoxin, by evaluating the interaction between digoxin and its monoclonal antibody from UV-Vis’s absorption spectrum, resulting in a limit of detection as low as 2 ng/mL and is still in digoxin’s pharmaceutical range with higher sensitivity at higher digoxin concentration indicating the biosensor works properly.17\n\nLSPR has also been used to quantify third-generation cephalosporins in environmental samples and human serum. LSPR-bacteriolysis signals of bacteria on optical fiber probes have been used for rapid beta-lactam susceptibility testing, which can be used directly for TDM. These measurements were made using bacterial lysis signatures of Pseudomonas aeruginosa immobilized on gold nanoparticles modified optical fibers, which offer a rapid replacement for the time-consuming Kirby–Bauer disk diffusion tests typically used in tertiary care institutions and community health settings for drug susceptibility testing and faster, less expensive, and point-of-care antibiotic quantification alternative to chromatography coupled mass spectroscopic approaches with applications in therapeutic and environmental monitoring.18\n\nSurface enhanced Raman spectroscopy\n\nSERS utilizes metal nanoparticles or nanostructures to enhance the power of the Raman phenomenon. When two nanoparticles are placed close together, or if a metallic nanostructure has a rough surface, the localized electromagnetic field can be significantly increased, resulting in a significant amplification of the Raman scattering on the molecule adsorbed on the nanostructure, allowing researchers to track the number of molecules adsorbed on the metal, which depends on the drug concentration in the test solution.4\n\nThe metal surface significantly impacts the presence of very concentrated areas of extreme local field enhancement caused by surface plasmon resonance, which typically occurs in interstitial cracks in metal structures. Researchers create SERS substrates, or metallic nanostructures capable of causing a SERS effect, using a variety of approaches. These substrates, typically metallic nanoparticles coated with a Raman reporter and functionalized with specific receptors that recognize the analyte, make this technology appropriate for various biosensing applications. The therapeutic drug must promote interparticle connections for the aggregation process to take place.19\n\nMany medications can be detected and quantified in simple solutions, but the process becomes more difficult when dealing with biofluids. SERS is a technique used to quantify target analytes in biofluids. Still, it can be difficult to do so in samples like a human serum because other biomolecules can interfere with the SERS spectra. A new study has found that using noble metal thin films derived from self-assembled NPs created using pulsed laser ablation (PLA) procedures can improve SERS by producing unique nanostructures with good film-level SPR stability and reproducibility, which allows for better control of the chemical enhancement route in SERS.20\n\nVisual plasmonic colorimetric sensor\n\nVisual colorimetric is a quick and easy label-free detection method involving observing color changes resulting from molecular recognition events. Metal nanoparticles, such as gold and silver, are commonly used as probes in colorimetric studies due to their unique electrical and optical properties. When these nanoparticles aggregate and approach one another, the surface plasmon band shifts to a longer wavelength, changing the color of the nanoparticles. The size, shape, distance, and medium of metal nanoparticles can significantly affect their surface plasmon resonance absorption.21\n\nColorimetric assays offer great potential for remote clinical effects and toxicity monitoring to optimize drug dosage and patient response at the point of care. In a research, a colorimetric sensor was used to detect the concentration of antidepressants in biological fluids. Citrate-capped silver nanoparticles (CIT-Ag NPs) were used as a probe to monitor fluoxetine concentration. The fluoxetine caused the CIT-Ag NPs to aggregate, resulting in a color change from yellow to dark brown and a shift in the absorbance peak and surface plasmon band. This demonstrates the potential of colorimetric assays to monitor drug concentration in real-time at the point of care.22\n\nSPR imaging\n\nSPRI is a technique that determines the spatial distribution of RI in individual cells. This method has been used to measure responses in various cells, such as rat mast cells, mouse keratinocytes, human epidermal carcinoma cells, and human basophils. Additionally, this technique can differentiate between the responses of different cell types grown together on the sensor chip.23\n\nPiezoresistive sensors\n\nPiezoresistive sensors convert mechanical events into resistance values. They can be modified with biomolecular receptors to interact with specific molecules, which causes a change in resistance due to molecular recognition. This makes them useful in various applications such as biosensing, drug delivery, and medical diagnosis.24\n\nMicrocantilevers\n\nMicrocantilever-based sensors have many advantages, such as being lightweight and not requiring fluorescent labeling, making them highly compatible with integrated circuits. Label-free microcantilever biosensors allow for downsizing, high sensitivity, and real-time analysis. A cantilever is a structural element that is supported at one end and carries a load on the other. Cantilever deflection can be detected using electrical or optical-level techniques. Electrical detection is more portable and suitable for point-of-care or individualized diagnostics as it does not require additional space and alignment for a laser, optics, and detectors.24\n\nElectrochemical biosensors are devices that use the principle of an oxidation or reduction reaction to detect specific molecules. These sensors typically involve a coating of enzymes, which catalyze the reaction of the target molecule. This causes a change in the current flow, which can be measured and used to determine the concentration of the target molecule. Electrochemical biosensors are highly specific and sensitive, making them suitable for detecting a wide range of biomolecules. They are also relatively simple to use and can be made portable for point-of-care applications. However, they may require frequent calibration and maintenance to ensure accurate results.25\n\nElectrochemical biosensors are a type of biosensor that use electrochemical methods for detection. These biosensors can be divided into conductivity measurement biosensors and potential measurement biosensors. Both types use electrodes as signal transducers, which convert biological changes into electrical signals. Recent advancements in electrical devices have made it possible to shrink these biosensors down to on-chip devices. This allows for in vivo monitoring, where the biosensor is placed inside the body or portable devices for on-site monitoring. This miniaturization has made it possible to use electrochemical biosensors in various applications, including medical diagnostics and environmental monitoring. There are a few ways the electrodes can be introduced to the desired sample26:\n\nMicroneedle based\n\nTransdermal microneedle-based electrodes are used to detect various analytes in bodily fluids. These electrodes are receiving attention due to their ability to quickly and painlessly sense biomarkers in interstitial fluid. Additionally, they can be used for medication administration.27,28\n\nField effect transistor based\n\nThe electrodes are connected to the transistors’ gate and alter the conductivity of the transistor to change the drain current (Id). Researchers have increasingly focused on field-effect transistors (BioFETs) as biosensors over the past two decades because of their noninvasive detection, simple pretreatment, ultrasensitive response, and real-time readout. BioFETs have enabled molecular and cellular assays to shift towards point-of-care (PoC) diagnostics.29\n\nPrinted electrode based\n\nElectrodes are created from conductive ink and printed onto a substrate. Traditional electrochemical sensors and biosensors used in transdermal microneedles (TDM) require specialized labs with expensive equipment and trained personnel, making them inefficient. Printed electrode-based technology offers a new alternative for sensors that are robust, repeatable, and sensitive to target molecules. These sensors are also low cost and easy to fabricate, making them non-labor intensive. This technology has the potential to revolutionize the field of TDM and make sensing and diagnostics more accessible and affordable. Printed electrode-based biosensors may also be proven helpful in the field of point-of-care diagnostics.30\n\nThe working electrode is decorated using the molecular imprinting technique (MIT), which uses synthetic materials obtained by polymerizing functional monomers and crosslinker molecules in the presence of a template. The measurement strategy based on the “gate-controlled effect” is then used, which has several benefits, such as anti-disturbance ability and adaptability. The MIP film has specificity for the analyte similar to an antibody, ensuring more accurate and trustworthy analysis. The strategy is independent of the analyte’s electrochemical activity, broadening the range of medicines detected by TDM. Ultrasensitive and selective electrochemical sensors have already been developed using MIT and gate effect basis, with MIP membrane serving as a suitable sensing agent due to its exceptional recognition capabilities toward target molecule.31\n\nPencil graphite electrode based\n\nThe working electrodes used are pencil leads, a more practical, quicker, and straightforward method of modifying the electrode surface compared to other methods. Electrochemical pre-treatment of the pencil-graphite electrodes (PGE) eliminates the need to modify the electrode surface with harmful substances. Utilizing pencil-graphite electrodes provides several benefits, such as avoiding sample contamination and being simple to use as they do not require any pre-treatment. They also meet ongoing sensitivity, selectivity, and repeatability requirements. The pencil lead electrodes are cost-effective, and the graphite material is easy to obtain. Additionally, pencil lead electrodes are a sustainable alternative to other electrodes as they can be easily replaced and recycled.32\n\n\nApplication of biosensors for therapeutic drug monitoring\n\nCancer is a major non-communicable disease that causes millions of deaths each year. One of the most commonly diagnosed types of cancer is breast cancer. Doxorubicin is a widely prescribed medication for treating breast cancer, as it has shown effectiveness over time. However, due to its potential side effects, it is important to administer it in controlled doses during chemotherapy. Monitoring and assessing its effects in biological contexts after therapy is crucial for ensuring its safe and effective use. Continual monitoring and assessment are necessary for safe and effective treatment.5\n\nA highly sensitive and potent electroanalytical biosensor was successfully developed for detecting doxorubicin. Single-wall carbon nanotubes (SWCNTs) and ds-DNA was subsequently modified the surface of the glassy carbon electrode (GCE). Additional evaluation on the effectivity of the Doxorubicin-DNA complex also evaluated through molecular docking using several bioinformatic tools. The receptor molecule was kept rigid on the carbon surface while the target molecule (doxorucubin) allowed moving on its simulation freely. The simulation confirmed the intercalation of adenin-guanine bases from ds-DNA. Low detection concentration of 0.6 nM was reported using differential pulse voltammetric (DPV) technique.33\n\nA plasmon-coupling assay has been used to detect methotrexate at clinically relevant doses using a naked-eye assessment. This test involved free methotrexate and folic acid gold nanoparticles competing for gold nanoparticles functionalized with human dihydrofolate reductase (hDHFR) (Au NP). The hDHFR-functionalized Au NPs were fixed on a glass sensor that was put into a portable 4-channel LSPR reader. This allowed for estimating the concentration of methotrexate quickly (in minutes) and sensitively (in the nanomolar range) using total internal reflection plasmonic spectroscopy. The assay caused massive bathochromic shifts resulting in spectacular color changes that were visible to the naked eye for methotrexate at clinically meaningful concentrations. The results indicate that therapeutic drug monitoring of standard chemotherapeutic treatment is possible through eye inspection.34\n\nA new method for identifying potential anticancer drugs is being researched using electrochemistry to study DNA-drug interactions. One powerful naturally occurring anticancer medication is paclitaxel, derived from the Western yew tree. However, its effectiveness is limited by a narrow therapeutic window and patients’ varying elimination half-lives. A fast and reliable method for measuring paclitaxel is needed to address these issues. This method uses a pencil-graphite electrode and differential pulse voltammetry to study the interaction of paclitaxel with salmon sperm DNA. The reduction of guanine and adenine oxidation signals in response to paclitaxel contact was used as an indicator for paclitaxel detection. The experiment used a typical three-electrode cell with Ag/AgCl/KCl, platinum wire, and pencil-graphite electrodes as a reference, auxiliary, and working electrodes. The pencil-graphite electrode was prepared by sonication, rinsing, drying, and pre-treatment with ds-DNA in an acetate buffer solution.32\n\nChemotherapeutic drugs are used to treat various types of cancer, but they can cause side effects such as nausea and vomiting. To limit these negative effects and ensure patient compliance, it is essential to treat patients effectively. The primary treatment for chemotherapy-induced nausea is ondansetron (OND). However, traditional OND-monitoring methods can be expensive and require a well-equipped laboratory. To adjust its dose during chemotherapy, monitoring of OND is necessary. An ion-selective electrode potentiometry sensor is a low-cost, easy-to-use, non-destructive approach for OND monitoring. The sensor’s membrane design includes three variables: plasticizer, ion exchanger, and ionophores. The sensors are calibrated by measuring the potential differences between the working electrode and the counter electrode when immersed in OND solution, and pre-treated human plasma sample.35\n\nParkinson’s disease (PD) is the second most common neurological disorder. It causes disability, impacts the quality of life and financial stability of patients and their families, and increases healthcare costs. It is estimated to affect 7 to 10 million people worldwide, roughly equivalent to half the population of New York City.28\n\nLevodopa (L-DOPA) has been the most effective treatment for Parkinson’s disease since it was first introduced in the 1960s. It has been the gold standard for treating the condition for over 50 years. L-DOPA is a precursor to dopamine, a neurotransmitter that is essential for motor pathways and is lost in Parkinson’s disease. By boosting dopamine levels, L-DOPA helps to alleviate the symptoms of Parkinson’s disease.28\n\nThere is a need for a wearable device to continuously monitor L-DOPA levels in the blood or other bodily fluids of Parkinson’s patients. Continuous monitoring requires a device that can be worn for long periods and frequently measure L-DOPA levels. Studies have been conducted on minimally invasive and non-invasive methods for monitoring L-DOPA in PD patients. One example is a wearable chemical sensing platform using a microneedle electrode array to monitor L-DOPA continuously. This device uses a unique dual-mode sensing approach that combines electrochemical measurements and redox and biocatalytic processes. This multimodal sensing approach improves the information capacity of the microneedle sensor array and increases redundancy. The device has excellent analytical performance when tested in a phantom gel simulating skin and in the skin of mice, with high sensitivity, a significant linear dynamic range, outstanding stability, and high selectivity. Such efficient L-DOPA monitoring in real-time would allow for appropriate dosing and better control of Parkinson’s disease.28\n\nHowever, the effectiveness of L-DOPA can vary depending on the individual’s dietary habits, age, gender, and drug administration history. If the dosage is not adjusted accordingly, it can negatively impact the patient’s motor and cognitive abilities. Monitoring L-DOPA levels is important for the effective treatment of Parkinson’s disease. The best way to determine the correct dosage is to evaluate the patient’s motor abilities, but this approach can be challenging and make dosing uncertain. Point-of-care testing is difficult as it requires clinicians to assess the patient’s motor abilities.36\n\nHuman perspiration is a convenient and non-invasive alternative to blood as it contains many biomolecules. Like other pharmacological compounds, L-DOPA is excreted through sweat, and its concentration in sweat may be correlated with human plasma. A study designed a wearable sensor packaged into a sweatband (s-band) based on electrochemical detection, incorporating gold dendritic nanostructures onto the electrodes, resulting in a remarkable enhancement of the L-DOPA sensor’s detection limit to approximately 1 M in sweat solution. The sensor is produced on a polyethylene terephthalate (PET) substrate using a typical three-electrode configuration with a functionalized L-DOPA sensing electrode as the working electrode, an Ag/AgCl top layer as the reference electrode, and an Au top layer as the counter electrode. The tyrosinase enzyme can convert L-DOPA secreted in sweat during amperometric measurement to dopaquinone, generating a Faradaic current that can be calibrated to estimate the L-DOPA concentration in the resulting sweat.36\n\nBiosensors are a crucial tool in disease detection and medication monitoring. Patch-type devices, which detect biomarkers in biofluids such as sweat, are particularly popular. These non-invasive devices allow for real-time and continuous analysis of biomarkers. Recent technological advancements have led to the development of smart e-patches for monitoring schizophrenia medication, and electrochemical sensors for continuous monitoring of drug intake through perspiration measurement.37\n\nPierre Fabre Pharmaceuticals created a wearable electrochemical biosensor called the Smart e-Patch to monitor a new medicinal molecule called F17464, a D3 antagonist that binds to dopamine D3 receptors. The research was completed using Nova 1.11 software, AUTOLAB PGSTAT204 compact, screen-printed electrodes (SPE) from Dropsense, a sweat collection patch from PharmChem, and chemicals from Sigma. The Smart e-Patch has three layers: a porous sweat adhesive, a sweat-collecting patch containing a biosensor for medication measurement, and a protective textile layer. It is based on a commercially available sweat-collecting patch with a 3-electrode configuration. An electrochemical biosensor is positioned close to the drug release patch and examined using differential pulse voltammetry (DPV) to detect the concentration of the B compound. Ascorbic and uric acid are used as interfering substances for sensor selectivity tests, while parameters that must be addressed include concentration, temperature, and pH. The Smart e-Patch is a wearable electrochemical biosensor that can detect the presence of F17464 in sweat and potentially transmit the data to a mobile device. The study has shown that the sensor is selective and capable of detecting F17464 and can be designed to continuously measure and monitor F17464 in sweat without interference from other pharmaceuticals.38\n\nEpilepsy is a complex disorder caused by neurological circuits, cells, and molecules dysfunction. Antiepileptic drugs (AEDs) can effectively reduce the frequency of seizures. Still, the type and dosage of these medications are crucial due to their direct interaction with the central nervous system and brain. Currently, around 30 targeted AEDs available, but challenges such as medicine resistance, unpleasant side effects, and precise monitoring remain. Examples of AEDs include phenobarbital, primidone, phenytoin, carbamazepine, oxcarbazepine, valproate, ethosuximide, gabapentin, and lamotrigine. TDM of AEDs is necessary to optimize drug administration due to the unpredictability of pharmacokinetics, limited target range, and difficulty in separating toxicity symptoms from laboratory findings. Utilizing nanoparticles can facilitate the examination of these compounds.26\n\nA nanocomposite sensor of reduced graphene oxide and Pt nanoparticles immobilized on a modified glassy carbon electrode (nPtGN/GCE) has been developed. The electrochemically catalyzed phenobarbital (PB) reactions with the modified electrode showed exceptional activity. This sensor was used to develop a mediator-free PB detection sensor, which has proper LOD and linearity, and can reliably detect PB in actual samples.26\n\nBiosensors are becoming increasingly crucial in anti-epileptic drug (AED) monitoring due to their ability to simultaneously measure multiple AEDs and their metabolites in biological samples. These new techniques are expected to simplify, quicken, and measure AED levels in the blood more cost-effective. They can be used in pharmacokinetic research, bioequivalence testing, and therapeutic drug monitoring. One of the AEDs, phenytoin, has a narrow therapeutic dose range that requires therapeutic drug monitoring. Sensors based on piezoresistive microcantilevers have been developed for detecting chemical interactions and biomolecular recognition in a liquid environment. These sensors can detect surface tension or deflection changes and associated resistance changes. They can detect phenytoin by using immobilized antibody molecules.24\n\nTDM of antiepileptic and antipsychotic drugs has been done for decades, but TDM for antidepressants is still relatively new. Assessing treatment safety and efficacy through TDM of antidepressants is particularly valuable in primary care settings.\n\nAntidepressant medication is used during the acute phase of the condition to produce remission without creating adverse effects and to prevent recurrence or relapse during ongoing or maintenance therapy. To achieve these objectives, medicine selection and dosing must be individualized for each patient. TDM may be helpful in primary care for monitoring adherence, adjusting medication, preventing toxicity, and documenting idiosyncratic reactions.39\n\nWearable sensor technology can meet the need for precision medicine, but on-body devices for quick, targeted medication screening are still a relatively new concept. A wearable sensor that is adaptable, deformation-resistant, and non-invasive is incorporated into gloves to selectively and non-invasively measure therapeutic drugs and biomarkers in sweat samples. Using a screen-printing process and carbon ink for the working and auxiliary electrodes, the sensors were manually printed on the fingertips of the gloves using a squeegee. The sensor inserted in the glove can simultaneously monitor paracetamol, paroxetine, ethinylestradiol, and uric acid as significant health indicators, highlighting the potential for pharmacological and biomarker monitoring in patients with bipolar disorder, depression, hormone replacement therapy, and early menopause to improve therapeutic efficacy with minimal adverse effects.30\n\nAntibiotic monitoring is crucial to prevent antimicrobial resistance. A minimally invasive method, such as microneedle biosensors, is preferred for tracking the administration of antibiotics, including beta-lactam antibiotics. These biosensors can penetrate the stratum corneum and minimize pain and blood drawn, as they do not reach blood vessels or nerve endings in the dermis. Research has shown that a microneedle-based real-time continuous antibiotic detection method using a pH-sensitive iridium oxide layer can detect local pH changes caused by β-lactam interaction with β-lactamase.27\n\nEtimicin (ETM) is a drug with a limited therapeutic index, making monitoring its use crucial for clinical use. Different analytical methods for determining ETM have been proposed, but there are still unsolved problems. AgNPs, with their unique electrical and optical properties, possess higher absorption coefficients than AuNPs, allowing for sensitive colorimetric detection. A test tube containing an appropriate concentration of ETM in a urine sample matrix and cit-capped AgNPs can be transferred to a spectrophotometric cell to measure the absorbance of various ETM concentrations, and the sensing system’s color change can also be captured by a digital camera.21\n\nA biosensor is a valuable tool for monitoring the concentration of digoxin, a drug with a narrow therapeutic range, in human blood serum. Surface plasmon resonance (SPR) technology is an effective method for detecting immediate chemical contact, and gold nanoparticles (GNPs) have proven helpful in SPR-based analysis. The LSPR property of GNPs allows for developing sensors with high detection accuracy. The GNPs were synthesized using the Turkevich method and the concentration was determined using UV-Vis spectrophotometry. The anti-digoxin monoclonal antibody was then immobilized on the functionalized GNPs, and the interaction between digoxin and the antibody was evaluated using the UV-Vis absorption spectrum.17\n\nAn SPR biosensor has been developed for therapeutic medication monitoring amikacin (AK) in blood serum or plasma. Due to its toxicity risks and narrow therapeutic range, AK is an antibiotic that requires TDM. The sensor is highly sensitive and desirable for TDM, with a sensitivity of 1.4 ng/mL and a limit of quantification of 0.33 ng/mL. The sensor is based on an indirect competitive immunoassay with AK immobilized on a gold surface and has good reproducibility and reusability.38\n\nA microfluidic biosensor, called miLab, has been developed for simultaneous monitoring of piperacillin/tazobactam and beta-lactam antibiotics in various biological samples such as plasma, bronchoalveolar lavage fluid, saliva, and urine. The biosensor was fabricated using dry film photoresist technology, and it consists of two zones: an immobilization area and an electrochemical cell, separated by a hydrophobic barrier to prevent contamination. The platform uses electrochemical sensing to detect specific antibiotics, and it has been validated using HPLC (high-performance liquid chromatography). The results of this study were in good agreement with the gold-standard analysis and showed that the antibiotics’ concentration and clearance behavior were accurately monitored.40\n\nSeveral autoimmune disorders are caused by tumor necrosis factor-alpha (TNFα). Adalimumab (ADM), which has a high specificity and affinity for TNFα, makes anti-TNα agents safe and efficient in biological treatments. To address such problems, tailored TDM is crucial since it can guide dosing by capturing the dynamic pharmacokinetic profile of the patient’s prescription medication during therapy.41\n\nA portable sensor for detecting ADM in plasma samples has been developed to provide quick, accurate results within 12 minutes. The sensor combines a fiber-optic (FO) sensing probe for bioassay implementation, an FO-SPR readout device, and a disposable iSIMPLE microfluidic cartridge. The device can also be used for TDM of other biological medications at the point of care. The sensor is highly sensitive, provides real-time monitoring, and is versatile, compact, self-powered, and mobile.42\n\nTDM has been developed for COVID-19 monitoring to help track the efficacy of antibiotic therapy for bacterial co- or superinfections that may occur during SARS-CoV-2 infection, which can compromise the immune system. A microfluidic multiplexed polymer-based electrochemical biosensor combined with CRISPR/Cas-powered assays for nucleic acid testing was able to identify SARS-CoV-2 from diverse biomolecule classes and detect the presence of protein-based β-lactam antibiotic. This method is able to identify individuals infected with variants of SARS-CoV-2, and can be done without cross-contamination.43\n\nA label-free biosensing device for TDM has been developed to detect infliximab therapeutic antibodies using plastic optical fiber (POF). The device uses the SPR sensing technique to detect specific binding between anti-IFX antibody immobilized on the POF sensing region and IFX diluted in buffer and human serum. The results showed that the device could detect IFX in a concentration-dependent and specific manner, with LODs of 23.5 and 73.5 ng/mL for buffer and human serum, respectively. However, the LOD obtained by this POF biosensor is insufficient for measuring the lowest clinically relevant concentrations of IFX. This limitation can be improved by conjugating the SPR-POF sensing region with gold nanoparticles, which have been previously demonstrated to increase sensitivity through excitation of LSPR.44\n\nA study has developed a decentralized and affordable method for TDM by using smartphones and portable spectrometers. The method uses a colorimetric change in a nano paper-based analytical device/curcumin-embedded bacterial cellulose nano paper (NAD/CEBC) bio platform to detect Fe(III) and deferoxamine. This is achieved by creating a Fe(III)-curcumin complex, which liberates curcumin from the bio-platform in Fe(III) presence and reduces color intensity. The smartphone camera is placed in a homemade light control box to observe the color changes and the average color intensity of images captured with a smartphone camera is determined. This method produced a LOD for deferoxamine of 8.2 nM with an RSD value of ≤3.6% and is highly equivalent to conventional spectrometers.45\n\nAn n-channel metal-oxide-semiconductor field-effect transistor (n-MOSFET) is a reliable biosensor that can identify a single target and be used for continuous medication monitoring. The device has an enlarged gate and a drug-specific DNA aptamer that addresses the issues. This biosensor can detect the presence of the targeted pharmaceutical tenofovir (TFV) and can be employed for real-time drug monitoring by real-time monitoring impedance tests. The tests reveal the quality of TFV binding to the aptamer and the fewest non-specific interferences under flow conditions. The biosensor works by using an external gold electrode that is functionalized with a drug-specific aptamer and exposed to the measurement sample, which is physically connected to the gate of the transistor. When a voltage is applied, a current flows through the induced channel beneath the gate dielectric.46\n\nAn ion-selective sensor was developed to monitor drug effects on nicotinic acetylcholine receptors (nAChRs) in living cells. The sensor uses floating electrodes and a carbon nanotube field-effect transistor (CNT-FET) coated with a potassium ion-selective membrane. This allows the device to recognize potassium ions flowing through the membrane, which are released in the body by stimulating nAChRs on PC12 cells with acetylcholine or nicotine. This technology allows for quantitative monitoring of the effects of drugs on these receptors in real-time.47\n\n\nFuture scope\n\nBiosensor technology has the potential to greatly improve the therapeutic drug monitoring (TDM) process for patients. Biosensors are highly flexible and small in size, which allows for continuous, real-time TDM. Some future development directions for biosensors in TDM include incorporating multianalyte sensing to achieve thorough TDM evaluation, developing a sensing-therapeutic feedback system that utilizes drug delivery to enable a smarter healthcare platform, overcoming the obstacle of power by leveraging energy harvesting or storage methods to enable continuous operation, improving wireless communication methods to send real-time monitoring findings over long distances, developing integrated, multifunctional, and self-sustaining systems for wearable chemical sensors and incorporating point-of-care testing to make TDM more accurate and closer to the patient’s condition.\n\nTDM is traditionally done in laboratory settings. However, recreating conditions that closely mimic the patient’s environment is difficult. The term “point of care” (POC) or bedside testing refers to diagnostic tests that are not performed in a laboratory but rather as close to the patient as possible. POC TDM is believed to improve patient care by providing more accurate results in a patient’s specific environment.48\n\nFiber optic surface plasmon resonance (FO-SPR) combined with self-powered microfluidics is one example of biosensor development towards POC testing, specifically for the therapeutic drug monitoring (TDM) of adalimumab. This study demonstrates the potential of FO-SPR biosensing in POC using adalimumab as a model case. It highlights the immense potential of FO-SPR biosensing in POC, and it also has promise for bedside TDM of other medications such as immunosuppressants, antiepileptic therapies, etc. This is because bioassays are very customizable.42\n\nThe internet of things (IoT) is rapidly advancing, and wearable physical sensors are becoming increasingly important for healthcare monitoring. These sensors, such as those used for therapeutic medication monitoring, allow for real-time patient health monitoring. In addition to physical sensors, chemical sensing technologies also show great potential for use in personalized healthcare. The future of wearable chemical sensors is expected to include integrated systems that can sense, treat, and sustain themselves. For these systems to be successful, chemical and physical sensors must be developed and integrated into the next generation of IoT sensors for therapeutic drug monitoring (TDM) practice. These sensors will be critical in advancing personalized healthcare through real-time monitoring and treatment.\n\nMultianalyte sensing is a promising approach for thorough TDM evaluation. Developing a sensing-therapeutic feedback system that utilizes drug delivery is essential to achieve smart healthcare. Power is a significant obstacle for continuous TDM, but energy harvesting and storage methods can overcome this. Short-distance communication is a limitation of current wireless communication methods for real-time monitoring. For wearable chemical sensors to be effective, it is necessary to integrate software and hardware and develop wireless technologies for long-distance data exchange.49\n\nOne of the limitations of biosensors is their detection specificity, as they are typically designed to detect only one type of molecule. However, current research is focused on developing biosensors that can detect multiple analytes at once. This is known as multiplexing and is being applied in TDM. One way to achieve multiplexing is by creating a biosensor platform to detect multiple analytes on-site in TDM for antibiotics. This type of biosensor can provide fast, accurate, and cost-effective results. The multiplexed biosensors can potentially improve the treatment and monitoring of patients receiving antibiotics.40\n\nBiosensors can detect multiple analytes, requiring various reagents and enzymes to be implanted. Current biosensor development is focused on detecting one type of molecule from multiple samples, such as blood, urine, saliva, and sweat. Research40 has shown that the detection accuracy of a specific molecule in plasma, EBC, saliva, and urine is high compared to the gold standard for TDM analysis, the HPLC. The use of biosensors in TDM analysis is a promising field of research.\n\n\nConclusions\n\nIn this article, a review was carried out on biosensor technology to assist the therapeutic drug monitoring (TDM) process. The development of TDM began in the early 1900s and continues to the present. Due to the need for TDM that is flexible, low-cost, can measure in real-time, and can be used comfortably by patients, biosensors are a promising technology for TDM processes.\n\nThis article explains several types of biosensors that are being developed for TDM. These types are optical sensors, mechanical sensors, and electrochemical sensors. The types of drugs that can be monitored by TDM are increasingly diverse every year. Currently, the types of drugs that TDM can do with biosensors are anti-cancer drugs, neurological diseases such as Parkinson’s and schizophrenia, antiepileptics, antidepressants, antibiotics, and diseases caused by viruses such as COVID-19.\n\nWith so much research on biosensors for TDM, several developments will come. Several things being developed in biosensors for TDM are enabling POC for TDM, combining biosensors with IoT systems for TDM, and enabling multiplexed on-site for TDM.\n\n\nAuthor contributions\n\nWS: Writing - Review & Editing, Supervision, Project Administration, Funding Acquisition. AS: Writing - Review & Editing, Supervision, Project Administration, Funding Acquisition, IA: Conceptualization, Methodology, Validation, Investigation, Resources, MFN, ACHA, DAS, FAN: Data Curation, Writing - Original Draft, Visualization, CS: Supervision, Project Administration, Funding Acquisition.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgements\n\nWe thank the School of Electrical Engineering and Informatics, Institut Teknologi Bandung, and the School of Electrical Engineering, Telkom University for the research support.\n\n\nReferences\n\nKang J-S, Lee M-H: Overview of therapeutic drug monitoring. Korean J. Intern. Med. 2009; 24(1): 1–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNwobodo N: Therapeutic drug monitoring in a developing nation: a clinical guide. JRSM open. 2014; 5(8): 2054270414531121. PubMed Abstract | Publisher Full Text\n\nMeneghello A, Tartaggia S, Alvau MD, et al.: Biosensing technologies for therapeutic drug monitoring. Curr. Med. Chem. 2018; 25(34): 4354–4377. Publisher Full Text\n\nMcKeating KS, Aubé A, Masson J-F: Biosensors and nanobiosensors for therapeutic drug and response monitoring. Analyst. 2016; 141(2): 429–449. 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PubMed Abstract | Publisher Full Text\n\nTajik S, Taher MA, Beitollahi H, et al.: Electrochemical determination of the anticancer drug taxol at a ds-dna modified pencil-graphite electrode and its application as a label-free electrochemical biosensor. Talanta. 2015; 134: 60–64. PubMed Abstract | Publisher Full Text\n\nHassani Moghadam F, Taher MA, Karimi-Maleh H: Doxorubicin anticancer drug monitoring by ds-dna-based electrochemical biosensor in clinical samples. Micromachines. 2021; 12(7): 808. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYockell-Lelièvre H, Bukar N, Toulouse J, et al.: Naked-eye nanobiosensor for therapeutic drug monitoring of methotrexate. Analyst. 2016; 141(2): 697–703. PubMed Abstract | Publisher Full Text\n\nAbdel Rahman MA, Atty SA, El-Mosallamy SS, et al.: Experimentally designed electrochemical sensor for therapeutic drug monitoring of ondansetron co-administered with chemotherapeutic drugs. BMC chemistry. 2022; 16(1): 1–12. Publisher Full Text\n\nTai L-C, Liaw TS, Lin Y, et al.: Wearable sweat band for noninvasive levodopa monitoring. Nano Lett. 2019; 19(9): 6346–6351. PubMed Abstract | Publisher Full Text\n\nKilic T, Brunner V, Audoly L, et al.: Smart e-patch for drugs monitoring in schizophrenia. 2016 IEEE International Conference on Electronics, Circuits and Systems (ICECS), IEEE. 2016; pp. 57–60.\n\nLosoya-Leal A, Estevez M-C, Martínez-Chapa SO, et al.: Design of a surface plasmon resonance immunoassay for therapeutic drug monitoring of amikacin. Talanta. 2015; 141: 253–258. PubMed Abstract | Publisher Full Text\n\nPiacentino D, Bianchi E, De Donatis D, et al.: Therapeutic drug monitoring of antidepressants: An underused but potentially valuable tool in primary care. Front. Psych. 2022; 13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAtes HC, Mohsenin H, Wenzel C, et al.: Biosensor-enabled multiplexed on-site therapeutic drug monitoring of antibiotics. Adv. Mater. 2022; 34(2): 2104555. PubMed Abstract | Publisher Full Text\n\nLin S, Yu W, Wang B, et al.: Noninvasive wearable electroactive pharmaceutical monitoring for personalized therapeutics. Proc. Natl. Acad. Sci. 2020; 117(32): 19017–19025. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQu J-H, Ordutowski H, Van Tricht C, et al.: Point-of-care therapeutic drug monitoring of adalimumab by integrating a fo-spr biosensor in a self-powered microfluidic cartridge. Biosens. Bioelectron. 2022; 206: 114125. PubMed Abstract | Publisher Full Text\n\nJohnston M, Ates HC, Glatz RT, et al.: Multiplexed biosensor for point-of-care covid-19 monitoring: Crispr-powered unamplified rna diagnostics and protein-based therapeutic drug management. medRxiv. 2022.\n\nZeni L, Perri C, Cennamo N, et al.: A portable optical-fibre-based surface plasmon resonance biosensor for the detection of therapeutic antibodies in human serum. Sci. Rep. 2020; 10(1): 1–9. 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}
|
[
{
"id": "173907",
"date": "13 Jun 2023",
"name": "Henrik Endeman",
"expertise": [
"Reviewer Expertise TDM antibiotics"
],
"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\nComments\n\nI have a few major concerns\nThis manuscript describes ways to perform TDM, starting with the statement that this is 'essential and necessary'. Well, that is not true, or you have to review that. Now you can get the feeling we are forced to use biosensors and TDM based on an unjustified argument.\n\nI checked several references and found in some cases (see below) that statements are not in line with the result of the reference, or the reference is also a review, clinical guide, or something else, but not original work\nIntroduction\nThe authors state that TDM is essential and necessary in the first paragraph followed by the statement that it will optimize treatment outcome. Now nobody will deny that correct dosing is an important activity in medicine, but whether TDM improves outcome is too my knowledge not common sense. They use a 'clinical guide' as reference, but doubt whether this will underline this statement. I feel we have to see the potential of TDM, and the necessity to examine its effects on outcome, and other endpoints, but just saying it is essential and necessary is, for now, untrue.\nExplain internet of things based TDM systems\n'Furthermore, biosensors can potentially aid in the real-time monitoring of deadly diseases, greatly assisting medical experts in their treatment' This statement is far too blunt. The reference they use here (5) has a far more nuanced view on this topic\nFigure 1; what do the authors mean with 'clinical judgement'?\nGuideline paragraph\nThe psychiatry of the human body? Might be physiology?\nTDM for antibiotics\nWhy should microneedle the preferred method of tracking? I would see direct measurement in the circulation, or at the place of infection, is the preferred method. Furthermore, for beta-lactam, they do not measure the antibiotic, but metabolic changes with might be caused by antibiotics, in healthy humans.\nDigoxin is not an antibiotic.\nConclusion\nStrange phrases such as 'that TDM can do with biosensors\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? No\n\nIs the review written in accessible language? Partly\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
},
{
"id": "214949",
"date": "16 Oct 2023",
"name": "Matteo Conti",
"expertise": [
"Reviewer Expertise Pharmacology",
"TDM",
"chromatography"
],
"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 review deals with a very interesting topic and presents an interesting collection of studies on biosensors in Table 1.\n\nHowever, the paper is in need of an English language revision. Sentences are often too direct and conclusive of the author's ideas without considering possible different views. As a result, the point of view of the authors, despite being often agreable, could be seen as partial and not supported by facts.\nAffirmations such as \" HPLC methods are expensive and incapable..\" should be attended and presented in a more balanced way.\nLimitations in the use of biosensors have not been discussed.\nClinical pro and cons on biosensors applications in POCT should be taken into account. There are many papers in the literature dealing with problems and pitfalls of POCT in the clinics that should be considered.\nTaking into account only the mechanistic chemical analytical point of view is a serious flaw of the whole study.\nTDM applications have many requirements. One is fast turn-around-time but specificity, sensitivity, precision ets... are all very relevant.\nAll of these factors must be taken into account to provide a scholar's deepness to this full review\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? No\n\nIs the review written in accessible language? No\n\nAre the conclusions drawn appropriate in the context of the current research literature? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-171
|
https://f1000research.com/articles/12-170/v1
|
13 Feb 23
|
{
"type": "Research Article",
"title": "COVID-19 vaccines knowledge and acceptance among Indonesian adults in Java Island",
"authors": [
"Annette d'Arqom",
"Peter Asa",
"Amalia Putri Andriani",
"Mhd Zamal Nasution",
"Nurmawati Fatimah",
"Arifa Mustika",
"Lilik Djuari",
"Junaidah Yusof",
"Peter Asa",
"Amalia Putri Andriani",
"Mhd Zamal Nasution",
"Nurmawati Fatimah",
"Arifa Mustika",
"Lilik Djuari",
"Junaidah Yusof"
],
"abstract": "Background: To increase vaccination coverage, it is important to understand COVID-19 vaccination programs and respondents’ acceptance. Therefore, this study aimed to measure respondents’ knowledge of the COVID-19 vaccine and its acceptance among Indonesian adults in Java. Methods: A web-based survey was distributed through social media on self-claimed knowledge, risk and benefits of the vaccine, as well as respondents’ acceptance and experiences of the vaccination. The survey period was from March to July 2021, and 910 responses were included for further analysis. The frequency of each categorical factor, including self-claimed knowledge of the COVID-19 vaccine, their descriptive benefit and side effects of the COVID-19 vaccine, and their experiences receiving or not receiving the vaccine were explored. Predictor factors on vaccine knowledge and acceptance are investigated using multivariate ordinal regression analysis. Results: This study showed that almost all the respondents in both groups have knowledge about COVID-19 vaccination, or at least ever heard about it. The main source of information is social media. More than two third of respondents from each group had already received a COVID-19 vaccine or were at least on the waiting list. Moreover, a quarter of the respondents still hesitate to receive the vaccination. Only less than 10% of respondents reject the vaccination, with the strongest reason being scared of the side effect. Moreover, it found that respondents’ knowledge of the vaccination was influenced by age, medical background, a history of relatives who tested positive for COVID-19, source of information, economic status, and education levels. Moreover, the acceptance was influenced by age, knowledge about vaccines, and having medical background. Conclusions: This study showed high levels of knowledge and acceptance of the COVID-19 vaccine among adults in Java. Increasing understanding or knowledge about COVID-19 vaccine risks and benefits is necessary to reduce vaccination hesitancy.",
"keywords": [
"acceptance",
"COVID-19",
"hesitancy",
"knowledge",
"vaccines"
],
"content": "Introduction\n\nThe COVID-19 situation has improved due to high vaccination coverage (Dye, 2022). Unfortunately, virus mutagenicity produces new variants known to reduce vaccine effectiveness. Boosters have been provided to maintain the protective effect of the vaccine. Even though many researchers continue to develop new vaccines with high efficacy, doubts regarding their effectiveness and safety remain an issue (Shukla et al., 2022).\n\nSeveral studies have shown a relationship between sociodemographic and physiological factors and vaccine acceptance. The sociodemographic factors include age, type of occupation, marital status and monthly income (Faturohman et al., 2021). Moreover, psychological factors might affect vaccination acceptance, adherence and completion (Pandolfo et al., 2022; Yanto et al., 2021). Moreover, misinformation about the COVID-19 pandemic, including the therapy and vaccination, constitutes a huge challenge to overcome (d'Arqom et al., 2021; Pristiyono et al., 2021).\n\nIn Indonesia itself, the current president, Joko Widodo, became the first Indonesian to become vaccinated on January 13, 2021. Since then, the Indonesian government has implemented vaccination programs for certain Indonesian population groups such as Indonesia’s medical personnel and the elderly. When this study was conducted, the vaccination for the general Indonesian adult population had just started, following the vaccination for healthcare professionals, the elderly, and individuals with comorbidity (Jiao & Aditya, 2021).\n\nHowever, various concerns have risen from the general population regarding the vaccine. Among these are views towards the vaccine’s effectiveness, its lack of research, misinformation about its side effects, religious beliefs, fear of injection etc. (Fakhriani et al., 2022; Hidayana et al., 2022; Simanjorang et al., 2022; Theodorea et al., 2021). The Indonesian government ordered the vaccine from China and approved the emergency use for mass vaccinations; unfortunately, due to the concern above, vaccine acceptance was only about 64.8% as reported by UNICEF, WHO, and ministry of health (UNICEF et al., 2020). In the end, to increase vaccine coverage, the Indonesian government made COVID-19 vaccination a requirement for all social aspects such as transportation, direct cash assistance programs (bantuan langsung tunai), obtaining passports, and other public services (Gunawan J et al., 2022). This strategy remains in effect. With this mandate, vaccine acceptance increased from 60 to 86.81% (Kemenkes, 2022). However, the debate on mandatory vaccines involves human rights issues (King et al., 2022).\n\nAs Java is the most developed island in Indonesia and the most populated, most government facilities and programs are concentrated in this area, including the COVID-19 vaccination programs during the early implementation. Therefore, this study focused on an adult population in Java (Arifin & Anas, 2021). Moreover, knowledge and awareness are part of individual factors affecting vaccine acceptance (Erchick et al., 2022). Thus, this study aimed to measure the effect of COVID-19 vaccine knowledge and COVID-19 acceptance among Indonesian adults in Java during the first implementation of the COVID-19 vaccination mandatory programs.\n\n\nMethods\n\nThis cross-sectional study on COVID-19 vaccination among Indonesian adults in Java during the second wave of the pandemic was part of the Dietary Supplement, COVID-19 Vaccine Acceptance, and Mental Health among Indonesian Adults project. This study followed the Helsinki Declaration and was approved by the Health Research Ethics Committee, Faculty of Medicine, Universitas Airlangga (No. 86/EC/KEPK/FKUA/2021). The data were collected from March to June 2021 using a web-based survey generator (www.surveyplanet.com). The survey was distributed online on social media and via email. Before entering the survey, respondents were provided with a landing page consisting of the objective of the study, brief explanation of the survey, the responsible person, and an informed consent page containing permission to use the data anonymously. The respondents provided their consent by choosing the YES button. Multiple submission was prevented by the web-based generator. The inclusion criteria of the respondents were Indonesian citizen, older than 18 years old, and residing in Java when the study was conducted. The minimum sample size was 383, calculated with 5% margin of error, 95% confidence level, and unknown population number which filled with 100,000. This study followed the Checklist for Reporting Results of Internet E-Surveys (CHERRIES) guidelines, and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (Eysenbach, 2004; Vandenbroucke et al., 2007).\n\nThree sections of the questionnaire were developed and distributed online to measure respondents’ COVID-19 knowledge and acceptance. The sections covered sociodemographic information of the respondents, their knowledge of COVID-19 vaccine effects and their acceptance of COVID-19 vaccination. The sections of vaccine knowledge were modified from a questionnaire from UNICEF (UNICEF et al., 2020) and the COVID-19 vaccine acceptance behaviours were developed by a medical doctor and evaluated by three experts, two pharmacologists and a social science expert. Face validity was performed concerning 20 respondents to ensure their understanding of the questions, including the wording and format. A copy of the questionnaire can be found in Extended data.\n\nRespondents were divided into two groups based on their sex: male and female. COVID-19 vaccine general knowledge and vaccine acceptance behaviours were measured using nominal scales. Data were processed and analysed using Microsoft Excel and SPSS 24.0 (IBM, Chicago, IL, USA), and visualized using GraphPad Prism 5.0. Descriptive analysis for each categorical variable was measured, followed by the chi-square test to observe differences between groups. For analysis, we converted the occupation into unemployed and employed, and religion into majority and non-majority. Multivariate ordinal regression analysis was performed to determine determinant factors of self-claimed vaccine knowledge and acceptance. All models were mutually adjusted for all potential confounders, such as sex, age, marital status, employment status, economic status, education, religion, insurance, history of testing positive for COVID-19, as well as the history of family members or relatives testing positive for COVID-19. The dummy variables included sex, marital status, religion, medical background and employment status. Vaccine acceptance points were contracted into reject, hesitate, and accept (respondents who received at least one vaccine or on the waiting list). Significance was defined as a p-value <0.05.\n\n\nResults\n\nThe questionnaires recorded 1,006 responses from March to June 2021. Only 910 responses were valid after the exclusion criteria. The 96 responses were excluded due to domicile outside Java. From these 910 responses, the majority were female, most numerous in the 18 to 25-year-old age group, with marital status single or unmarried, and average economic status. The majority of female respondents were unemployed and had graduated from high school, while the majority of male respondents were employed and held a bachelor’s degree (p=0.000 and p=0.005, respectively). Table 1 summarizes respondent characteristics.\n\nMost respondents reported never experiencing COVID-19 symptoms such as fever, sore throat, coughing, aches and pain, loss of taste and smell, etc. More female respondents reported these conditions compared with male respondents. Only 175 (19.2%) respondents reported that they ever experienced COVID-19 symptoms, with more male respondents confirmed to have symptoms compared with female respondents, both with or without lab confirmation (Figure 1A, p= 0.002). However, the proportion of the respondents did not differ regarding knowing relatives who contracted COVID-19 (Figure 1B).\n\n(A) History of contracting COVID-19, and (B) History of family/relatives testing positive for COVID-19.\n\nAll respondents have some knowledge regarding the vaccination programs being initiated by the government, with more male respondents reporting having good knowledge levels, and more female respondents reporting having sufficient knowledge about the vaccine (p= 0.040). Less than 1% of males and females confessed never hearing about the vaccination programs (Figure 2A). No difference was found concerning respondents’ knowledge on benefits of obtaining the COVID-19 vaccine, including preventing infection and spreading infection, preventing fatality from COVID-19, and even though they contract the disease, they will only exhibit mild symptoms (Figure 2B). Similar knowledge was also observed concerning the side effects of vaccination. The respondents knew that side effects ranged from mild to severe, from soreness at the injection site to anaphylactic shock (Figure 2C). They confessed that the main source of their information was social media, friends/family members, news and others (Figure 2D).\n\n(A) Self-claimed knowledge of the respondents, (B) benefits of COVID-19 vaccination, (C) side effect of the COVID-19 vaccine and (D) source of information about COVID-19 vaccination programs.\n\nWhen this study was conducted, COVID-19 vaccination remained limited for healthcare providers, the elderly, people with comorbidity and just reaching general adulthood. However, data of general adults were recorded and placed on a waiting list. Therefore, vaccine acceptance in this questionnaire was divided in six categories: received two shots, received one shot, received more than three shots, on a waiting list, hesitating, and rejecting the COVID-19 vaccine.\n\nThe majority of respondents were willing to accept COVID-19 vaccines, with more female respondents receiving two doses of the COVID-19 vaccine, and more male respondents on the waiting list. One-third of male respondents hesitated whether to receive a shoot or not during this study period, which was more than female respondents (25%). The rejection number was less than 10%, with a higher proportion comprising male respondents (Figure 3A). Among respondents who received the vaccination, the strongest reason to receive was its safety, followed by its possibility to reduce COVID-19 fatality (Figure 3B). The three major side effects experienced by respondents receiving vaccination were soreness at the injection site, drowsiness, and myalgia or body aches. Only one male respondent experienced an anaphylactic reaction, even though more than 1% of male and female respondents reported allergic reactions such as itchiness and swelling (Figure 3C). For those still hesitant to receive the COVID-19 vaccine, almost two-thirds would consult healthcare professionals and their family members or friends. Different patterns concerning to whom respondents would consult were observed in this study. In all, 5.3% of the female respondents considered consulting health cadres, which was higher than that of male respondents (3.77%). Moreover, a smaller portion of female respondents considered consulting a government officer or their teacher, while none of the male respondents considered it. Less than 2% of males and females would not consult anyone, except themselves (Figure 3D). Furthermore, the strongest reasons for not receiving the COVID-19 vaccine were fear of side effects, insufficient information about this program, and doubt concerning its effectiveness and safety (Figure 3E).\n\n(A) Vaccine acceptance, (B) strongest reason to receive COVID-19 jabs, (C) side effects experienced after receiving the vaccine, (D) who hesitating respondents will consult about the programs and (E) reason for vaccine rejection.\n\nOrdinal regression was performed to predict sociodemographic factors associated with respondents’ COVID-19 knowledge and acceptance. Table 2 shows the results from modelling the outcome as a function of several independent variables including age, sex, marital status, work, economic status, education, religion, insurance, having a relative contract COVID-19, and testing positive for COVID-19. The model in Table 2 shows that young adults were 2.654 times and 2.071 times more likely to have a good knowledge on COVID-19 vaccinations than older subjects (18-25 year olds 95% CI 1.534 to 4.592, p=0.000; >25-35 year olds 95% CI 1.130 to 3.796, p= 0.018, respectively). Respondents with a medical background were 2.176 times more likely to possess knowledge of COVID-19 shots (95% CI 1.586 to 2.984, p=0.000). Another positive predictor factor was their knowledge about relatives that had or never had contracted respondents that did not know about this matter. Respondents that could defined that they had relatives who contracted with COVID-19, either yes or no, have higher knowledge about COVID-19 vaccine compared with respondents that did not know about this matter. Respondents that had relatives with COVID-19 were 1.902 more likely to have a good knowledge about COVID-19 vaccination programs (95% CI 1.239 to 2.920, p= 0.003), in contrast, respondents with no COVID-19 positive relatives were 1.583 time more likely to have knowledge about the vaccination (95% CI 1.014 to 2.471, p= 0.043). In addition, respondents following related information, through social media and webinars were more likely to have a higher knowledge level concerning COVID-19 compared with respondents receiving information from other sources (social media: AOR 2.456, 95% CI 1.180 to 5.112, p= 0.016; webinars: AOR 3.563, 95% CI 1.524 to 8.331, p= 0.003, respectively).\n\nThe negative predictors to knowledge COVID-19 vaccination programs were economic and education status. Respondents with lower economic status, below average and average, were less likely to have a good knowledge on COVID-19 vaccinations (below average: AOR 0.439, 95% CI 0.244 to 0.790, p= 0.006; average: AOR 0.438, 95% CI 0.278 to 0.689, p= 0.000). Similarly, respondents with lower education were also less likely to have a good knowledge on vaccinations as respondents below high school level education were 0.120 more likely to have a good knowledge about this program (95% CI 0.057 to 0.254, p=0.000) and high school graduates were 0.490 more likely to have a good knowledge about this program (95% CI 0.286 to 0.838, p=0.009).\n\nMoreover, for COVID-19 vaccination acceptance, at this study period, young adults (18-35 years old) have higher odds to receive and to accept the vaccination (18-25 years old: AOR 0.071, 95% CI 0.031 to 0.159, p= 0.000; >25-35 years old: AOR 0.287, 95% CI 0.114 to 0.724, p= 0.008), as well as middle age adults (>45-55 years old: AOR 0.222, 95% CI 0.087 to 0.567, p= 0.002). Respondents with no or less knowledge about COVID-19 vaccination programs also less likely to receive the jab. Respondents that never heard about these programs were 0.035 times more likely to obtain a vaccination (95% CI 0.005 to 0.239, p=0.001), In contrast, respondents that only heard about government programs were 0.071 times more likely to receive the COVID-19 shot (95% CI 0.035 to 0.145, p=0.000). Respondents with little knowledge about vaccination programs were 0.455 times more likely to receive a jab (0.208 to 0.994, p= 0.048). The only significant positive predictor was whether the respondents had a medical background (AOR 1.488, 95% CI 1.019 to 2.175, p=0.040). The result of ordinal regression for COVID-19 vaccine acceptance was showed in Table 3.\n\n\nDiscussion\n\nJava island is the densest and the most developed island in Indonesia. The capital city of Indonesia is located in the west part of this island. The infrastructure, including transportation and health-related structure, is most complete and advanced compared to other islands in this country (Handayani & Kumalasari, 2015). As the densest island, Java also contributes 68% of the COVID-19 cases in Indonesia. Therefore, the vaccination program was started on this island with the fastest spreading of the vaccination (Arifin & Anas, 2021).\n\nThis study found that most of the respondents have a knowledge about the program, or at least have ever heard about the COVID-19 vaccination program. Only small portion of the respondents had never heard about it. Most of the respondents understand about the benefit and side effects of vaccination, from mild to severe cases. The positive determinant factors of COVID-19 vaccine understanding were respondents with young age and had medical background. Respondents that can be defined as having or did not have relatives with COVID-19, rather than did not know, had higher odds of having good self-claimed knowledge about this vaccine. Moreover, respondents received information from social media, webinars, and literature or journal. Meanwhile respondents with a lower level of education and lower self-reported economic status were less likely to have a good self-claimed knowledge about this government mass program. A similar finding was reported from 449 university students in Bangladesh that concluded medical students had higher odd of having positive knowledge about vaccines, as well as students majoring in economic and business, and science and technology (Rahman et al., 2022). However, our study did not break down the medical-related field background, such as clinical doctors, medical lecturers, pharmacist, nurses, etc. as a study in Vietnam reported that the last two professions had lower knowledge about the COVID-19 vaccine (Duong et al., 2022). Our findings also support that low income and education were related to low levels of knowledge, as reported in 1708 adults in Vietnam. However, in term of young age, this current study showed better self-claimed knowledge than a study in Vietnam (Duong et al., 2022). A study in 1009 Turkey adults also found that respondents with bachelor degrees were more likely to have good knowledge regarding COVID-19 vaccination (Sonmezer et al., 2022).\n\nEven though during COVID-19 pandemic, social media was criticized due to its circulation about the misinformation, including on vaccine, in our study, respondents who got information form social media had higher odd to have good knowledge on COVID-19 vaccination, as well as for them who received information from webinar and literature/journal, compared to news, information from friend/family, etc. We cannot find the study that showed the source of information as a positive predictor factor on COVID-19 vaccine knowledge, but half of the respondents in Turkey, that concluded 62.7% have positive perceptions, used social media as their source of information regarding the COVID-19 vaccine (Sonmezer et al., 2022). However, a study in 233 university students in Nigeria reported only 20.6% had a good knowledge on COVID-19 vaccination, and 60% of the respondent received information from social media (Orok et al., 2022). This discrepancy might be caused by our study using self-claimed knowledge, instead of measuring it.\n\nIt has been reported that a good knowledge or understanding of vaccination is important for a successful vaccination program, such as in the influenza vaccine (Yaqub et al., 2014), including in the COVID-19 vaccine (Al-kafarna et al., 2022; Yupari-Azabache et al., 2022). As this study was conducted at the beginning of the vaccination program for general adults; therefore, the experience of COVID-19 vaccination was divided into six categories, including waiting list and hesitated. Our study showed that 60-70% of respondents had already received at least one vaccine and registered on a waiting list. Due to the limited stock of vaccine numbers, cold chain storage, vaccinator, etc., the vaccination program was faster in urban areas than in rural areas, even in Java (Arifin & Anas, 2021). The public sentiment about the vaccine used in Indonesian COVID-19 vaccination program on its early implementation has become a challenge for the government (Xu et al., 2022). Data from Twitter mining showed that 56% of Indonesian had negative tweet in January 2021 (Pristiyono et al., 2021). Lack of confidence about vaccine efficacy, safety, and various personal reason was major concern found in this study. The acceptance options were further minimized in the multivariate analysis as reject, hesitate, and accept (consisted of respondents had received at least one jab and on the waiting list). Our study found a young adult and middle age adult respondents were less likely to accept the vaccination, as well as respondents that never heard, ever heard, and had a little knowledge about this vaccination. Almost half of younger respondents (18-25 years old) were still hesitant to receive COVID-19 vaccination, even though they claimed to have a good or enough knowledge about the vaccine. A similar finding was also reported in a study of 6,226 Palestinian adults, with 37.8% of them did not believe in the efficacy of COVID-19 as protection toward SARS-CoV-2 infection, even though younger Palestinians showed higher knowledge (Al-kafarna et al., 2022). Our study also found that middle age respondents also have lower odd accept the vaccination. Their rejection and hesitancy was more likely due to their possibility to develop comorbidity diseases (Fan et al., 2021) and higher risk to develop adverse event (Almufty et al., 2021; Orebi et al., 2022). Our study also supports that less knowledge about COVID-19 vaccine also significantly associated with lower COVID-19 acceptance. A similar finding was also reported in Vietnam, where individual with less knowledge is more likely to reject COVID-19 vaccination (Duong et al., 2022). The only significant positive predictor factor was having medical background, which might be related that the healthcare professionals were among the priority to receive the vaccination, and more likely due to higher level of knowledge as reported in Bangladesh and Vietnam (Duong et al., 2022; Rahman et al., 2022).\n\nAs this study only covers one most developed and densest islands in Indonesia, a study with wider coverage is necessary. Moreover, as this study was conducted in the beginning of the vaccination program, a follow-up about the reason behind high vaccination coverage in Indonesia should be investigated and analysed as a lesson for future recommendations. Measurement of knowledge, instead of self-claimed, might show more complete picture, even though the results in this study mostly have similar finding with other studies.\n\nTaken together, this study showed high COVID-19 vaccine knowledge and acceptance among adults on Java Island. Increasing understanding or knowledge about COVID-19 vaccine risks and benefits is necessary to reduce vaccination hesitancy. Vigorous campaigns and dissemination of information are needed to increase knowledge of young adults, people at high risk, low economic background, low education level and individuals with the nonmedical-related background. Moreover, because social media constitutes the highest source of information, it could be used for stakeholders to share the correct information about the pandemic and its vaccination programs, including booster programs.",
"appendix": "Data availability\n\nMendeley data: COVID-19 Vaccine Understanding and Acceptance in Java. https://doi.org/10.17632/7y7mg4r9b4.2 (d’Arqom, 2022).\n\nThis project contains the following underlying data:\n\n- 910 Vaccine Java Data.xlsx\n\n- Erratum 910 Vaccine Java Data.xlsx (correction of the labelled on the column O on the 910 Vaccine Java Data.xlsx)\n\nMendeley data: COVID-19 Vaccine Understanding and Acceptance in Java. https://doi.org/10.17632/7y7mg4r9b4.2 (d’Arqom, 2022).\n\nThis project contains the following extended data:\n\n- Supplement Vaccine.docx (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\nAl-kafarna M, Matar SG, Almadhoon HW, et al.: Public knowledge, attitude, and acceptance toward COVID-19 vaccines in Palestine: a cross-sectional study. BMC Public Health. 2022; 22(1): 529. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlmufty HB, Mohammed SA, Abdullah AM, et al.: Potential adverse effects of COVID19 vaccines among Iraqi population; a comparison between the three available vaccines in Iraq; a retrospective cross-sectional study. Diabetes Metab. Syndr. Clin. Res. Rev. 2021; 15(5): 102207. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArifin B, Anas T: Lessons learned from COVID-19 vaccination in Indonesia: experiences, challenges, and opportunities. Hum. Vaccin. Immunother. 2021; 17(11): 3898–3906. PubMed Abstract | Publisher Full Text | Free Full Text\n\nd'Arqom A, Sawitri B, Nasution Z, et al.: \"Anti-COVID-19\" Medications, Supplements, and Mental Health Status in Indonesian Mothers with School-Age Children. Int. J. Women's Health. 2021; 13: 699–709. PubMed Abstract | Publisher Full Text | Free Full Text\n\nd'Arqom A:COVID-19 Vaccine Understanding and Acceptance in Java. [dataset]. Mendeley Data. 2022; V2. Publisher Full Text\n\nDuong MC, Duong BT, Nguyen HT, et al.: Knowledge about COVID-19 vaccine and vaccination in Vietnam: A population survey. J. Am. Pharm. Assoc. 2022; 62(4): 1197–1205.e4. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDye C: The benefits of large scale covid-19 vaccination. BMJ. 2022; 377: o867. Publisher Full Text\n\nErchick DJ, Gupta M, Blunt M, et al.: Understanding determinants of vaccine hesitancy and acceptance in India: A qualitative study of government officials and civil society stakeholders. PLoS One. 2022; 17(6): e0269606. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEysenbach G: Improving the quality of Web surveys: the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). J. Med. Internet Res. 2004; 6(3): e34. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFakhriani R, Ulfa M, Maryani N, et al.: Investigating Knowledge toward COVID-19 Vaccination: A Cross-sectional Survey in Yogyakarta, Indonesia. Open Access Maced. J. Med. Sci. 2022; 10(E): 865–874. Publisher Full Text\n\nFan ZY, Yang Y, Zhang CH, et al.: Prevalence and Patterns of Comorbidity Among Middle-Aged and Elderly People in China: A Cross-Sectional Study Based on CHARLS Data. Int. J. Gen. Med. 2021; 14: 1449–1455. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFaturohman T, Kengsiswoyo GAN, Harapan H, et al.: Factors influencing COVID-19 vaccine acceptance in Indonesia: an adoption of Technology Acceptance Model. F1000Res. 2021; 10: 476. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGunawan J, Aungsuroch Y, Fisher M, et al.: Identifying and understanding challenges to inform new approaches to improve vaccination rates: A qualitative study in Indonesia. J. Nurs. Scholarsh. 2022. (1527-6546 (Print)). Publisher Full Text\n\nHandayani W, Kumalasari NR:Migration as Future Adaptive Capacity: The Case of Java — Indonesia.Hillmann F, Pahl M, Rafflenbeul B, Sterly H, editors. Environmental Change, Adaptation and Migration: Bringing in the Region. Palgrave Macmillan UK;2015; (pp. 117–138). Publisher Full Text\n\nHidayana I, Amir S, Pelupessy DC, et al.: Using a health belief model to assess COVID-19 vaccine intention and hesitancy in Jakarta, Indonesia. PLOS Global Public Health. 2022; 2(10): e0000934. Publisher Full Text\n\nJiao C, Aditya A: Indonesia Begins COVID-19 Vaccine Rollout – and Jokowi Is First to Get Jab. TIME;2021, 13 January 2021.Reference Source\n\nKemenkes: Vaksinasi COVID-19 Nasional (National COVID-19 Vaccination). Ministry of Health of Republic of Indonesia;2022. Retrieved 20 November.Reference Source\n\nKing J, Ferraz OLM, Jones A: Mandatory COVID-19 vaccination and human rights. Lancet. 2022; 399(10321): 220–222. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOrebi HA, Emara HE, Alhindi AA, et al.: Perceptions and experiences of COVID-19 vaccines’ side effects among healthcare workers at an Egyptian University Hospital: a cross-sectional study. Tropical Medicine and Health. 2022; 50(1): 37. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOrok E, Ndem E, Daniel E: Knowledge, attitude and perception of medical students on COVID-19 vaccines: A study carried out in a Nigerian University [Original Research]. Front. Public Health. 2022; 10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPandolfo G, Genovese G, Iannuzzo F, et al.: COVID-19 Vaccination and Mental Disorders, What Has Been Accomplished and Future Direction. Brain Sci. 2022; 12(2). PubMed Abstract | Publisher Full Text | Free Full Text\n\nPristiyono RM, Ihsan MAA, Anjar A, et al.: Sentiment analysis of COVID-19 vaccine in Indonesia using Naïve Bayes Algorithm. IOP Conference Series: Materials Science and Engineering. 2021; 1088(1): 012045. Publisher Full Text\n\nRahman MM, Chisty MA, Alam MA, et al.: Knowledge, attitude, and hesitancy towards COVID-19 vaccine among university students of Bangladesh. PLoS One. 2022; 17(6): e0270684. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShukla SK, Patra S, Das TR, et al.: Progress in COVID research and developments during pandemic. VIEW. 2022; n/a(n/a): 20210020. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSimanjorang C, Pangandaheng N, Tinungki Y, et al.: The determinants of SARS-CoV-2 vaccine hesitancy in a rural area of an Indonesia–Philippines border island: A mixed-method study [10.1016/j.enfcle.2022.03.002]. Enfermería Clínica (English Edition). 2022; 32: 376–384. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSonmezer MC, Sahin TK, Erul E, et al.: Knowledge, Attitudes, and Perception towards COVID-19 Vaccination among the Adult Population: A Cross-Sectional Study in Turkey. Vaccines. 2022; 10(2): 278. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nTheodorea CF, Widyarman AS, Dewanto I, et al.: COVID-19 Vaccines in Indonesia: Knowledge, Attitudes, and Acceptance Among Dental Professionals [Original Research]. Front. Med. 2021; 8PubMed Abstract | Publisher Full Text | Free Full Text\n\nUNICEFNITAG, WHOKemenkes: COVID-19 Vaccine Acceptance Survey in Indonesia 2020.Reference Source\n\nVandenbroucke JP, von Elm E , Altman DG, et al.: Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and Elaboration. PLoS Med. 2007; 4(10): e297. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXu H, Liu R, Luo Z, et al.: COVID-19 vaccine sensing: Sentiment analysis and subject distillation from twitter data. Telematics and Informatics Reports. 2022; 8: 100016. Publisher Full Text\n\nYanto TA, Octavius GS, Heriyanto RS, et al.: Psychological factors affecting COVID-19 vaccine acceptance in Indonesia. Egypt J Neurol Psychiatr Neurosurg. 2021; 57(1): 177. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYaqub O, Castle-Clarke S, Sevdalis N, et al.: Attitudes to vaccination: a critical review. Soc. Sci. Med. 2014; 112: 1–11. Publisher Full Text\n\nYupari-Azabache IL, Díaz-Ortega JL, Bardales-Aguirre LB, et al.: Factors Associated with the Acceptance of COVID-19 Vaccines in Citizens of Northern Peru: Cross-Sectional Study. Risk Manag Healthc Policy. 2022; 15: 1705–1715. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "172034",
"date": "18 May 2023",
"name": "Gilbert Sterling Octavius",
"expertise": [
"Reviewer Expertise COVID-19 Vaccine Research (Social aspect)"
],
"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 have read the article which attempted to analyze the knowledge and acceptance of Indonesians regarding COVID-19 vaccines. While this article has its merits, such as a solid sample size, several points need to be addressed:\nThe introduction could be rephrased to ensure the readers understand what the authors are trying to convey. Several phrases, such as \"In Indonesia itself, the current president, Joko Widodo, became the first Indonesian to become vaccinated on January 13, 2021\", do not add coherency or essential points to the introduction and yet disrupt the whole flow.\n\nThe authors mentioned that the study aims to \"..measure the effect of COVID-19 vaccine knowledge and COVID-19 acceptance...\" However, based on the results and discussion, the aim of the study is not answered as the authors tend to respond to what factors influenced vaccine knowledge and acceptance in Javanese individuals.\n\nIf this work is part of another study, has it been published elsewhere? If so, please cite the paper so other readers can refer to that study.\n\nOperational definitions must be stated clearly, even though the authors adopted the questionnaires elsewhere. For example, what constitutes vaccine acceptance?\n\nA statistician must be consulted as all univariate results are presented without an odds ratio and 95% CI, while the p-value is 0.000. An overhaul of the statistics and Results section is needed. After the Results section is revised, the Abstract section must also be rephrased.\n\nThe authors must explain several rationales in choosing the reference for multivariate analysis. For example, why is \"others\" being selected as a reference point for source of information?\n\nUsing stack bars to visualize the data may not be appropriate. It is confusing, and the y-axis is off (as it jumps from 30 to 80%), potentially misleading the readers.\n\nThe authors need to include a limitation section.\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": "168166",
"date": "02 Jun 2023",
"name": "Nirachon Chutipattana",
"expertise": [
"Reviewer Expertise Health education and behavioral 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\nStudying COVID-19 vaccine knowledge and acceptance is an important issue. Although it is not a novel idea at the moment, it may help to reduce vaccination hesitancy, increase access to booster vaccination, and provide vaccination programs in the event of a pandemic in the future. I believe it will be beneficial if the authors work hard to improve the clarity and consistency of the article on all topics.\nRelationship to Literature\nAccording to the sentence \"Unfortunately, virus mutagenicity produces new variants known to reduce vaccine effectiveness.\" - it would be better if you explained the significance of vaccines.\n\nWhat happens if people do not get immunized?\n\nThe sentence “Even though many researchers continue to develop new vaccines with high efficacy, doubts regarding their effectiveness and safety remain an issue” is irrelevant to the research objectives.\n\nProvide statistics on COVID-19 deaths worldwide, in Asia, and in Indonesia.\n\nWhat are psychological factors?\n\nAccording to the sentences “Moreover, psychological factors might affect vaccination acceptance, adherence and completion (Pandolfo et al., 2022; Yanto et al., 2021). Moreover, misinformation about the COVID-19 pandemic, including the therapy and vaccination, constitutes a huge challenge to overcome (d'Arqom et al., 2021; Pristiyono et al., 2021).” - a lack of connection between sentences.\n\nAccording to the sentence \"In Indonesia itself, the current president, Joko Widodo, became the first Indonesian to become vaccinated on January 13, 2021.\" It would be more helpful to specify when Indonesian citizens started receiving vaccinations.\n\nExplain why the relationship between sociodemographic factors and COVID-19 vaccine knowledge is necessary.\n\nExplain why the relationship between sociodemographic factors and COVID-19 vaccine acceptance is necessary.\n\nPlease explain why you want to examine the relationship between sociodemographic factors and sex in Table 1.\n\nIt should explain why you must classify by sex.\n\nWhat concept or theory do you apply?\n\nPlease explain how your work differs from previous studies.\n\nMethodology\nPlease reference the sentence \"...calculated with 5% margin of error, 95% confidence level, and unknown population number which filled with 100,000.\"\n\nExplain the sampling method.\n\nPlease explain the questionnaire on knowledge and acceptance of COVID-19 vaccines, such as how many items it has, how the questions are explained to the participants, and the scale used to measure them.\n\nShow the results of tests of validity and reliability.\n\n\"Respondents were divided into two groups based on their sex: male and female. COVID-19 vaccine general knowledge and vaccine acceptance behaviours were measured using nominal scales.\" - should move to the instrument section.\n\nWhy does the 'Analytic procedure' section only explain occupation and religion?\n\nExplain how to test the main assumptions in multivariate ordinal regression and what the results are.\n\nResults\nIf you want to show the chi-square test in Table 1 and the information in Figures 2 and 3, write down your research objectives.\n\nExplain the medical background.\n\n“Another positive predictor factor was their knowledge about relatives that had or never had contracted respondents that did not know about this matter.” - means you compared with whom?\n\nTo make it easier for the audience to understand, I propose that you change a reference category in the dummy coding of Tables 2 and 3, such as economic status, education, age, and knowledge. However, if you want to keep it the same, please clarify your results and discussion.\n\nAccording to the paragraph “Java island is the densest and the most developed island in Indonesia....Therefore, the vaccination program was started on this island with the fastest spreading of the vaccination (Arifin & Anas, 2021).”, I suggest that the author move it to the beginning of the Methods section with the subheading 'Study Area'.\n\nIn the first paragraph of your discussion, summarize your major and novel findings.\n\nHow does the sentence \"Moreover, respondents received information from social media, webinars, and literature or journal\" help to explain the previous sentence?\n\nThe sentence “However, in term of young age, this current study showed better self-claimed knowledge than a study in Vietnam” is an exaggeration.\n\nPlease expand on the sentence “This discrepancy might be caused by our study using self-claimed knowledge, instead of measuring it” to better understand.\n\nAccording to the sentence “Our study showed that 60-70% of respondents had already received at least one vaccine and registered on a waiting list” - you should present data that includes both men and women in your figure.\n\nPlease reconsider whether sex classification is helpful for research discussion. In Tables 2 and 3, I noticed that sex was not associated with COVID-19 vaccine knowledge or acceptance.\n\n“The acceptance options were further minimized in the multivariate analysis as reject, hesitate, and accept (consisted of respondents had received at least one jab and on the waiting list).” - should be revised and moved to the instrument section. Put citations that state the grouping “reject, hesitate, and accept” as well.\n\nFactors that have been discovered to be statistically significantly correlated and discussed should provide recommendations.\n\nIt should include a conclusion section.\n\nWhich factor has the most influence on COVID-19 vaccine knowledge and acceptance? Please explain.\n\nImplications for research\nPlease clearly explain how this research bridges the gap between theory and practice.\n\nPlease explain how this research could impact upon society.\n\nQuality of Communication\nAvoid using redundant words. Avoid using the word \"moreover\" several times. For example, \"Moreover, psychological factors might affect vaccination acceptance, adherence and completion (Pandolfo et al., 2022; Yanto et al., 2021). Moreover, misinformation about the COVID-19 pandemic, including the therapy and vaccination, constitutes a huge challenge to overcome\".\n\nThere is a lack of connection in some paragraphs.\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": []
}
] | 1
|
https://f1000research.com/articles/12-170
|
https://f1000research.com/articles/12-169/v1
|
13 Feb 23
|
{
"type": "Research Article",
"title": "Development and validation mental training model: Mental Toughness Training Circle (MTTC)",
"authors": [
"Sutoro .",
"Tri Setyo Guntoro",
"Miftah Fariz Prima Putra",
"Sutoro ."
],
"abstract": "Background: A systematic and comprehensive mental training program to enhance athletes’ mental toughness is critical. The aim of this study was to develop and validate a set of athletes’ systematic mental training programs. Methods: A mental toughness training program was developed, and the validity and reliability were tested on experts, practitioners, and athletes. Training program was analyzed using content validity index (I-CVI and S-CVI) and modified Kappa (k*). Furthermore, estimation of reliability of mental training model was analyzed by internal consistency approach with Cronbach’s alpha and inter-rater reliability (IRR) approach by using intraclass correlation coefficients (ICC). Result: A mental toughness training circle (MTTC) was successfully developed with four sections: general preparatory, specific preparatory, precompetitive, and competitive with 11 mental skills (positive thinking, mental log, goal-setting, breathing, relaxation, concentration, self-talk, mental imagery, leadership, managing anxiety, and managing emotions). Validation assessment found that the I-CVI and S-CVI values (S-CVI/Ave and S-CVI/UA) were 1.00, each suggesting excellent content validity. The modified Kappa value (k*) was 1 and categorized as excellent. The results of the reliability test using Cronbach's alpha showed that a value was in the range 0.723 to 0.835 with an overall value of 0.803. The results of the ICC analysis also confirmed that MTTC had a very high reliability coefficient value of 0.803. In addition, there was no significant difference from respondents’ assessment as proved by obtaining value of F=0.754 with a p=0.644 (>0.05). This suggested that respondents tend to be consistent in assessing MTTC as a mental training set which was categorized as relevant (scale 3) or very relevant (scale 4). Conclusion: MTTC which has four sections with 11 mental skills is a set of mental training programs that have high quality. Further studies to validate this program in a bigger sample size is required.",
"keywords": [
"Mental toughness",
"mental training",
"psychological skill",
"mental toughness training circle",
"MTTC"
],
"content": "Introduction\n\nThe increasing pressure experienced by athletes in the modern era1 has made the topic of mental toughness (MT) popular among scholars.2 Therefore, in the field of sports psychology, studies on the topic of MT have been conducted several times3,4 and there are still many that can be explored in this area.5 Furthermore, in the history of the development of Mental Skill Training (MST) in sports, the involvement of scientists from the Soviet Union were inseparable. In the 1950s, Avksenty Cezarevich Puni was credited for his work in creating a systematic mental training program.6 The application of systematic mental training by the Soviets to athletes was then followed by other eastern European countries such as Germany and Romania.7 However, because the article was in Russian, the publication received little global attention, thus Ryba and his colleagues6 translated Puni's work into English.\n\nIn simple terms, MT describes a person's ability to persevere and focus on reaching specific goals.8 Athletes who have MT will become much better and consistent in determination, focus, confidence, and under pressure management.9,10 Furthermore, Clough and his colleagues11 developed an instrument to measure MT using four dimensions which were widely known as the 4Cs (i.e., commitment, challenge, control, and confidence). The work of Clough and his colleagues11 is based on the hardiness theory suggested by Kobasa.12 In contrast to that, Gucciardi et al. developed an MT measurement tool using “personality psychology” as a framework. From this work, Gucciardi13 concluded that “MT as a personal capacity to produce consistently high levels of subjective (e.g., personal goals or strivings) or objective performance (e.g., sales, race time, GPA) despite everyday challenges and stressors as well as significant adversities.” The other experts, Sheard and his colleagues14 developed MT based on “positive psychology” paradigm as stated by Seligman & Csikszentmihalyi.15\n\nMT can be comprehended as a combination of emotions, attitudes, behaviors, and values that enable individuals to overcome the constraints and pressures they experience while remaining consistent in maintaining motivation and concentration to meet specific goals.16 Although there are many definitions suggested by experts10,13,17 these definitions are inconsistent18 and often become conceptual debates.13 Nevertheless, in general MT is a multidimensional concept and is often associated with resolute self-confidence, persistence or capability of bouncing back from failure, capability of dealing with pressure and difficulties effectively, and capability of maintaining concentration despite encountering several distractions.19 Similarly, Gucciardi10 stated that MT generally refers to themes such as belief, focus, motivational drive, control, and regulation of the self (e.g., thoughts, feelings) during training and competition.\n\nMT is a compatible process and if used in an effective balance can create an optimal pattern to achieve success.20 Athletes with high MT levels are likely to have positive reactions, are better at dealing with pressure5,21 and show better performance.22 On the other hand, if athletes have low MT level, situations where they face pressure will result in negative reactions such as nervousness, unstable emotions, loss of concentration and behavior beyond the athletes’ internal control.11 Elite athletes are likely to have higher MT level than non-elite athletes.23 Having high MT level can make athletes feel confident, relaxed, calm, and enthusiastic and consistently pursue the target or its purpose.\n\nBased on perspective of sports science, the success or failure of athletes is determined by many complex factors.24 Generally, there are four influential aspects, namely physical, technical, tactical, and psychological.19,25 That means, in competitive sports it is not only the physical, technical and tactical that have a role but the mental (psychological) aspect of the athletes is also very influential. Indeed, there are many variables that contribute to determining the outcome of a competition, according to Gould et al.,26 in world prestigious sport events (e.g. the Olympics), the most influential factor that determines the outcome of a match and athletes’ performance in the field is MT. This happens because at the world elite level, physical and technical factors are relatively the same, considering that athletes have been trained with a variety of training programs and the latest methods.27 Therefore, at that level, it is believed that the athletes’ mental factor contributes greatly in the field.26,28 US professional tennis player, Alexandra Stevenson, states that “Mental toughness is 90 percent of the game”.29 The same thing was also stated by Australian swimming legend, Elka Graham, that “In training everyone focuses on 90% physical and 10% mental, but in the races it’s 90% mental because there's very little that separates us physically at the elite level”.30 Even though MT has the greatest influence on the outcome of a competition, the facts shows in the field that mental training is often neglected.31,32 In fact, mental training is very important for athletes, both elite-professional level athletes and beginner level athletes.3,28,33\n\nGenerally, coaches recognize that the mental aspect influences the success of athletes.34 From the perspective of athletes, especially elite and super elite athletes, they also admit that MT is a vital aspect for them.5,9 On the other hand, especially in Indonesia, coaches do not prepare specific mental training programs and tend to focus on physical and technical aspects.31,35 This fact that occurs in Indonesian sports coaching is different from coaching and training overseas which has integrated physical, technical, tactical and mental training in the training menu.26,28,36 As matter of fact, the development of modern sports in Indonesia can be seen after Indonesia's independence37 but unfortunately interventions related to the mental aspects of athletes have not been applied much. One of the reasons for this is due to the trainers’ limited knowledge about structured and integrated mental training program for athletes.28 Because of this, the mental training programs are not given to them.\n\nSeveral models of mental training have been designed by experts. However, we have not found an explanation of how they are carried out systematically and the terms used by experts regarding mental training are also varied. There are those who call it Psychological Skill Training (PST),38–41 Mental Skill Training (MST),16,42 Mental Training Skill (MTS)43 and Mental Toughness Training (MTT).44,45 These terms are often used interchangeably by experts. (see example:38) Therefore, this article does not attempt to differentiate the use of existing terms related to intervention or providing mental training to athletes because we conclude the focus of the goal is the same, namely, to improve the mental quality of athletes or to create a winning mentality.\n\nMental toughness interventions in athletes have been carried out by experts.16,33,39,46 However, studies on mental training programs applied in the field are still partial. Johnson47 only applied mental training by providing one aspect of the exercise, namely self-talk. Mellalieu48 only used goal setting to improve athletes’ performance. In contrast, other researchers used a set of mental training programs consisting of five psychological skills,38–41 while Gucciardi16 used two different mental program sets to improve athletes' mental toughness. An expert43 made MTS but unfortunately it has not been tested further and in a wider context. Ragab44 gave MTT to athletes for eight weeks, but the procedures and stages of the mental training program given were not explained in detail. Therefore, we see the need for a mental training program that is arranged systematically and comprehensively to improve athletes' mental toughness. While there are already a set of mental training programs made for athletes, we offer an alternative mental training program that is systematically structured and interrelated. Hence, the purpose of this research is developing and validating systematic mental toughness training programs for athletes.\n\n\nMethods\n\nThe protocol of the study was approved by the Health Research Ethics Committee, Faculty of Sport Sciences, Universitas Negeri Semarang with the number 266/KEPK/EC/2022. All respondents were requested to provide the written informed consent before participating in this study. Those who received the module and assessment form via email and WhatsApp also had to sign the written informed consent prior to participating in the study and return it together with completed assessment form to authors.\n\nThis research is a type of development research. The development step in this research modifies the procedure proposed by Rodrigues et al.49 There are two stages in this study, namely (i) developing a set of mental toughness training program, and (ii) testing the validity and reliability of the model.\n\nWe started the development step by conducting a literature review. We reviewed articles, e-books, and books related to Mental Toughness (MT). Scientific data search engines (ScienceDirect, PubMed, and DOAJ) were used to search for relevant literature. Moreover, we also used Google Scholar to add relevant references. We used specific keywords in searching namely: “mental toughness” or “mental training” or “mental skill” or “psychological training” or “psychological skill.” The search was carried out from 15–29 August 2022. Based on the literature review,15,16,33,38–48 we created a training model to improve athletes’ mental quality or to make athletes have winning mentality (mindset of growth, abundance, and success).\n\nThere were two inclusion criteria used for experimental and non-experimental studies (review). For original studies, the criteria for articles that were analyzed further were (1) testing or providing mental training, and (2) using athletes as research samples. For review article, the criteria used were (1) a review of the results of mental training, and (2) discussing mental training programs. Outside of these criteria, the literature will not be analyzed further.\n\nThe available references were analyzed descriptively, and we found that: (1) There were researchers who tested the provision of mental training, but this was limited to one mental skill. (2) There were experts who used a set of mental training programs with different number of skills, for example, five mental skills and six mental skill exercises. However, these available set of programs are not comprehensive and still needs to be improved considering some mental skills are still not included in the programs such as positive thinking and breathing. These skills are needed by athletes to build MT. In addition, the training stages for each mental skill are not explained in detail. (3) There were different terms used in giving names to each stage or group of mental training such as categorization into basic mental skills and advanced mental skills, some used the term mental skill types, namely foundation, performance, personal development skills, and team skills. Some refer to them by skill level terms, namely performance skills, preliminary skills, and basic skills. Based on the those results of the available references, we concluded that: (1) the terms in the training program used are relatively unfamiliar to coaches and there was confusion in integrating mental training programs with physical training programs, techniques, and tactics, and (2) there needs to be an alternative mental training program that is more comprehensive, and each mental skill is related to other skills. Therefore, we developed a program called mental toughness training circle (MTTC). In this program, we use terms that are quite familiar to coaches in preparing training programs so far, namely general preparatory, specific preparatory, precompetitive, and competitive. These terms are commonly used by coaches in preparation of training programs.\n\nWe then analyzed each skill commonly used by experts and researchers in an effort to shape the MT. In addition, we also looked at the impact of these mental training skills on the psychological aspects of athletes. Taking these aspects into consideration, we found there were 11 mental skills are needed for athletes to have MT, namely positive thinking, mental log, goal-setting, breathing, relaxation, self-talk, concentration, mental imagery, leadership, managing anxiety, and managing emotions. After choosing these eleven skills, we then included them into training component stages that have been made (i.e., general preparatory, specific preparatory, precompetitive, and competitive). To determine which stage the mental skill belongs to, we decided based on (1) the characteristics of the mental training, (2) the stage or phase of the training, (3) the level of difficulty of the training, and (4) the purpose of the mental skill training. Based on this, we included five mental skills in the general preparatory stage, four in the specific preparatory stage, and two in the precompetitive stage.\n\nParticipant’s criteria\n\nAfter the MTTC training model was successfully developed, we tested the model into four groups of respondents. The criteria of the four groups of respondents involved: (1) sport psychologist who has a Doctoral degree; (2) sport training expert who has Doctoral degree; (3) internationally licensed sport trainers; and (4) outstanding athletes. The internationally licensed sport trainers were trainers who had coached Indonesian national team with Doctoral degree in Sport Sciences or had experiences at national level competitions in Indonesia with a Master degree in Sport Sciences. The outstanding athletes those who had achievements at the national or international level or won a medal at the SEA (Southeast Asian) Games, the Asian Games, or participated in the Olympics.\n\nResearch participants and selection\n\nThe experts were chosen for their educational background, experience, and achievements. There were four criteria for the experts we involved. The experts were selected using non-random sampling technique with purposive sampling. The experts were contacted using phone and we asked them if they were willing to be experts in our research. If they agreed to be experts in this study, the assessment form was provided. Expert judgment is needed so that the model developed has good quality. In end of the study, nine experts participated. As suggested previously50 the recommended number of experts for content validity is between six and ten but no more than ten is recommended. As there were already nine experts who provided ratings, we decided that this was sufficient as it was in line with the recommendation.\n\nThe final experts consisted of three sport psychologists who has a Doctoral degree, one sport training experts who has Doctoral degree, three internationally licensed sport trainers; and two outstanding athletes.\n\nStudy instrument and data collection\n\nTo assess the validity of the MTTC model, an assessment form was used to collect data was an assessment form. The assessment form consisted of three parts, namely (1) instructions, (2) mental training model with a brief description of mental training model, and (3) assessment form. The model and the assessment form were handed over to respondents in person or online via email and WhatsApp for evaluation and assessment. Five experts participated online and four experts in person. Data collection and analysis were conducted from October 3, 2022 to November 3, 2022.\n\nFor each question in the assessment form97, the possible responses were in the form of a Likert scale with a range of 1 (very irrelevant) to 4 (very relevant). The score 1 indicates that the prepared part in the mental training program is not relevant to the concept of the mental training program, while the number 4 indicates that the program is relevant to the concept of the mental training program. The four scales were chosen to avoid having a middle value and this is as suggested by Lynn51 in content analysis. In addition, the assessment sheet also included a “comments” or “suggestions” section to get input from respondents.\n\nThe data from the expert assessment97 was entered in Excel by one author. After that, the second author verified the data. The data was coded with numbers one to nine, indicating there were nine experts.\n\nResearch data were analyzed by using Content Validity Index (CVI). CVI is the degree to which an instrument has an appropriate sample of items to construct being measured.52 In this study, CVI analysis was calculated based on each dimension of the mental training program or known as Item-level Content Validity Index (I-CVI) and Scale-level Content Validity Index (S-CVI).53 I-CVI is the Content Validity of individual items or the proportion of content respondents giving the item a relevance rating of 3 or 4. S-CVI is the Content Validity of the overall scale, and is divided into two, namely the proportion of items on a scale that achieves a relevance rating of 3 or 4 by all the respondents (S-CVI/UA) and the average of the I-CVIs for all items on the scale (S- CVI/AVE). S-CVI/UA is a universal agreement calculation method while S-CVI/Ave is an averaging calculation method.52,53 With a total of nine respondents, the minimum acceptable CVI value is 0.78.51\n\nAlthough the CVI is widely used by researchers in testing content validity, the index does not consider value increment due to chance agreements.54 Thus, there are experts who suggest that Kappa statistical analysis should also be used55 which Pollit51 later modified the Kappa analysis with the notation k*, namely kappa designating agreement on relevance. Before calculating k*, the probability of a chance occurrence (Pc) should be identified, and the following is the formula:\n\nN represents the number of respondents and A represents the number of relevant assessments (scales 3 and 4). After Pc value is calculated, the analysis progressed by calculating k* using the proportion of agreements on relevance (I-CVI). The formula as follows:\n\nThe criteria used to evaluate the value of k* are as follows: Poor=k<0.40; Fair=k of 0.40 to 0.59; Good=k of 0.60–0.74; and Excellent=k>0.74.56,57\n\nThe reliability of the mental training model was analyzed by using the internal consistency approach with Cronbach's alpha58,59 and Inter-Rater Reliability (IRR) approach using the Intraclass Correlation Coefficients (ICC).60,61 This was chosen because in social studies, Cronbach's alpha and ICC are analysis that are often used by researchers to test reliability.59,61 The criteria used to interpret the reliability analysis are coefficient values>0.50=low reliability; coefficient values 0.50–0.75=moderate reliability; value>0.75=good reliability.58,61 Research data analysis was conducted by using IBM SPSS version 26 programs (IBM Corp, Armonk, NY, USA) or the open-access alternative could be STATA (StataCorp LLC, College Station, TX, USA) or R (The R Foundation for Statistical Computing, Vienna, Austria).\n\n\nResults\n\nIn this study, we have succeeded in developing a systematic mental toughness training program model for athletes. The model created is an integrated training model, which means each psychological skill or mental skill is related to other skills (Figure 1). There were 11 programs that the researchers developed and each program referred to mental skills that could be used by athletes to improve the quality of their mental toughness. Eleven programs of the mental toughness training circle (MTTC) are presented in Table 1.\n\n\n\n1. Understand basic concept of mental toughness, namely positive thinking;\n\n2. Understand and identify the benefits of positive thinking for athletes;\n\n3. Provide examples of positive and negative thinking in sport context;\n\n4. Identify the thought process until now, whether it tends to be positive or negative;\n\n5. Practice and get used to positive thinking in daily life.\n\n\n\no Three days of face-to-face practice\n\no Four days of independent practice and habituation\n\n\n\n1. Understand basic concept of mental toughness, namely mental log;\n\n2. Understand and identify the benefits of making mental log;\n\n3. Provide examples of mental logs made by athletes;\n\n4. Explain and fill in the mental log book;\n\n5. Practice and get used to recording activities and feelings in daily life, especially those related to training and competing.\n\n\n\no Three days of face-to-face practice\n\no Four days of independent practice and habituation\n\n\n\n1. Understand basic concept of mental toughness, namely goal-setting;\n\n2. Understand and identify the benefits of making goal-setting;\n\n3. Provide examples of goal-setting made by athletes;\n\n4. Making goal-setting;\n\n5. Get used to activities written in goal-setting to be achieved in training process and/or matches.\n\n\n\no Three days of face-to-face practice\n\no Four days of independent practice and habituation\n\n\n\n1. Understand basic concept of mental toughness, namely breathing;\n\n2. Understand and identify the benefits of doing breathing exercise;\n\n3. Practice each type of breathing;\n\n4. Get used to doing breathing exercises.\n\n\n\no Three days of face-to-face practice\n\no Four days of independent practice and habituation\n\n\n\n1. Understand basic concept of mental toughness, namely the types of relaxation;\n\n2. Understand and identify the benefits of doing relaxation exercises;\n\n3. Practice each type of relaxation techniques;\n\n4. Get used to doing relaxation exercises.\n\n\n\no Three days of face-to-face practice\n\no Four days of independent practice and habituation\n\n\n\n1. Understand the basic concept of mental toughness, namely the definition of concentration;\n\n2. Understand and identify the benefits of doing concentration exercise;\n\n3. Practice concentration exercises;\n\n4. Get used to doing concentration exercises.\n\n\n\no Three days of face-to-face practice\n\no Four days of independent practice and habituation\n\n\n\n1. Understand basic concept of mental toughness, namely the types of self-talk;\n\n2. Understand and identify the benefits of doing self-talk;\n\n3. Practicing each type of self-talk technique;\n\n4. Get used to doing self-talk exercises.\n\n\n\no Three days of face-to-face practice\n\no Four days of independent practice and habituation\n\n\n\n1. Understand basic concept of mental toughness, namely mental imagery;\n\n2. Understand and identify the benefits of doing mental imagery;\n\n3. Practice mental imagery exercises;\n\n4. Get used to doing mental imagery exercises.\n\n\n\no Three days of face-to-face practice\n\no Four days of independent practice and habituation\n\n\n\n1. Understand basic concept of mental toughness, namely leadership;\n\n2. Understand and know the benefits of having spirit of leadership;\n\n3. Practice to be a leader;\n\n4. Get used to being a leader for themself and others.\n\n\n\no Three days of face-to-face practice\n\no Four days of independent practice and habituation\n\n\n\n1. Understand basic concept of mental toughness, namely anxiety;\n\n2. Accept and be aware that anxiety is part of sport;\n\n3. Understand and identify the benefits of being able to manage anxiety;\n\n4. Understand and know how to manage anxiety;\n\n5. Get used to doing anxiety control exercises.\n\n\n\no Three days of face-to-face practice\n\no Four days of independent practice and habituation\n\n\n\n1. Understand basic concept of mental toughness, namely emotion;\n\n2. Accept and be aware that emotions are part of sport;\n\n3. Understand and identify the benefits of being able to manage emotion;\n\n4. Understand and know how to manage emotion;\n\n5. Get used to doing exercises to manage emotion.\n\n\n\no Three days of face-to-face practice\n\no Four days of independent practice and habituation\n\nMTTC model is in the form of a circle which has four sections: general preparatory consists of positive thinking, daily notes, goal setting, breathing, and relaxation; specific preparatory consists of concentration, self-talk, mental imagery, and leadership; precompetitive consists of managing anxiety and managing emotion; competitive relates to assistance during competition/match. Even though there are four sections, for the mentoring phase, the researchers did not make a specific program, because at that stage the mental training given to athletes would be tested so that the mental coach’s role was as a trainer or just as a person who helped athletes if there were any problems. All of the sections are interrelated and the terms (general preparatory, specific preparatory, precompetitive, and competitive) were deliberately chosen because they conformed to the terminology of training programs that were commonly used by trainers in developing physical training programs, techniques, and tactics (terminology of training programs can be seen in Bompa & Buzzichelli.36 By equating these terms (general preparatory, specific preparatory, precompetitive, and competitive) which was to ascertain that there would be no confusion from the trainers so that the mental training program could be carried out in harmony with the physical, technical, and tactical training programs.\n\nThe MTTC model consisted of 11 mental skills that were trained on athletes and each skill was described in three stages, namely: Introduction, Main section, and End section. The introduction section consisted of: pray, apperception, deliver the scope (Scope), and state the objectives (Objective). This section was acronymized for POSE. The Main Section consisted of two types. First type, for the first day of training (beginning of training) each program consisted of: Explaining training menus, Explaining the benefits, Discussions, Instructions, Tasks and Challenges. This section was acronymized for EMBEDDED. Second type, the training on the second and third meetings consisted of: Reflection, Confirmation, and Discussion; acronymized for RECORD. The last part of the training model was the End section. The End section consisted of: Briefly reviewing the material (Highlights), Evaluation, and Pray. This section was acronymized for HAPPY.\n\nAfter the mental training program was developed, the program was then tested on nine respondents. The results of content validity analysis are presented in Table 2. Based on CVI analysis, both I-CVI and S-CVI (S-CVI/Ave and S-CVI/UN) it appears that the developed program has I-CVI, S-CVI/Ave and S-CVI/UN, each of which has value of 1.00 in the “Appropriate” category and this shows that the program has very high content validity value. The test results using the Kappa modification (k*) also found very high value of 1 and were included in the “Excellent” category. Based on each stage in the mental skill training program and as a whole, it appears that the program has a very high validity value, based on respondents’ approval score of 9 with a proportion of consensus of 1.\n\nHAPPY: Highlights, Evaluation, and Pray; I-CVI: Item-Content Validity Index; k*: Modified Kappa; Pc: probability of a chance occurrence; POSE: Pray, Apperception, Scope, and Objectives; EMBEDDED: Explanation, Benefit, Discussion, Instruction, Tasks and Challenges; RECORD: Reflection, Confirmation, and Discussion; S-CVI: Scale-Content Validity Index; S-CVI/Ave: Scale-Content Validity Item/Average; S-CVI/UA: Scale-Content Validity Item/Universal Agreement.\n\nThe reliability test results are presented in Table 3. Analysis using Cronbach's Alpha (a) found the reliability value of each training program ranged from 0.723 to 0.835, whereas the overall reliability value of the training program was 0.803. Using ICC, a value of 0.803 was obtained with a p<0.001. In addition, the results of the respondents’ assessment showed that there was no significant difference, can be proven by the value of F=0.754 with p=0.644. These results indicate that the reliability value of the program is very high.\n\n\nDiscussion\n\nThe purpose of this study was to develop and validate athletes’ mental toughness training program. The results of the validity test showed that the developed program had high validity value on both I-CVI and S-CVI (S-CVI/Ave and S-CVI/UA), each of which was 1.00. If the I-CVI value was >0.78 it was considered excellent content validity52,53 while for S-CVI/Ave a value of 0.90 was included in the category of excellent content validity.53 The same result was found in the Kappa modification value (k*), which was equal to 1. Given the value >0.74, the validity value was included in the excellent category.56,57 Thus, it can be stated that the mental training program created has a very good level of content validity.\n\nThe content validity value obtained was very good because in the testing process there were no respondents who gave a score of 1 or 2 for each dimension that was assessed in the developed program. Research data showed that respondents tended to give a score 3 or 4 and thus made the CVI score high. This indicates that the respondents have high approval and think that the developed program has good quality.\n\nThe results of the reliability test using Cronbach's Alpha showed that the value of a was in the range of 0.723 to 0.835 for each dimension, while the overall value of the coefficient a was 0.803. The results of ICC analysis also confirmed that the training program that we developed and tested has very high reliability coefficient value, which was 0.803. The reliability coefficient value was categorized as very good58,61 and was above the minimum value required by Nunnally & Bernstein of 0.7062 and Fleiss of 0.75.63 Thus, it can be mentioned that the mental training program developed and tested has very good reliability value.\n\nRespondents who examined the MTTC model had similar agreement that no one gave score 1 or 2 but tended to give 3 or 4. This can be proved by obtaining an F value=0.754 with p=0.644 which indicated there was no difference based on the respondents’ assessment and the scores given were consistent. Based on this result, it can be stated that respondents tend to assess and perceive that the mental training program that we have developed has very good substance quality.\n\nThe results of the study found that there were eleven mental toughness skills which were divided into four sections in the training program, namely general preparatory, specific preparatory, precompetitive, and competitive. The mental toughness training model that we created was different from the model created by Vealey64 which divided the skills into four types (i.e., foundation skills, performance skills, personal development skills and team skills); Lesyk43 which divided into three levels (i.e., basic skills, preparatory skills, and performance skills); and Hardy65 divided it into two sections (i.e., basic and advanced). From this it appears that there is novelty in the phases/stages, the use of terms, and the substance of the mental toughness trainings that researchers have made compared to existing models.\n\nThe 11 mental skill exercises that we have developed were broken down into three sections in each program, namely: introduction, main section, and end section. In the introduction section was acronymized for POSE which consisted of Pray, Apperception, Scope, and Objectives. The Main Section consisted of two types. On the first day of training or training at the beginning of each program, it consisted of Explanation, Benefit, Discussion, Instruction, and Tasks and Challenges. This section was acronymized for EMBEDDED. The second part consisted of Reflection, Confirmation, Discussion. This section was acronymized for RECORD. The last part of the training model was the End section, which consisted of Highlights, Evaluation, and Pray. This section was acronym for HAPPY. Thus, if we look at mental training programs such as PST,38–41 MST,15,41 MTS43 and MTT,43,44 the training programs we have developed seemed to be more comprehensive and systematic in training mental skills of athletes.\n\nMTTC is more comprehensive because in the program there were eleven mental skills that used to train athletes. The first training was on positive thinking and our data indicating that each item of within this section had I-CVI value of 1.00 and Kappa modification (k*) value of 1 suggesting each item was appropriate had excellent criteria. We put positive thinking in the first part because this would be the foundation for the next training process. In fact, our responses or reactions to certain situations is a manifestation of what is in the mind. In our life, we never stop thinking, both consciously and unconsciously.66 The thought of being in a difficult situation can trigger unpleasant or emotional reactions.67 Through the thinking process, people will perceive, then respond accordingly.68 Positive thoughts have massive power in the process of achieving success69 and this is in accordance with the positive psychology approach.15 World basketball legend, Michael Jordan, believed that success is something that comes from the mind.70 Furthermore, he stated that mental toughness is far stronger than physical prowess.71\n\nThe second training was on mental logging. Our data found that each item of within this program had I-CVI value of 1.00 and Kappa modification (k*) value of 1 suggesting each item was appropriate had excellent criteria. Keeping a mental log may seem trivial but we see that this is very important for athletes to do in mental training program. Writing a mental diary is not only useful for recording the athletes’ experience, but more importantly, it can also note sources for correcting what the athletes lack or are weaknesses.72 In the mental log, athletes can write down what is on their minds, images, fears, emotions, and other experiences that are considered important,31 especially those related to training and competition. Therefore, the athletes will have a blueprint for thoughts, feelings and actions to take.72 According to Indonesian sport psychologist, Ali Maksum, the Indonesian badminton legend who had won gold medal in the Olympics and world championship, Susi Susanti, is an example of an athlete who used a mental log.72\n\nThe third training was on goal setting and all items were also appropriate had excellent criteria indicating by I-CVI value of 1.00 and Kappa modification (k*) value of 1. In providing mental training, goal-setting was one of the skills that was often used in sports contexts.73 Thus, expert say that making goal-setting is one of the basics or beginnings in a set of mental training programs.74 A transformation and improvement will occur more easily if athletes formulate or set goals or targets to be achieved.75 Teaching athletes in goal-setting is believed to be important in maintaining and improving the mentality of athletes, especially related to focus and motivation.28 The results of the study prove that athletes receive many benefits from goal-setting.76\n\nThe fourth and fifth training was on breathing exercises and relaxation. Our data indicated that all items within these sections had I-CVI value of 1.00 and Kappa modification (k*) value of 1 suggesting each item was appropriate had excellent criteria. According to experts, breathing exercises are generally associated with relaxation, concentration and meditation, whereas in Indonesia, especially for martial art athletes, breathing exercises are not only used for the above purposes but are also used to raise basic strength or inner strength.77 Thus, breathing exercises will be very helpful in supporting further mental exercises such as relaxation, concentration, mental imagery, managing anxiety, and managing emotions. In addition, to be able to perform all the abilities that have been trained in a competition requires relaxed mental and physical condition.31 Relaxation is a state in which there is no pressure either physically, emotionally or mentally.28,72 The results of the study show that providing relaxation has positive impact on psychological condition and performance of athletes on the field.78,79 Hence, the biggest benefit of doing relaxation exercises regularly is that the athletes will have the ability to reduce muscle stiffness due to pressure on their psychological condition.28,75 If athletes can do relaxation training, this will help the other mental trainings such as concentration training, mental imagery, managing anxiety, and managing emotions.\n\nThe sixth and seventh of the training were on concentration and self-talk practices. From our analyses it could be suggested that all items within both sections were appropriate had excellent criteria (I-CVI value and Kappa modification (k*) value were 1.00 and 1, respectively). Based on literature, the term concentration is often interchanged with attention and focus.80 Concentration is a cognitive functional component30 which plays major role in sports for athletes.31,81 Thus, concentration is needed for every athlete so that they can perform peak performance.28,82 Concentration is a state in which a person's awareness is fixed on a certain object at a certain time.31,72,81 There are two keywords that can be used to explain concentration, namely “here and now”.72 Hence, a person can be said to have concentration when that person focuses on what he/she faced at that time and in that place, instead of focusing on elsewhere.80 In addition, studies that examine self-talk in sports contexts have found that it has an influence on mood, emotion73 and athletes’ performance.83 Self-talk is divided into two, namely positive self-talk (e.g., “I am an outstanding athlete”) and negative self-talk (e.g., “this time I will perform badly again”).75,84\n\nThe eighth training was on mental imagery and our data suggested that each item of within this program was appropriate had excellent criteria. The terms mental imagery and visualization are often used interchangeably,27 despite having differences for an expert.30 Mental imagery can be understood as the ability to use multiple senses to build experiences in the mind by eliminating external stimuli.70 Based on this, there are three aspects that need to be highlighted. First, building experience, namely the athletes’ ability to reconstruct experiences in their mind; second, multi-sensory involvement, namely the athletes’ ability to use the senses of sight, taste, touch, and hearing; and third, eliminating external stimuli, namely the athletes’ ability to minimize distractions that caused while building experiences in their mind.70 Basically, mental imagery can be understood as the athletes’ ability to devise the experiences related to sports performance in their mind.85 The results of the study showed that mental imagery had a positive effect on athletes’ performance.86 Therefore, mental imagery needs to be trained on athletes in a mental training program.85,86\n\nThe ninth training was on leadership and our data suggested that each item of within this program was appropriate had excellent criteria. Basically, leadership can be understood as a person's ability to influence others, both in mind and behavior, to achieve a specific goal.28,64 The debate about whether leaders were born or can be made has been an issue for a long time.87 However, we do not want to linger on this discourse. In sports, leadership traits are not only needed for coaches, but also for athletes. When athletes have strong leadership within, they will be able to guide themself to focus on a specific goal, namely success or high achievement. Therefore, we made leadership a part of the mental training program for athletes. By leading and developing the spirit of leadership in athletes, we believe these athletes can lead themselves, their teammates, and lead in a wider context, so that opportunities for success become more tangible.\n\nThe tenth was on managing anxiety and this section also had appropriate had excellent score from all experts. Anxiety is a normal condition for humans30 and this often appears in the context of sports88,89 so that the athletes’ anxiety dimension is often studied by associating it to other aspects.90 In general, the factors that cause anxiety for athletes can be grouped into two aspects, namely internal and external factors.84 Then based on criteria or level, anxiety can be divided into three, high, medium and low. Anxiety levels that are too high or too low have a negative impact on athletes’ performances,91 while moderate level of anxiety is believed to have a positive impact on athletes’ performances.92,93 Therefore, it is important for athletes to be able to manage anxiety properly, so they can show their best performance.\n\nThe eleventh was on managing emotion. Our data found that each item of within this program was appropriate had excellent criteria. Basically, emotion is mood condition that is experienced by an individual.74 Emotion can help athletes show their best performance, but on the other hand, it can also make athletes perform far below their abilities.94 Therefore, one of the abilities that athletes must have is the ability to manage emotions.32 There are two types of emotions, namely positive emotion and negative emotion. Positive emotion, for example is feelings of joy and happiness, while example of negative emotion is anger and sadness. Someone who has positive emotion will likely to be flexible, think creatively and find solutions more quickly when faced with problems.95 In competitive sports, there are several reasons that cause athletes to be emotional, for example, the behavior of opponents, referees, coaches, personal problems, upset about their own performance.74 Emotion management training program should be carried out for athletes by informing them that all emotions, both positive and negative, are part of the reality that exists in sports competition.43 Thus, managing emotion needs to be done properly to enhance and improve athletes’ performance. Based on this, it appears that the mental trainings that previously stated can be a solution and to help mastering other mental skills. Thus, we mentioned that these training models were interrelated. Therefore, we conclude that MTTC model training program can be an alternative to provide mental training for athletes.\n\nEven though the systematic and comprehensive mental training program has been developed and has been validated, this research has limitations. First, although the program has been validated by sport psychologists, sports training expert, coaches with national and international achievements, as well as athletes with achievements at national and international levels, the program has not been tested directly on athletes on the field. Therefore, for further research, field testing will be needed to research empirically the effectiveness of the program in developing the mentality of winning athletes. Second, the training program is a set of designs related to mental training for athletes that have been designed systematically. That means, the program does not focus on the individual needs of athletes. In contrast, there are experts who stated that mental training programs need to be developed and modified according to the needs of athletes.96 In other words, interventions or providing mental trainings need to accommodate the needs and conditions of athletes. Third, the program does not explain how to determine the mental toughness of athletes after finishing the training program. In fact, the main purpose of the mental training model is to develop mental qualities. Hence, we recommend tests related to the mental aspects of athletes.\n\n\nConclusions\n\nThis research has succeeded in creating a new mental training model called the MTTC model. The results of the validation found that the I-CVI and S-CVI values (S-CVI/Ave and S-CVI/UA) were 1.00 each, which categorized as excellent content validity. For the Kappa modification value (k*) = 1, which categorized as excellent. The results of the reliability test using Cronbach's Alpha showed that the value of a was 0.723 to 0.835 for each program and for the entire training program p=0.803. The results of ICC analysis also confirmed that MTTC had very high reliability coefficient value, which was 0.803. In addition, there was no significant difference from respondents’ assessment which can be proved by obtaining F=0.754 with p=0.644. That signifies that, respondents likely to be consistent in assessing MTTC as a mental training set, which then categorized as relevant (scale 3) or very relevant (scale 4). Therefore, this study has contributed to exploring the area of MT and providing practical guidance related to mental training for athletes.",
"appendix": "Data availability\n\nFigshare: ‘Development and validation mental training model: Mental Toughness Training Circle (MTTC)’. https://doi.org/10.6084/m9.figshare.21628514. 97\n\nThis project contains the following underlying data:\n\n- Expert Assessment Data.xlsx [Tables containing the raw data of the study]\n\nFigshare: ‘Development and validation mental training model: Mental Toughness Training Circle (MTTC)’. https://doi.org/10.6084/m9.figshare.21628514. 97\n\nThis project contains the following underlying data:\n\n- Module and assessment form-English [Document containing the English version of module and assessment form]\n\n- Module and assessment form-Indonesian [Document containing the Indonesian version of module and assessment form]\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nWe would like to thank you to all experts during the study. Also, we would like to thank Anggit Wicaksono and Gustiana Mega Anggita (Universitas Negeri Semarang) for their assistance in this research.\n\n\nReferences\n\nMiddleton SC, Martin AJ, Marsh HW: Development and validation of the mental toughness inventory (MTI): A construct validation approach.Gucciardi D, Gordon S, editors. Mental toughness in sport: Developments in theory and research. New York:Routledge; 2011; p. 91–106. Publisher Full Text\n\nGucciardi DF: Mental Toughness: Taking Stock and Considering New Horizons.Tenenbaum G, Eklund RC, Boiangin N, editors. Handbook of sport psychology. 4th ed.Wiley & Sons, Inc; 2020; p. 2020. Publisher Full Text\n\nSheard M: Mental Toughness: The mindset behind sporting achievement. East Sussex:Routledge Taylor & Fracis Group;2013. Publisher Full Text\n\nGucciardi DF, Gordon S, Dimmock JA: Towards an understanding of mental toughness in Australian football. J. Appl. Sport Psychol. 2008; 20(3): 261–281. 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[Dataset]. Figshare. 2022. Publisher Full Text"
}
|
[
{
"id": "196919",
"date": "02 Jan 2024",
"name": "Ali Maksum",
"expertise": [
"Reviewer Expertise Sports Psychology"
],
"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 intention of this research is good but conceptually and methodologically there are weaknesses. First, using the term \"circle\" in MTTC is inappropriate because the mental training process is a stage or phase, not a circular cycle. Second, it is necessary to clarify the definition of each mental skill so as not to give erroneous and misleading interpretations. Third, the determination of 11 types of mental skills is not based on in-depth analysis. For example, is \"leadership\" a form of mental skill in athletes? Isn't \"breathing\" part of relaxation or concentration training? Besides that, determining the type of mental training should be based on an in-depth assessment. Fourth, the placement of certain mental skills at certain stages such as general preparation and pre-competition seems forced. Fifth, the description in Table 2 does not need to be displayed because it is not urgent. Sixth, there is an invalid logic that the main examination of a training model is on its effectiveness in achieving goals, not on content analysis and consistency. Seventh, the mental skills are structured more towards individual sports. What about team or group sports?\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? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "231236",
"date": "08 May 2024",
"name": "Vikas Singh",
"expertise": [
"Reviewer Expertise Educational Leadership",
"Teaching and Learning",
"Professional Development",
"Pedagogy and Education and LearningCurriculum",
"Pedagogy",
"Program Development",
"Sport Performance",
"Mental Health",
"Sport Development",
"Mindfulness-Based Cognitive Therapy",
"Yoga Research",
"Yoga as Therapy",
"and and Meditation"
],
"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\nI've now read the document. Key words and abstract are acceptable. The article will further scholarly discourse and is pertinent to the journal's theme. The report has a clear organisation, and the study's methodology was sound. I think the research problem's topic matter truly noteworthy. Without a doubt, it will advance the pertinent subject of study. The paper's conceptual organisation is noteworthy. Without requiring any major revisions, the work could to be approved.\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": "231231",
"date": "09 Sep 2024",
"name": "Rozita Abdul Latif",
"expertise": [
"Reviewer Expertise socio-psycho",
"sport sociology",
"physical education",
"well-beingl ifestyle"
],
"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 relevant, demonstrating the development of a new model in mental training. The generated model is a combination of skills implemented by previous researchers. The article outlines a series of mental training programs developed across four distinct stages with engaging nomenclature to shape a positive mindset. The writing is compelling and easily understandable. However, it's noteworthy that the use of the term 'HAPPY' differs from the term in Table 2, denoted as 'HEPY'.\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/12-169
|
https://f1000research.com/articles/12-166/v1
|
13 Feb 23
|
{
"type": "Brief Report",
"title": "‘The brighter the worse’: Lead content of commercially available solvent-based paints intended for residential use in Pakistan",
"authors": [
"Durr-e-Amna Siddiqui",
"Lucia Coulter",
"Charlie Loudon",
"Zafar Fatmi",
"Lucia Coulter",
"Charlie Loudon",
"Zafar Fatmi"
],
"abstract": "Background: Environmental pollution and exposure to lead (Pb) through household paint continue to be a great concern, especially for low- and middle-income countries (LMICs). Methods: We measured the Pb levels of solvent-based paints commercially available in Karachi, Pakistan. We visited major markets and collected commonly available brands of paint, sampling the yellow, red, and white colors of each. The paint samples’ Pb content was measured using inductively coupled argon plasma atomic emission spectrometry (ICP-AES). Results: Of the 60 analyzed paint samples, 24 (40%) contained Pb levels of >100 ppm (beyond the legal limit in Pakistan), with a maximum of 97,000 ppm (dry weight). Sixteen (76.2%) of the 21 yellow paints (range: 5,100–97,000 ppm, IQR: 36,900 ppm), seven (37.0%) of the 19 red paints (range: 220–1,800 ppm, IQR: 255 ppm), and one (5%) of the 20 white paints (870 ppm) contained Pb levels of >100 ppm. Of the 60 paints, 45 were produced by domestic Pakistani companies (51% exceeding the limit) and 15 by multinational companies (7% exceeding the limit). Conclusions: Although Pakistani regulations have restricted Pb content in paints to <100 ppm since 2017, these regulations are poorly implemented, as highlighted by this study. We therefore recommend that paint manufacturers comply with national standards and internationally recommended Pb limits to ensure the health and safety of children and other populations in Pakistan.",
"keywords": [
"lead exposure",
"lead paint",
"heavy metal pollution",
"lead poisoning",
"residential paint",
"Pakistan"
],
"content": "Introduction\n\nExposure to lead (Pb) among children through Pb-based house paints has been a global concern over the last 50 years. Despite regulatory and safety measures for paint manufacturers and bans on the use of Pb in house paints, Pb-based house paints are still produced and used globally, largely in low- and middle-income countries (LMICs) (Clark et al., 2006; Ewers et al., 2011; Kumar & Gottesfeld, 2008; Lin et al., 2009; Megertu & Bayissa, 2020; Montgomery & Mathee, 2005; Njati & Maguta, 2019; O'Connor et al., 2018). Paints constitute a significant source of environmental Pb pollution, particularly of the home environment (Adebamowo et al., 2007; Clark et al., 2006; Ewers et al., 2011; Kumar & Gottesfeld, 2008; Lin et al., 2009; Njati & Maguta, 2019; O'Connor et al., 2018).\n\nPb exposure can cause various health problems, ranging from anemia and hypertension to impaired function of the immune, reproductive, and nervous systems. Children who are exposed to Pb exhibit a dose-dependent reduction in brain volume, as well as deficits in school performance and measures of intelligence (Cecil et al., 2008; Chandramouli et al., 2009; Evens et al., 2015; Lanphear et al., 2005). These deficits persist into adulthood (Mazumdar et al., 2011; Shih et al., 2006). Globally, 800 million children are estimated to have elevated blood lead levels (BLLs >5 μg/dL) (UNICEF & Pure Earth, 2020). 5 μg/dL is a commonly used reference level, although lower BLLs are still considered dangerous (CDC, 2022).\n\nA recent systematic review found that Pakistan had the second-highest mean childhood BLLs among LMICs (9.27 μg/dL) and estimated that 46.7 million children in Pakistan have BLLs >5 μg/dL (Ericson et al., 2021). Economic losses due to Pb exposure in Pakistan alone are estimated to be $38 billion, equivalent to 7.8% of GDP (Attina & Trasande, 2013). In Pakistan, multiple sources of Pb exposure have been recognized, including food, house dust, respirable dust, and to a lesser extent surma and petrol (Fatmi et al., 2017). Although paint is an important contributor to Pb in house dust, and associations have been found between raised childhood BLLs and Pb paint in homes, very little research relating to paint Pb levels in Pakistan has been published (Khan et al., 2001).\n\nThis study therefore investigated the Pb content of solvent-based residential use paints commercially available in Pakistan. A previous study identified that the majority of solvent-based paints in Pakistan had high Pb levels (Khalid et al., 2017). Since then, the Pakistan Standards and Quality Control Authority introduced a mandatory standard limiting the Pb content of paint to 100 ppm (WHO, 2022). The opportunity to assess the effectiveness of the new standard further motivated this review of Pb levels in paints available on the market. The study findings may help policymakers and regulators enforce Pakistan’s Pb paint standards.\n\n\nMethods\n\nThe study was carried out in Karachi, Pakistan. Given Karachi’s position as Pakistan’s most populous city and industrial hub, we assumed that the majority of national paint brands would be readily available. Four paint markets, which included nine shops, were identified based on snowball sampling in diverse socioeconomic areas of Karachi in November 2021. Paint brands were also identified through snowball sampling until the same brands began recurring. Solvent-based paint samples of 21 different brands were bought in three colors (red, yellow, and white). If a certain color was not available, a similar color was selected. Altogether, 60 samples were obtained. Each sample was assigned a numeric label and information on paint cans pertaining to Pb content, safety precautions, and standardization was recorded.\n\nUntreated wooden stirring implements were used to thoroughly stir each paint and apply it as a 0.5–1 mm coating to a 10 cm × 10 cm Pb-free, food-grade polypropylene surface. Stirring and application were performed with a separate wooden implement for each specific paint. A fresh pair of medical-grade nitrile gloves was used to handle each paint sample. Samples were allowed to dry in an open room for seven days. Once the paints were dry, they were peeled off the polypropylene surface and placed in sterile Pb-free polyethylene bags. Again, a fresh pair of medical-grade nitrile gloves was used to handle each sample. The packaged dried paints were then posted to a laboratory for analysis.\n\nEach paint sample was analyzed for total Pb content by the Wisconsin Occupational Health Laboratory, using the National Institute for Occupational Safety and Health 7303 method (NIOSH, 2003). Paint scrapings were prepared by heating in a hot block digestion tube for 15 minutes at 95°C with 1.25 ml hydrochloric acid, before cooling for five minutes. They were then heated for a further 15 minutes at 95°C with 1.25 ml nitric acid, before cooling and dilution to final volume. The samples were then analyzed by the laboratory using inductively coupled argon plasma atomic emission spectrometry (ICP-AES) with a Perkin Elmer Avio 500 Spectrometer. Calibration with control samples and operating conditions were determined according to manufacturer specifications.\n\nThe laboratory is accredited by the American Industrial Hygiene Association (AIHA) under the US EPA Environmental Lead Laboratory Accreditation Program and participates in the Environmental Lead Proficiency Analytical Testing program. Strict quality control procedures were maintained according to the accreditation guidelines, which meet all international program requirements and comply with ISO/IEC 17025 and ISO/IEC 17043. The laboratory’s analytical methods and certifications are also consistent with those recommended by the World Health Organization for measuring Pb in paint (WHO, 2020).\n\nTotal Pb content was reported in parts per million (ppm) dry weight. Samples with concentrations below the reporting limit of the analytical procedures used were reported as <60 ppm.\n\n\nResults\n\nTable 1 summarizes the Pb concentrations of all paint sampled in the current study and groups them by color. For the 60 samples collected, the mean Pb concentration was 8,158 ppm. We found a maximum Pb concentration of 97,000 ppm, which is almost 1,000 times the standard limit.\n\n* Calculation assumes paints measured to have Pb levels of <60 ppm have a Pb content of 30 ppm.\n\nYellow paints had the highest Pb content among all the brands sampled for the study. Approximately 76.2% (n=21) of the yellow paints had Pb concentrations of >100 ppm. The mean concentration of yellow color paints was 23,021 ppm and the maximum value was 97,000 ppm. Approximately 36.8% of the samples of red paints (n=19) had Pb levels of >100 ppm. The color with the lowest Pb content was white, with only one sample containing Pb levels of >100 ppm.\n\nOnly one of the paint samples from multinational brands had Pb levels of >100 ppm. Multinational brands had lower mean (1,228 ppm) Pb levels than both national and local brands. National brands had mean and median Pb levels of 5,354 ppm and <60 ppm respectively, with 34.8% (n=8) of paints containing Pb. The highest concentration of lead was found in brands local to Karachi, with more than 68% (n=15) containing levels exceeding 100 ppm and a mean Pb level of 15,807 ppm (Table 2).\n\n* Calculation assumes paints measured to have Pb levels of <60 ppm have a Pb content of 30 ppm.\n\nTable 3 pertains to labeling on paint cans and whether adequate safety information was displayed. Of the 60 paint samples, 42 had no labeling mentioning Pb and of those almost half (46.2%) had Pb levels of >100 ppm. By contrast, of the 18 samples labeled Pb-free, four had Pb levels of >100 ppm, with a mean of 2,407 ppm and a maximum value of 18,000 ppm.\n\n* Calculation assumes paints measured to have Pb levels of <60 ppm have a Pb content of 30 ppm.\n\nTable 3 further classifies paints based on product standards manufacturers claimed to have followed, per can labeling. Relevant product standards included Pakistan standards and international standards. Twenty-three samples were labeled with international standards, including ISO, IAS, OHSAS, and Malaysian standards. Of these more than one-third (n=8) had Pb levels of >100 ppm, with a mean of 4,444 ppm and a maximum of 48,000 ppm. Nine samples were labeled Pb-free and with either international or Pakistan standards; of these, two had Pb levels of >100 ppm, with a mean Pb level of 2,112 ppm and a maximum of 17,000 ppm.\n\nFifteen paints sampled appeared with the same brand and color combination in Khalid et al.’s (2017) study. Three brands had two colors appear in both studies, and another three brands had three colors appear in each study. All of the six brands that appeared in both studies were multinational or national brands. Of the fifteen paints that appeared in both studies, nine had a lower Pb content than in 2017, one had a higher Pb content, and five remained the same. All of the brands present in both studies had reduced their maximum Pb content since 2017. The greatest decrease was from 110,000 ppm in 2017 to 18,000 ppm in 2021. Of the six brands present in both studies, four still had Pb content in 2021 that was above the national standard. Only two brands had brought their Pb levels into line with standards.\n\n\nDiscussion\n\nPakistan has lagged behind in implementing its Pb paint regulations. Its first paint regulations were issued in 2017, allowing only paints with Pb levels of <100 ppm (WHO, 2022). Further effort is required to fully implement those regulations. 40% of the paints sampled in this study had Pb levels higher than the legal limit. Almost one-fifth (18.3%) of the paints had Pb levels of >10,000 ppm, and the highest Pb concentration detected was 97,000, almost 1,000 times the legal limit. Pakistan’s mean paint Pb concentration of approximately 8,000 ppm is within the range observed in other Asian countries (O'Connor et al., 2018).\n\nComparing our results to those published in 2017, we note a decrease in paint Pb content. While 40% of the paint samples collected in our study were above the allowable limits, in the previous study 60% failed to comply with the standards (Khalid et al., 2017). There is, however, some uncertainty in interpreting comparisons between the two studies, as the sampling took place in different cities and the range of paints sampled was not identical.\n\nThe current study finds that yellow paints contain the highest Pb levels. More than three-quarters (76.2%) of the yellow paints sampled had Pb levels of >100 ppm. By contrast, only 36.8% of red paints and 5% of white paints exhibited high Pb levels. These findings are consistent with previous studies (Clark et al., 2009, 2015). The most common Pb additives in paints are yellow and red pigments (lead chromates), driers (lead octoate and lead naphthenate), and anticorrosives (lead tetroxide) (UNEP, 2022). Lead carbonate is used in white paints, but has now been largely replaced by titanium dioxide. Given that the average Pb content of colored paints is higher, paint manufacturers likely intentionally add Pb to augment color (O'Connor et al., 2018). Notably, even the yellow paint produced by a multinational brand with a high market share had 18,000 ppm, exceeding national limits.\n\nThe current study finds that labeling of cans is not accurate or universally practiced. 22% of paints labeled Pb-free contained Pb levels above 100 ppm, up to a maximum of 18,000 ppm. Such false labeling has been identified elsewhere, especially in countries where there is no regulatory control. A study of paints in South and Southeast Asia revealed that almost 18% of paints labeled Pb-free contained high Pb levels of up to almost 56,000 ppm, undermining the reliability of such labeling (Weinberg & Clark, 2012). Within Pakistan, the 2017 study showed a similar result, where 43% of paints labeled Pb-free contained high Pb levels (Khalid et al., 2017).\n\nPakistan currently has a vast, largely unregulated paint market, wherein, according to industry reports, the unorganized sector accounts for an estimated 34% of production and numerous cheaper brands come under its umbrella (Khalid et al., 2017). In a study conducted in India, the unorganized sector comprised small businesses, while all large firms and multinationals fell under the category of organized (Mohanty et al., 2013). Applying a similar lens to the current study, and considering all local Karachi brands to fall under the category of unorganized, we find that not a single brand from this sector follows the standards. The two highest Pb levels detected, 97,000 ppm and 70,000 ppm, were found in these brands. This is reflected in the India study as well, where 93% of paints sampled within the unorganized sector had Pb of >300 ppm. It is likely that cost-cutting practices and a lack of regulatory adherence by the unorganized sector poses a major barrier to the curbing of Pb in paint.\n\nLimitations of the current study include that it was conducted solely in Karachi, and only investigated residential-use solvent-based paint, so it may not provide a representative picture of paints in Pakistan. Further research into the impact of current paint lead levels on national health, through blood lead level testing, would also be of benefit.\n\nThe technology to produce Pb-free paint is being put to use in Pakistan, but there remains ample room for improvement. A substantial proportion of paint being sold continues to put lives and health at risk.\n\n\nAuthor contributions\n\nConceptualization, Z.F. and L.C.; methodology, D.S., Z.F., and L.C.; software, D.S.; validation, D.S., Z.F. and L.C.; formal analysis, D.S.; investigation, L.C., and D.S.; resources, L.C., and Z.F.; data curation, D.S.; writing – original draft preparation, D.S.; writing – review and editing, Z.F., L.C. and C.L.; visualization, D.S.; supervision, Z.F.; project administration, D.S. All authors have read and agreed to the published version of the manuscript.\n\n\nEthical considerations\n\nInstitutional Review Board Statement: The Aga Khan University Ethics Review Committee (Karachi, Pakistan) approved this study under its ‘Exemption’ category (#2022-7187-20616).",
"appendix": "Data availability\n\nFigshare. Lead content of commercially available solvent-based paint in Pakistan. https://doi.org/10.6084/m9.figshare.21594231 (Siddiqui et al., 2023).\n\nThis project contains the following underlying data:\n\n• Data file 1. Lead content of commercially available solvent-based paint in Pakistan.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\n\nAcknowledgments\n\nWe greatly acknowledge the contribution of James Hu for editing and improving the language of the manuscript.\n\n\nReferences\n\nAdebamowo EO, Clark CS, Roda S, et al.: Lead content of dried films of domestic paints currently sold in Nigeria. Science of the Total Environment. 2007; 388(1-3): 116–120.\n\nAttina TM, Trasande L: Economic costs of childhood lead exposure in low- and middle-income countries. Journal of Environmental Health Perspectives. 2013; 121(9): 1097–1102.\n\nCenter for Disease Control: Blood Lead Reference Values. 2022.US Department of Health & Human Services.Reference Source\n\nCecil KM, Brubaker CJ, Adler CM, et al.: Decreased brain volume in adults with childhood lead exposure. PLoS Medicine. 2008; 5(5): e112.\n\nChandramouli K, Steer CD, Ellis M, et al.: Effects of early childhood lead exposure on academic performance and behaviour of school age children. Archives of Disease in Childhood. 2009; 94(11): 844–848.\n\nClark C, Rampal K, Thuppil V, et al.: The lead content of currently available new residential paint in several Asian countries. Environmental Research. 2006; 102(1): 9–12.\n\nClark CS, Rampal KG, Thuppil V, et al.: Lead levels in new enamel household paints from Asia, Africa and South America. Environmental Research. 2009; 109(7): 930–936.\n\nClark CS, Speranskaya O, Brosche S, et al.: Total lead concentration in new decorative enamel paints in Lebanon, Paraguay and Russia. Environmental Research. 2015; 138: 432–438.\n\nEricson B, Hu H, Nash E, et al.: Blood lead levels in low-income and middle-income countries: a systematic review. The Lancet Planetary Health. 2021; 5(3): e145–e153.\n\nEvens A, Hryhorczuk D, Lanphear BP, et al.: The impact of low-level lead toxicity on school performance among children in the Chicago Public Schools: a population-based retrospective cohort study. Environmental Health. 2015; 14(1): 1–9.\n\nEwers L, Clark CS, Peng H, et al.: Lead levels in new residential enamel paints in Taipei, Taiwan and comparison with those in mainland China. Environmental Research. 2011; 111(6): 757–760.\n\nFatmi Z, Sahito A, Ikegami A, et al.: Lead Exposure Assessment among Pregnant Women, Newborns, and Children: Case Study from Karachi, Pakistan. International Journal of Environmental Research and Public Health. 2017; 14(4).\n\nKhalid IS, Khaver AA, Brosché S: Lead in solvent-based paints for home use in Pakistan. IPEN;2017.Reference Source\n\nKhan AH, Khan A, Ghani F, et al.: Low-level lead exposure and blood lead levels in children: a cross-sectional survey. Archives of Environmental Health: An International Journal. 2001; 56(6): 501–505.\n\nKumar A, Gottesfeld P: Lead content in household paints in India. Science of the Total Environment. 2008; 407(1): 333–337.\n\nLanphear BP, Hornung R, Khoury J, et al.: Low-level environmental lead exposure and children’s intellectual function: an international pooled analysis. Environmental Health Perspectives. 2005; 113(7): 894–899.\n\nLin G, Peng R, Chen Q, et al.: Lead in housing paints: An exposure source still not taken seriously for children lead poisoning in China. Environmental Research. 2009; 109(1): 1–5.\n\nMazumdar M, Bellinger DC, Gregas M, et al.: Low-level environmental lead exposure in childhood and adult intellectual function: a follow-up study. Environmental Health. 2011; 10(1): 1–7.\n\nMegertu DG, Bayissa LD: Heavy metal contents of selected commercially available oil-based house paints intended for residential use in Ethiopia. Environmental Science Pollution Research. 2020; 27(14): 17175–17183.\n\nMohanty A, Budhwani N, Ghosh B, et al.: Lead content in new decorative paints in India. Environment, Development and Sustainability. 2013; 15(6): 1653–1661.\n\nMontgomery M, Mathee A: A preliminary study of residential paint lead concentrations in Johannesburg. Environmental Research. 2005; 98(3): 279–283.\n\nNIOSH: NIOSH manual of analytical methods. 4th ed.2003.\n\nNjati SY, Maguta MM: Lead-based paints and children's PVC toys are potential sources of domestic lead poisoning: A review. Environmental Pollution. 2019; 249: 1091–1105.\n\nO'Connor D, Hou D, Ye J, et al.: Lead-based paint remains a major public health concern: A critical review of global production, trade, use, exposure, health risk, and implications. Environment International. 2018; 121: 85–101.\n\nShih R, Glass T, Bandeen-Roche K, et al.: Environmental lead exposure and cognitive function in community-dwelling older adults. Neurology. 2006; 67(9): 1556–1562.\n\nSiddiqui D-e-A, Coulter L, Loudon C, et al.:Underlying data for: ‘The brighter the worse’: Lead content of commercially available solvent-based paints intended for residential use in Pakistan. [DATASET].2023. Publisher Full Text\n\nUN Environment Program: Lead paint reformulation technical guidelines. Geneva, Switzerland:2022.Reference Source\n\nUNICEF & Pure Earth: The toxic truth: children’s exposure to lead pollution undermines a generation of future potential. 2nd ed.New York, USA:2020.Reference Source\n\nWeinberg J, Clark S: Global Lead Paint Elimination by 2020. IPEN;2012.Reference Source\n\nWorld Health Organization: Brief guide to analytical methods for measuring lead in paint. 2nd ed.Geneva, Switzerland:2020.Reference Source\n\nWorld Health Organization: Legally-binding controls on lead paint. Geneva, Switzerland:2022.Reference Source"
}
|
[
{
"id": "179367",
"date": "18 Jul 2023",
"name": "Jack Caravanos",
"expertise": [
"Reviewer Expertise Environmental Lead Exposure"
],
"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 Number: https://doi.org/10.12688/f1000research.128909.1\nTitle: ‘The brighter the worse’: Lead content of commercially available solvent-based paints intended for residential use in Pakistan\nAuthors: Siddiqui, Coulter, Loudon, Fatmi\nTitle\nWhile I understand the title, nowhere in the manuscript do the authors explain it. Either omit “The Brighter the Worse” and describe it in the Introduction. Also, is it universally true?\n\nAbstract\nThis is not exactly true “Paints constitute a significant source of environmental Pb pollution, particularly of the home environment”. It’s deteriorating (peeling, chipping) lead based paint that poses a risk. Intact LBP is not causing elevated BLL.\n\nAlso, I’m not keen on environmental Pb pollution, perhaps it should be “exposure.”\n\nDon’t start a sentence with a number or acronym. Spell out Pb (Lead…).\n\nToo strong of a word (enforce) in the sentence: The study findings may help policymakers and regulators enforce Pakistan’s Pb paint standards. Seems to imply that’s the hidden purpose of the study. Even though it may be true, soften it. (something like, “…. help policymakers and regulators better understand the extend of use of LBP.\n\nI don’t believe your study can fully defend this statement “these regulations are poorly implemented, as highlighted by this study.” I would soften it.\n\nAs regards this closing sentence “We therefore recommend that paint manufacturers comply with national standards and internationally recommended Pb limits to ensure the health and safety of children and other populations in Pakistan” I don’t believe this is appropriate for a scientific study. It’s judgmental (and can be seen as political) and somewhat demeans the research conducted. I would soften it.\n\nIntroduction\n2nd paragraph. You may want to include a sentence about the recent June 12th statement from the American Heart Association on the link between Pb and CVD. It further strengthens the paper’s goal.\n\n2nd paragraph, Perhaps you should use IHME numbers instead of (or in addition to) Pure Earth. See https://vizhub.healthdata.org/gbd-results?params=gbd-api-2019-permalink/d910c5f7d02e28d5159fad32f8471554\n\n2nd paragraph. This sentence needs fixing. “5 μg/dL is a commonly used reference level, although lower BLLs are still considered dangerous (CDC, 2022).” First, do not start a sentence with an integer use Five ug/dL instead of 5 μg/dL… Next the US CDC has abandoned using a health based BLL. They have adopted the policy of saying “no amount of lead in blood is without risk or safe” or, as you say, “the reference level”. You should probably say this. The way it’s written now, seems to imply below 5 is okay.\n\nI believe you need to add a paragraph on types of paints (oil versus latex, flat and gloss, and enamels). Everybody knows that oil-based paints are out of fashion and excessively toxic. The way the paper is presented implies, incorrectly, that all house paints are oil-based and thus may contain lead. I agree that lead containing oil-based paints are still used in situations where children can be exposed, but readers will wonder about flat, latex based (water) paints are dangerous.\n\nCOMMENT: Lead based paint standards are complicated worldwide. In the USA, the EPA definition of LBP is 0.5% or 5,000 ppm. Alternatively, the US has a deposition standard of 1.0 mg/cm2 (using XRF). But for paint on consumer products (i.e. toys), the US lowered the amount 0.009% or 90 ppm by weight. The authors use 100 ppm as the definition of paint (but technically the US value of 5,000 ppm or 1 mg/cm2 should be used. In short, the paints tested by US standards would not be classified as LBP. BUT if the Pakistani standard is 100 ppm, then the results are valid. As I said, it’s a complicated LBP world out there.\n\nOverall, Introduction is well done and written.\n\nMethods\nSAMPLING\nPlease clarify “snowball sampling”. I’m not familiar with that term and its not generally used.\nSampling strategy seems representative and well conceived.\n\nAPPARATUS:\nNo issues, I liked the idea of creating a paint film on a plastic base. Good.\n\nLAB PROCEDURES\nNo issues, good idea to use an accredited US based laboratory.\nPPM is not a proper analytical reporting unit. Chemists generally look down on this. May I suggest you start by using “mg/kg by weight” or “ug/g by weight” and then mention this is also the same as ppm-w.\n\nResults\nReasonably well-done presentation.\n\nGiven the wide range of lead values (some span 4 orders of magnitude), it’s more appropriate to use geometric mean and not the arithmetic mean. I would strongly advise redoing the statistics and using geometric mean and std. deviation.\n\nIn the 3rd paragraph, you mention multinational brands, national brands, local brands etc. However, you never described this categorization in your sampling section. It’s not clear what these are, and you need to describe them earlier. Especially since you are making conclusions about these different markets.\n\nWhile the data is strong and most of the time, obvious, the statistical testing is necessary. I.E. compare the lead content of the red paints to the yellow paints. Are they statistically different? What about national versus local paints. Are they statistically different? A simple t-Test may suffice. Of course, you cannot do this with results less that 3 samples.\n\nHandling values below detectable levels has always be tricky. You are using a 50% value of the LOD (i.e. <60 becomes 30 ppm). Another way is using this formula (LOD divide by the square root of 2) which comes to 42 ppm1. Either way is fine, but please explain and reference the method you use.\n\nGenerally, we stop using factions when values reach the thousands. Doesn’t add much value to say 8,157.65 as opposed to 8,158. I would drop the fractions.\n\nIn the last paragraph of RESULTS, you all of a sudden introduce a new variable; manufacturing date. I’m okay with this but somewhere earlier, you should mention that you planned to do this. It just suddenly appeared.\n\nTables\nIn table 1, you use IQR without defining it. Please fix (and perhaps explain it’s use).\n\nAdd the word “Pakistan” after Karachi in the title of Table 1. Don’t assume all readers are familiar with this.\n\nI would have like to see an actual label from the study or yellow paint can. Possible?\n\nChange Pb to Lead in the titles of the Tables.\n\nConsider centering the data.\n\nOmit fractions (1,111.99 should be 1,112).\n\nInclude statistical “p” values where appropriate.\n\nDiscussion\nBe very careful of direct judgmental statements like this: “Further effort is required to fully implement….” While you and I may feel this way, this is a presentation of scientific data and not generally in your position to “require anything”. You can of course suggest or recommend but using the word require, is not appropriate for this type of paper.\n\nThere are other parts of the discussion where you seem to strongly state an action that must be taken. Please remove or reword this accordingly.\n\nI would have liked to see a discussion on the use pattern of oil-based paints in Pakistan. How much of the market is oil-based paint, where is it used and describe the exposure patterns. After all, the simple presence of LBP doesn’t necessarily implied exposure. A comparison to latex based paints would be interesting.\n\nPerhaps, under additional research, the authors can suggest next steps in characterizing this exposure source.\n\nOverall\nWell done survey research of significant environmental health importance. With these changes, I would recommend publication.\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? Partly\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": "214186",
"date": "24 Nov 2023",
"name": "Matthew Dietrich",
"expertise": [
"Reviewer Expertise Environmental geochemistry",
"lead (Pb) evaluation in different environmental media."
],
"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\nOverview\nThe brief report entitled, \"`The brighter the worse`: Lead content of commercially available solvent-based paints intended for residential use in Pakistan\" analyzes the lead (Pb) composition of various paints still available commercially in Pakistan--specifically, Karachi, Pakistan. Unfortunately, despite regulatory changes in 2017 restricting Pb concentrations in paints sold within Pakistan to below 100 ppm, many paints sampled still exceed this threshold. This brief report draws the conclusion from the 60 paints sampled that paint Pb regulations have been poorly implemented thus far across Pakistan. Thus, more work is needed to reduce exposure risk from paints for children and other vulnerable populations in Pakistan.\nThis is a well-written piece that is easy to understand, clear in its scientific methodology, and important for raising awareness on potential Pb exposure risks in the environment even following regulatory change. While a publishable and important piece of work, there are several items needing addressing before publication, both minor and some of greater overall importance to the narrative.\nIntroduction\n\"particularly in the home environment\"\n\"5 μg/dL is a commonly used reference level, although lower BLLs are still considered dangerous (CDC, 2022).\"\nI would suggest perhaps adding some more language around this to provide context--the current CDC blood lead reference value is 3.5 μg/dL (which is indeed lower than most countries), and most contend there is \"no safe level of exposure.\" However, there has been recent push-back against some of this alarm-ism and the ever-moving guidelines, which is perhaps worth mentioning in some capacity through Roy et al. (2023) or other similar literature.\n\"Since then, the Pakistan Standards and Quality Control Authority introduced a mandatory standard limiting the Pb content of paint to 100 ppm (WHO, 2022).\"\nClarification is needed as to whether this is just for residential paint use only, or commercial and residential applied paints. Also, if this applies to both paint manufacturing and distribution, or just the manufacturing. Based on the title of the paper, I assume only residential paints, but clarification within the manuscript is needed.\nMethods\n\"snowball sampling\"\nI am not familiar with this term. Clarification likely needed.\n\"If a certain color was not available, a similar color was selected.\"\nThis is sort of vague and some elaboration is needed. A similar color to basic red, yellow, and white pigments?\n\"Each sample was assigned a numeric label and information on paint cans pertaining to Pb content, safety precautions, and standardization was recorded.\"\nI downloaded the very helpful supplementary file, but is it also possible to include the date of production? Is this commonly recorded on the paint cans? I'm not sure how long these paints have been on the shelves, but is there any possibility at the selected Pakistan market that some samples had been on the shelves for 4+ years? Might be nice to have some clarifying language on this within the methods somewhere, because the 2017 date benchmark is so important to this work.\n\"...apply it as a 0.5–1 mm coating to a 10 cm × 10 cm Pb-free, food-grade polypropylene surface.\"\nAny chance this was measured by ICP or XRF to confirm it was Pb-free? Would be helpful to include in the supplementary if so.\n\"Samples with concentrations below the reporting limit of the analytical procedures used were reported as <60 ppm.\"\nSo was the laboratory limit of detection (LoD) only 60 ppm? Should clarify in the text.\nResults\nOverall, I would caution against reported the mean so much in the results. I understand it's difficult to report the median because of many samples below detection limit, but the mean will be largely skewed due to outliers like the 97,500 ppm measurement in the data. Would suggest geometric mean as a better indicator of central tendency, or at least acknowledgement that the arithmetic means reported will be heavily weighted by outliers.\nFor the mean, it should be elaborated in the text that the mean calculation assumes Pb concentrations of 30 ppm for samples below the LoD. Not a perfect method for substitution for calculations below LoD, and while other replacement methods are possible, at the very least there needs to be a more detailed explanation of what was chosen and why.\nTables:\nShould be consistent with the decimal places. would recommend none and just to the nearest whole number throughout based on the low general precision of the measurements based on a LoD of 60 ppm.\n\"...with 34.8% (n=8) of paints containing Pb.\"\nSpecify this is defined by Pb concentrations >100 ppm?\n\"The highest concentration of lead was found...\"\nShould read something like, \"The greatest abundance of Pb-containing paints...\" Instead of just pointing out the one extreme value and going into the large percentage of paints containing Pb.\n\"Of the 60 paint samples, 42 had no labeling mentioning Pb and of those almost half (46.2%) had Pb levels of >100 ppm.\"\nSays 47.62% in the table.\n\"Of these, more than one-third (n=8)...\"\nShould add comma.\n\"...international or Pakistan standards. Of these, two had Pb levels of >100 ppm...\"\n\"Only two brands had brought their Pb levels into accordance with standards.\"\nDiscussion\n\"Pakistan has lagged behind in implementing its Pb paint regulations.\"\nShould compare to at least several other countries for examples.\n\"Its first paint regulations were issued in 2017, allowing only paints with Pb levels of <100 ppm (WHO, 2022).\"\nAgain, clarification is needed a bit on this regulation--for all paints or just residential applied paints within Pakistan? Pertaining to manufacturing of the paints and distribution? If addressed in methods, not necessary to restate here.\n\"Pakistan’s mean paint Pb concentration of approximately 8,000 ppm is within the range observed in other Asian countries (O'Connor et al., 2018).\"\nAgain, would caution against over-interpreting the mean as this is largely skewed, non-normal data with outliers of high values.\n\"There is, however, some uncertainty in interpreting comparisons between the two studies, as the sampling took place in different cities and the range of paints sampled was not identical.\"\nBringing up the point on production dates of paints again--it just may be worth clarifying the likelihood that any paints sampled in this study were somehow produced in 2017 or earlier. This could be a moot point though if the <100 ppm regulation applies to all paints sold in Pakistan and not just the paint production, but as the manuscript currently reads, this isn't clear.\nDelete \"The current study finds that...\" to read:\n\"Yellow paints contain the highest Pb levels.\"\n\"By contrast, only 36.8% of red paints and 5% of white paints exhibited high Pb levels.\"\nClearly state \"high Pb levels\" means >100 ppm Pb.\n\"...with a high market share had 18,000 ppm Pb, exceeding national limits.\"\n\"In a study conducted in India, the unorganized sector was comprised of small businesses, while all large firms and multinationals fell under the category of the organized sector (Mohanty et al., 2013).\"\n\"...unorganized sector had Pb concentrations of >300 ppm.\"\n\"...unorganized sector pose...\"\n\"...provide a representative sample of paints in Pakistan.\"\n\"A substantial proportion of paint being sold continues to put lives and health at risk.\"\nWould reword this... The act of paint being sold doesn't directly put lives at risk, it's the application of these paints then deterioration over time that can lead to risk of exposure and then subsequent health risk.\nGeneral\nWould avoid using \"Pb levels\" as much as is currently used throughout the manuscript. \"Concentration\" is often more appropriate to use as scientifically concise language.\nWould remove the first part of the title to change to: \"Lead content of commercially available solvent-based paints intended for residential use in Pakistan\".\nWhile the yellow paint appeared to contain the most Pb content, the title is already long and many may not connect the title to implying that the brightness of the paint is related to more Pb content in Pakistan--particularly as some may conceptualize white paint as perhaps being \"brighter\" than yellow paint.\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? Partly\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
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https://f1000research.com/articles/12-166
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https://f1000research.com/articles/12-165/v1
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13 Feb 23
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{
"type": "Research Article",
"title": "Study of the hydraulic correlation in the removal of pollutants from synthetic wastewater by means of a filter with Musa Paradisiaca",
"authors": [
"Benito Mendoza",
"Sandra Gabriela Barrazueta Rojas",
"Mayra Alejandra Pacheco Cunduri",
"María José Andrade Albán",
"Elvis Aucancela",
"Sandra Gabriela Barrazueta Rojas",
"Mayra Alejandra Pacheco Cunduri",
"María José Andrade Albán",
"Elvis Aucancela"
],
"abstract": "Background: The objective of this work was to decontaminate synthetic sewage from fouracid blue (BRL) dye, with characteristics similar to those of the textile industry, to determine the correlation between flow rate, permeability and removal of hexavalent chromium (Cr+ 6), Cupper (Cu), chemical oxygen demand COD and color using Paradise Muse filter bed. Methods: three concentrations of BRL synthetic wastewater were prepared, determining the initial concentrations of Color, pH, COD, Cr +6 and Cu. In addition, the hydraulic characteristics of the fiber were determined in four types of fiber cut. The synthetic wastewater was filtered in a filtration cell with the three fiber cuts, using three speeds, the time used for these tests was 180 minutes. Water samples were collected every 5 minutes and then analyzed in the laboratory. Simple exponential smoothing was performed on the data obtained, and the statistical analysis of variance ANOVA of 2 factors. Results: The results show that flow velocity and permeability are correlated with color removal, COD and Cr+ 6, determining that the best treatment was to use 1 cm fiber and high flow velocity in which 77.92% and 70.01% for color and COD respectively. In contrast, for Cr+ 6 the best treatment was fiber at 1 cm and low flow velocity removing up to 80% of the concentration of this contaminant and for Cu the best treatment was fiber at 3 cm and low flow velocity removing up to 88.69%. Conclusions: It was determined that the Musa Pardisiaca fiber is capable of absorbing contaminants, but the effectiveness of the treatment depends on the initial conditions of the synthetic water, the cut of the fiber and the velocity. In addition, it is important to mention that, in order to lower heavy metal concentrations, low flow rates should be used.",
"keywords": [
"Bioadsorption",
"filter bed",
"musa paradisiaca",
"wastewater"
],
"content": "Introduction\n\nThe wastewater produced from anthropic origin produces alterations and environmental problems worldwide, these change the characteristics of ecosystems and encourage the spread of disease (Meneses Barroso et al., 2018). The textile industry is the main source of contamination of water sources, as its processes use chemicals, detergents, oils and others. For example, chemical dyes used by the textile industry for garment dyeing generate wastewater with intense colors, and disposal into the riverbeds produce changes in their ecosystem because they do not allow the passage of sunlight for the process of self-purification (Zhongming et al., 2021).\n\nThe textile, food, beverage and paper industries are the largest contributors to water resource pollution. Of the pollution that each of these productive sectors contributes 14.6% of industrial water pollution, worldwide, is associated with the textile industry. These figures refer to so-called low and middle income countries, located in Asia, Latin America, the Middle East, North Africa and the Caribbean (Grakova et al., 2021).\n\nWaste water from the textile industries has been a subject of study for many years because of environmental problems, since it has a high biological oxygen demand (BOD) and chemical oxygen demand (COD) which are discharged at high temperatures and can present heavy metals and other complex chemicals threatening the environment in which they are discharged (Feuzer-Matos et al., 2022).\n\nOne of the most relevant indicators of water pollution is color, this parameter is mainly associated with the textile industry that uses color diversity (Montoya Alvarez, 2019). Dyes are generally organic compounds that have the ability to impart color to fibers of various origins, whether textile, as well as leather, paper, plastic and even food (Jabar et al., 2020). For a substance to function as a dye it must have an adequate color, ability to attach to the tissue and resistance to the action of water. There are more than 100000 types of dyes available commercially and it is estimated that around 7000 new dyes are produced annually (Saxena & Gupta, 2020).\n\nThe environmental impact generated by these toxic substances has led the scientific community to develop different methods for the treatment of industrial effluents such as: precipitation, oxy-reduction, ion exchange, filtration, electrochemical treatment, membrane technologies and evaporative recovery. However, these methods have been quite costly, in addition to the formation, disposal and storage of sludge and waste, originating during the processes, which becomes a major problem to be solved (Ramírez Calderón et al., 2020).\n\nBecause of this bioadsorption processes arise as an alternative for the treatment of effluents produced by the textile industry using as a sorbent different materials of biological origin that are low cost and are in great abundance in nature. Moreover, its biosorbent transformation is not a costly process by treating agricultural waste that previously had no use (Elgarahy et al., 2021). That is, this method mainly seeks the removal of heavy metals in wastewater from the industrial sector, using different biological sorbent materials such as: algae, fungi, bacteria, fruit peels, agricultural products and some types of biopolymers. These materials are inexpensive and are found in great abundance in nature, moreover, their biosorbent transformation is not a costly process (Corral-Bobadilla et al., 2019).\n\nThe bioadsorption process involves a solid phase (biomass) and a liquid phase (water) contains dissolved the contaminant to be treated (in this case, the ions of heavy metals). In order for the bioadsorption process to be carried out successfully, there must be a high affinity between the functional groups of the biomass and the pollutant, since the phenomenon of bioadsorption of metal ions, using biological materials as adsorbents, can be performed by various physico-chemical and metabolic mechanisms in which the process of capturing heavy metals may differ (Das et al., 2021).\n\nIn general, the extraction of metals by residual biomasses is attributed to their proteins, carbohydrates and phenolic components containing carboxyl, hydroxyl, sulphate, phosphate and amino groups, which have a high affinity for metal ions, facilitating their capture (Corral-Bobadilla et al., 2019).\n\nThree classes of adsorption can be distinguished according to the type of attraction between solute and adsorbent. If the adsorption is given by the ion exchange in which the ions of a substance of interest are concentrated on a surface of the adsorbent material as a result of the electrostatic attraction between them, the adsorption is said to be of an electrical type. However, if the adsorbed molecule is not fixed at a specific place on the surface, but rather is free to move within the interface, adsorption is said to be due to van der Waals forces or also called physisorption. Incidentally, if the adsorbate forms strong bonds located in the active centers of the adsorbent, it can be said that adsorption has a chemical nature. It should be noted that in physisorption, the adsorbed species retains its chemical nature, while during the chemisorcion, the adsorbed species undergoes a transformation leading to a different species (Ratri et al., 2022).\n\nThere are variables that affect the phenomenon of bioadsorption such as temperature, pH, particle size and the presence of other ions. An elevated temperature may cause a change in sorbent texture and a deterioration of the material leading to a loss of sorption capacity (Corral-Bobadilla et al., 2019). The pH of the aqueous solution is an important parameter that controls the adsorption processes of metals in different adsorbents, due to the fact that hydrogen ions constitute a highly competitive adsorbate. The adsorption of metal ions depends both on the nature of the adsorbent surface and the distribution of the chemical species of the metal in the aqueous solution. The pH value of the aqueous phase is the most important factor in both cation and anion adsorption, the effect being different in both cases. Thus, while the adsorption of cations is usually favored for pH values higher than 4.5, the adsorption of anions prefers a low value of pH, between 1.5 and 4 (Sepulveda et al., 2022). Particle size effect adsorption takes place mainly inside the particles, on the pore walls at specific points. The amount of adsorbate (solute) that can be adsorbed is directly proportional to the volume, and it is well known that this volume is directly proportional to the external area and also that a small particle has greater surface area, greater area of the inner surface by the amount of pores per unit of mass. The presence of ions in the solution allows them to compete with metal in the interest of sorption zones (Corral-Bobadilla et al., 2019).\n\nAmong some of the wastewater treatment with vegetable fibers (Bioadsorbents) we can mention:\n\nEvaluation of the biosorbent power of orange peel for the removal of heavy metals, Pb (II) and Zn (II). In the present work we investigated the biosorption of Pb (II) and Zn (II) from the biomass of dried orange peel, crushed, with and without crosslinking treatment (with CaCl2). Of the 8 experiments, it was found that for Pb (II) showed removal percentage of 99.5 % with removal capacity of 9.39 mg Pb (II)/g orange peel. The best percentage of Zn (II) removal was 99.5%, whose removal capacity was 9.95 mg of Zn (II)/g orange peel (Fola Akinhanmi et al., 2020).\n\nUse of biosorbents for nickel and lead removal in binary systems. The adsorption of Pb (II) and Ni (II) on yam shells and palm bagasse was systematically studied in an individual and binary system, reaching for yam shells a maximum adsorption capacity of 362.45 for nickel and 68.14 mg/g for lead. For palm bagasse, an adsorption capacity of 162.64 mg/g was estimated for nickel and 90.28 mg/g for lead. In a binary system, an antagonistic effect was observed for the combined action of metals, although the removal of lead was significantly increased in yam shells when in solution accuses with nickel (Benettayeb et al., 2021).\n\nAdsorption of Cr+6 by Cocos nucífera L. in residual of Fibrocemento in Santiago de Cuba. This work studied the adsorption of Cr+6 using the fruit shell of the Cocos nucífera L. plant as organic biomass. The optimal adsorption values of Cr+6 are: pH of 3 units; particle size less than 0.074 mm; adsorbent dose of 5 g.dm-3 and contact time of 1 hour. At low metal concentration values (1,0; 1.5 and 1.84 mg.dm-3) was obtained removal percentage greater than 90, however at high concentration values (2.5 and 3 mg.dm-3), values lower than 90 % are obtained (Itankar & Patil, 2022).\n\nWithin this line of research, the work aims to decontaminate synthetic water prepared from the BRL blue dye with characteristics similar to that of a textile industry, to determine the correlation between the flow rate, permeability, removal of heavy metals (hexavalent chromium and copper), chemical oxygen demand (COD) and colour using a filter bed with paradisiacal musa fibre, so that future studies can determine the feasibility of the actual implementation of fiber at the textile industry level based on the results obtained in this research.\n\n\nMethods\n\nThe research work is experimental, and the procedure was divided into 5 parts: the characterization of the fiber musa paradisiaca, elaboration and characterization of the synthetic water, application of the natural fiber as filter bed and the characterization of the treated water. ANOVA analysis of two factors was performed to treat the results.\n\nIn the characterization of the natural fiber musa paradisiaca was used from the data reported in the work of Aucancela (2018), where the following were reported: pH, humidity percentage, ash percentage, organic carbon determination, lignin percentage, fiber density, porosity and permeability.\n\nFor the processing of synthetic wastewater, the color parameter was taken as the basis, considering a value of 4540 U Pt-Co for high concentrations because in the study \"Analysis of the fiber obtained from the rachis of the musa paradisiaca plant, used as a filter bed in the adsorption of the color parameter\" was observed that for high color concentrations (41305 U Pt-Co) the fiber is not effective in color adsorption (Aucancela, 2018, pag 20-25). Three wastewater types were made using the blue dye BRL in concentrations as indicated in Table 1. This in the drinking water base which has electrical conductivity values of 593 μS/cm, 7.1 pH, Cr+6, COD and copper with zero values.\n\nThe characterization of the synthetic wastewater was carried out, the pH and conductivity analysis with the multiparameter HACH HQ40d, for which the sample of 100 mL of synthetic water was placed in a beaker and the reading was done with the equipment. Color analysis, COD, hexavalent chromium (Cr+6) and copper (Cu) were performed using the HACH DR500 spectrophotometer following the different processes stipulated in the water analysis manual (Davidson et al., 2022; Hach Company, 2000):\n\nColor: use UV/VIS DR5000 equipment with parameter code 120 and wavelength at 455 nm (nanometers), take a deionized water sample in the 25 mL cell and use as white and mark as ZERO in the equipment, the sample is shaken for 1 minute and a sample of 25 mL is taken in the cell and placed on the computer, READ is clicked, and the value is recorded.\n\nCOD: The sample is shaken for 1 minute, then a 2 mL aliquot is taken with a graduated pipette and poured into the high-range COD-AC vial (0-1500 mg/L COD), in the same way 2 mL of deionized water is taken and poured into the high-range COD-AC vial (0-1500 mg/L COD), the vials are shaken gently with the samples and placed in the thermal reactor at 150 °C for 2 hours, after which the vials are allowed to cool. Then search the code 430 in the UV/VIS DR5000, use the vial with deionized water is clicked on ZERO, then the vial is placed with the synthetic water sample and READ is clicked, the COD value in mg/L is recorded.\n\nCr+6 and Cromo were samples sent to be analyzed at the Environmental Services Laboratory of the National University of Chimborazo, whose methods correspond to those described in Standard Methods Ed 21 (Rice et al., 2017)\n\nThe flow cell used for treatability tests has the following internal dimensions: internal diameter D = 6.4 cm and height L = 15.3 cm. The flow rate was controlled by a peristaltic pump obtaining high speed (V3 = 0,86 ml/s), average speed (V2 = 0.45 ml/s), low speed (V1 = 0.22 ml/s). The permeability was controlled by cutting the length of the fiber, so the treatment will be with normal fiber (Fn), fiber cut to 1cm (F1), to 2cm (F2) and to 3cm (F3). Table 2 shows the experimental design used and the abbreviations given for each of the treatability tests.\n\nEach test included a treatment lasting 180 minutes at continuous flow, pH, conductivity and color values were taken every 5 minutes giving a total of 36 samples, of COD, Cr+6 and Cu were analyzed at the beginning of treatment and in minutes 1, 5, 30, 60, 90, 120 and 180 giving a total of 8 samples. The same procedures and parameters described above were performed for the characterization of treated water.\n\nFinally, the Statistical Analysis was obtained the average of the 3 values obtained in the laboratory over the 180 minutes of treatment, applied data smoothing, this in order to correct erroneous values. The method used is a simple exponential smoothing, this method contains a self-correcting mechanism that adjusts forecasts in the opposite direction to past errors. It is a particular case of weighted moving averages of current and previous values in which weights decrease. It is used for both smoothing and forecasting (Wei & Chen, 2022). The equation used is (1):\n\nWhere: X^t = Average sales in units in the period, t, α = smoothing constant, X^t−1 = forecast sales in units of the period t-1,Xt−1 = Actual sales in units of the period t-1.\n\nThe data obtained in the experimentation were evaluated by the statistical analysis of the ANOVA variance of 2 factors with a significance level of 95%. The percentage of removal or adsorption of each of the analyzed parameters was obtained with the initial value and the value obtained at the end of the treatment. Finally, the coefficient correlation between the flow rate vs the percentage of removal of pollutants and the permeability vs the percentage of removal of pollutants was calculated to find whether or not there is a correlation between them.\n\n\nResults and Discussion\n\nTable 3 reports the results of the physico-chemical characterization of the fiber and Table 4 the hydraulic characteristics of the musa paradisiaca fiber obtained in the flow cell.\n\nThe values regarding the lignin percentage, ash percentage and density obtained in this research are similar to those reported by (Aucancela, 2018).\n\nThe permeability data allow us to observe the directly proportional relationship between the fiber cut and the permeability, the same has been observed with porosity whose data are close to the values reported in a study of hydraulic characterization of coconut fiber (similar to the paradisiacal muse) with a porosity of 81% (Luis Huertas Blanco et al., 2019).\n\nTable 5 shows the results of the characterization of the three types of synthetic water. As can be seen, synthetic wastewaters have color, Cr+6 and Cu concentrations similar to the characteristics of effluents from textile industries. Regarding conductivity, pH and COD, the values obtained are low because these parameters are influenced in the textile industry mainly by the dyeing and finishing processes making contact with other chemicals\n\nTable 6 shows the removal of contaminants in high concentration synthetic water after 3 hours of filtering water. The behavior for each parameter was different: Thus for the pH values are shown between 7.61 and 8.12 observing that the initial value of 8.16 is not altered staying within the range (5.5-9.5) for discharges to freshwater bodies (OFFICIAL RECORD, 2015). The conductivity presents mostly positive values whose results are better while increasing the flow velocity, reducing up to 22.33% in the F1CaV3 treatment. The color shows reduction values between 48.27 and 65.15% for each treatment. In the COD, better results were obtained while increasing the flow velocity, reducing up to 63.39% in the F1CaV3 treatment. Cr+6 reduction percentages are favorable for each treatment whose values are between 59.74 and 80.82% of removal. Finally, for Cu the percentages of reduction present fluctuations that, for example, in the treatment F3CaV2 is 18.03%, a small value relative to that obtained in the treatment F3CaV1 that was 83.54%.\n\nIn Table 7 pH remains under regulation. The conductivity shows positive removal values only for high flow rates by removing up to 7.73% in the F1CmV3 treatment. In color, reduction values are found between 52.71% and 69.67%. The COD presents almost mostly negative values meaning that, it was not possible to lower the concentration of this parameter but rather increase it by factors such as ripeness and decomposition, the presence of fine particles and even the presence of water-soluble salts presumed to possess the fiber. The percentages of reduction of Cr+6 are between 43.29 and 64.74% of removal and those of copper range between 45.92% and 88.69%.\n\nTable 8 shows the results obtained for each low concentration treatability test after 3 hours of filtering the water. For synthetic concentration wastewater, pH remains under regulation. The conductivity and the COD have almost mostly negative values meaning that, this parameter was not lowered but rather increased by the explained above. The color is between 51.14% and 67.93%, Cr+6 between 30.18% and 53.95% and Cu between 40.21 and 87.31%. Because unusual behavior was observed at the start of treatment in the treatability tests with the three concentrations of synthetic water referring to conductivity parameters, color and COD, it was necessary to apply more treatability tests with the pre-wash of the fiber, since it provides values to these parameters.\n\nThe conductivity, color and COD values with which the fibre provides are presented in Table 9 below. Obtaining an average of 39187.75 μs/cm, 446.92 UPtCo, 5215.83 mg/l, for conductivity, color and COD respectively. Among the factors that influence the contribution of conductivity, color and COD by the fiber is its state of ripeness and decomposition, the presence of fine particles and even the presence of water-soluble salts that the fiber is presumed to have.\n\nIt should be noted that, although fiber provides concentration values for conductivity, color and COD, this problem was solved by washing the fiber favoring treatment since, the fiber after washing did not lose its adsorption characteristics.\n\nTable 10 shows the results obtained for each treatability test after a 3-hour treatment by the filter bed for synthetic water of low concentrations with pre-wash of the fiber. The conductivity despite the washing of the fiber has almost mostly negative values that means that this parameter was not lowered, but it was reduced compared to the values obtained in Table 10. In color, the percentage of removal is between 69.86% and 77.92% and in the case of COD better results were obtained while the flow rate is increased and the fiber cut is lower. The pH presents percentages between 1.34% and 6.18%, the Cr+6 percentages of removal between 32.78% and 46.95%. Copper reported percentages between 32.35% and 79.60%.\n\nThe two-factor ANOVA is based on two hypothesis tests a null H0 and an alternative H1 that evaluate the two categorical variables. H0 states that all treatments are the same, meaning that there is no variation between the results in the treatability tests. H1 states that not all treatments are the same, meaning that there is variability between the results of one treatment and the other. The ANOVA variance analysis of two factors was performed using GNU PSPP open software and its statistical package Data Analysis for each parameter for all treatments according to the type of synthetic wastewater as follows with a confidence level of 95 %:\n\n• With fiber without prewash at high concentrations (Fsinlav.Ca.).\n\n• With fibre without pre-wash at medium concentrations (Fsinlav.Cm.).\n\n• With fiber without prewash at low concentrations (Fsinlav.Cb.).\n\n• With pre-washed fiber at low concentrations (Flav.Cb.).\n\nTable 11 shows the results of the ANOVA analysis of two factors for both the velocity variable and the permeability variable with respect to the removal of pollutants from synthetic wastewater of high, medium and low concentrations. The obtained values dictate that in the case of pH the hypothesis H0 was accepted for all concentrations in the variable permeability and the variable speed H0 was accepted for high and medium concentrations, that is, similar results are obtained in these treatments, however for Fsinlav. Cb and Flav. Cb treatments H1 was accepted which means that, in these treatments different results were obtained. In conductivity, H0 was accepted for all concentrations in the variable permeability, determining that all treatments are equal and H1 was accepted for all concentrations in the variable speed, determining that not all treatments are equal. Color hypothesis tests determined that in treatments where no fiber pre-wash was performed all treatments are the same in the two variables accepting H0, this is because, as already observed in the laboratory experiments the fiber treatment without prewash alter them, However, when prewashing is performed, conditions improve, which allows us to observe that there is variation in each treatment, accepting H1 in the permeability and velocity variable.\n\nIn COD H1 it was accepted for all concentrations in the variable speed. In the variable permeability only for low concentrations with pre-wash of the fiber H1 was accepted, while H0 was accepted for treatments of the different concentrations without pre-wash Cr+6 accepted H1 for each of the treatments in the two variables, which means that different removal results were obtained in each of the treatability tests performed for this parameter. Finally, for Cu, the flow velocities are adjusted to H1while in permeability H0 was accepted in each of the tests at different concentration.\n\nTo obtain the correlation coefficient, the removal percentage was correlated with the different velocities at the same permeability and the different permeabilities at the same velocity for each parameter at all concentrations. The correlation coefficient will allow us to know if the flow rate or permeability are related to the removal of pollutants where if the value approaches 1 the correlation will be strong or perfect and if it approaches 0 the correlation will be weak or zero. The sign determines whether it is directly proportional (positive sign) or inversely proportional (negative sign). Table 12 below shows the correlation coefficients obtained between the different permeabilities and velocities for each treatment according to its concentration.\n\nAlthough the correlation coefficient was obtained for all treatments, the analysis of those tests in which H1 was accepted in the ANOVA analysis of two factors and which are highlighted in bold in Table 13. Thus, at pH the results indicate the velocity and permeability does not influence the removal of this parameter. In the conductivity a significant and perfect correlation was obtained, that is to say, the flow velocity if it influences in a directly proportional way since, at higher speed, greater percentage of conductivity removal. In color, the correlation of permeability is strongly inversely proportional, since the coefficient values are between -0.85 and – 0.95 and in the case of velocity the correlation is directly significant and strong since the coefficient values are between 0.70 and 0.95. Which means that color removal in the pre-wash treatment of the fiber is more effective at lower permeability and higher flow rate. In the COD the variable velocity, the correlation are between 6 and 1, i.e. between moderate and perfect which means that the higher speed is, the decrease in COD, while for the variable permeability correlation coefficients are between -8.13 to -8.88, that is, the correlation is significant and strong which means that the lower permeability the removal of COD is greater. In the Cr+6, the coefficients of correlation between significant and perfect that are greater than -0.70 so the lower the permeability and the flow velocity, the removal of hexavalent chromium will be more effective. Finally, in the case of copper, it was determined that there is no suitable correlation between the flow rate and the removal of contaminants.\n\nThe following (Table 13) explains the best treatments for each parameter in the different concentrations:\n\n\nConclusions\n\nThe statistical analysis determined that the flow rate and permeability variables are correlated with the removal of conductivity, color, COD and Cr+6 while pH and Cu are not correlated.\n\nFor the permeability variable the correlation is inversely proportional while for the velocity variable in the case of conductivity, color and COD the correlation is directly proportional and for the case of Cr+6 the correlation is inversely proportional.\n\nThe best treatment was to use 1 cm of fiber and a high flow rate at which 23.37% was removed; 77.92% and 70.01% for color conductivity and COD respectively. For the Cr+6 the best treatment was with fiber at 1 cm and a low flow rate removing up to 80% the concentration of this contaminant. While for Cu the best treatment was fiber at 3 cm and low flow rate removing between 79% and 89%. Thus, proving that the filter bed of musa paradisiaca is effective for the removal of these contaminants.\n\nDespite obtaining good percentages of Cu removal, Cr+6 and color, in synthetic water of high concentration do not comply with the permissible limits established by Ecuadorian legislation so it is recommended to use the filter bed especially for wastewater of low concentrations or that have been treated in physical - chemical operations.",
"appendix": "Data availability\n\nZenodo, STUDY OF THE HYDRAULIC CORRELATION IN THE REMOVAL OF POLLUTANTS FROM SYNTHETIC WASTEWATER BY MEANS OF A FILTER WITH MUSA PARADISIACA https://doi.org/10.5281/zenodo.7559551. (Mendoza et al., 2023)\n\nThe project contains the following underlying data:\n\nData of Musa Paradisiaca.xlsx (The data presented in this file contains the results of the laboratory analyzes and the statistical analysis carried out with the Microsoft Excel Data Analysis statistical package.)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAucancela E: Study of the hydraulic correlation and the removal of pollutants in synthetic wastewater by means of a paradisiacal moss filter bed. Undergraduate thesis.2018. Reference Source\n\nBenettayeb A, Guibal E, Bhatnagar A, et al.: Effective removal of nickel (II) and zinc (II) in mono-compound and binary systems from aqueous solutions by application of alginate-based materials. Int. J. Environ. Anal. Chem. 2021; 1–22. Publisher Full Text\n\nCorral-Bobadilla M, González-Marcos A, Vergara-González EP, et al.: Bioremediation of waste water to remove heavy metals using the spent mushroom substrate of Agaricus bisporus. Water (Switzerland). 2019; 11(3). Publisher Full Text\n\nDas M, Thakkar H, Patel D, et al.: Repurposing the domestic organic waste into green emissive carbon dots and carbonized adsorbent: A sustainable zero waste process for metal sensing and dye sequestration. J. Environ. Chem. Eng. 2021; 9(5): 106312. Publisher Full Text\n\nDavidson J, Redman N; C. C.-J. of the W: Water quality, waste production, and off-flavor characterization in a depuration system stocked with market-size Atlantic salmon Salmo salar. Wiley Online Library. 2022; 1–17. Publisher Full Text\n\nElgarahy AM, Elwakeel KZ, Mohammad SH, et al.: A critical review of biosorption of dyes, heavy metals and metalloids from wastewater as an efficient and green process. Cleaner Engineering and Technology. 2021; 4: 100209. Publisher Full Text\n\nFeuzer-Matos AJ, Testolin RC, Pimentel-Almeida W, et al.: Treatment of Wastewater Containing New and Non-biodegradable Textile Dyes: Efficacy of Combined Advanced Oxidation and Adsorption Processes. Water Air Soil Pollut. 2022; 233(7). Publisher Full Text\n\nFola Akinhanmi T, Andrew Ofudje E, Idowu Adeogun A, et al.: Orange peel as low-cost adsorbent in the elimination of Cd (II) ion: kinetics, isotherm, thermodynamic and optimization evaluations. Bioresour. Bioprocess. 2020; 7: 34. Publisher Full Text\n\nGrakova AG, Novikova MA, Borisov AV: Technological Innovation to Reduce the Negative Environmental Impact of Industrial Wastewater. IOP Conference Series. Earth Environ. Sci. 2021; 666(2): 022091. Publisher Full Text\n\nHach Company: Manual of water analysis. Cell. 2000; 3(970).Reference Source\n\nItankar N, Patil Y: Assessing Physicochemical Technologies for Removing Hexavalent Chromium from Contaminated Waters—an Overview and Future Research Directions. Water Air Soil Pollut. 2022; 233(9). Publisher Full Text\n\nJabar JM, Odusote YA, Kazeem, et al.: Kinetics and mechanisms of congo-red dye removal from aqueous solution using activated Moringa oleifera seed coat as adsorbent.2020; 1: 3. Publisher Full Text\n\nLuis Huertas Blanco C, Savorio M, Sc M, et al.: Validation of the intelligent demand channel as irrigation control using capacitive probes, in tomato (Solanum lycopersicum) var. Gladiator in.2019.\n\nMendoza B, Rojas S, Cunduri M, et al.: STUDY OF THE HYDRAULIC CORRELATION IN THE REMOVAL OF POLLUTANTS FROM SYNTHETIC WASTEWATER BY MEANS OF A FILTER WITH MUSA PARADISIACA.2023. Publisher Full Text\n\nMeneses Barroso YM, Patiño Mantilla PA, Betancur Perez JF: Removal of chromium in industrial wastewater using Spirulina sp biomass, primary sedimentation and chemical precipitation. J. Agric. Environ. Res. 2018; 10(1): 141–152. Publisher Full Text\n\nMontoya Alvarez X: Technical Report Design of colors in Alpaca Fiber in a Laboratory of a Textile Company.2019.\n\nRamírez Calderón OA, Abdeldayem OM, Pugazhendhi A, et al.: Current Updates and Perspectives of Biosorption Technology: an Alternative for the Removal of Heavy Metals from Wastewater. Curr. Pollut. Rep. 2020; 6(1): 8–27. Publisher Full Text\n\nRatri D, Putra E, Wilopo W, et al.: Groundwater geochemistry and hydrogeochemical processes assessment in Bantul, Yogyakarta, Indonesia.2022; 958: 12013. Publisher Full Text\n\nOFFICIAL REGISTRATION: Agreement 97 A. NATIONAL LAW OF ECUADOR. 2015, November 4.Reference Source\n\nRice E, Baird R, Eaton A: Standard Methods for the Examination of Water and Wastewater ed-23rd. American Public Health Association (APHA), American Water Works Association (AWWA) and Water Environment Federation (WEF);2017.Reference Source\n\nSaxena A, Gupta S: Bioefficacies of microbes for mitigation of Azo dyes in textile industry effluent: A review. Bioresources. 2020; 15(4): 9858–9881. Publisher Full Text\n\nSepulveda P, Pavez O, Tume P, et al.: Biosorption of copper ions with olive pomace and walnut shell. Environ. Geochem. Health. 2022; 1–14. PubMed Abstract | Publisher Full Text\n\nWei X, Chen L: Dispersion of Family Ownership and Innovation Input in Family Firms. Sustainability (Switzerland). 2022; 14(14). Publisher Full Text\n\nZhongming Z, Linong L, Xiaona Y, et al.: UN World Water Development Report 2021 “Valuing Water.”. 2021."
}
|
[
{
"id": "163534",
"date": "14 Mar 2023",
"name": "Sinan Kul",
"expertise": [
"Reviewer Expertise Wastewater treatment",
"Environmental 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\nDo not use abbreviations in the title and abstract. Start from the introduction to using abbreviations and give the abbreviation in the sentence in which it is first mentioned.\n\nInstead of “Paradise Muse” in the Background section, “Musa Paradisiaca” can be used as in the whole study.\n\nCr (VI) or Cr6+ should be written instead of Cr+ 6. When I look at the other elements that appear in work, Cr (VI) would be more appropriate.\n\nToo many paragraphs are used in the study. Almost every sentence seems to be given in a paragraph. Combine different paragraphs with sentences that talk about the same thing. In this way, the integrity of the topic seems to be broken.\n\nCheck if there is an error in the expression (1.0; 1.5 and 1.84 mg.dm-3) on page 4.\n\nUse mg.dm-3 instead of mg.dm-3. Exponential expressions in units should not be written as prose. Correct the whole text by checking it like this. On page 4, write 593 µS cm-1 instead of 593 µS/cm.\n\n“(Aucancela, 2018, pp. 20-25).” Remove the phrase “, page 20-25” in the statement.\n\nWhat is “Cromo” on page 5?\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": "166475",
"date": "22 Mar 2023",
"name": "Rudolf Kiefer",
"expertise": [
"Reviewer Expertise natural polymers",
"sensors",
"ion selective membranes",
"composites"
],
"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 \"Study of the hydraulic correlation in the removal of pollutants from synthetic wastewater by means of a filter with Musa Paradisiaca\" reads a bit like a report than a scientific paper. There are some gaps that need be filled before that work is qualified in scientific writings\nThe introduction gives some interesting details but the goal in abstract as well introduction is missing. please include that. Also what is Musa Paradisiaca as nothing given in this work what it contains of, and its basically banana fiber but there different types of such.\n\nThere are no characterization of the used filter as it would be needed showing at least basics such as SEM and FTIR. please include those\n\nThere are vast data in this study and a Table does not give best overview. The authors should include Figures that readers can evaluate which system has best results. There need to be included a meaningful statistic.\n\nIt would also an advantage to include other filter system in removal of one as example Cr+6 in efficiency and compare it to the result in this work, please provide a Table of comparison.\n\nThe authors in general compare the results but what exactly is the mechanism to catch such ions from the water stream using Musa Paradisiaca? Please provide a meaningful scientific discussion\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?\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/12-165
|
https://f1000research.com/articles/12-162/v1
|
10 Feb 23
|
{
"type": "Software Tool Article",
"title": "Building a search tool for compositely annotated entities using Transformer-based approach: Case study in Biosimulation Model Search Engine (BMSE)",
"authors": [
"Yuda Munarko",
"Anand Rampadarath",
"David Nickerson",
"Anand Rampadarath",
"David Nickerson"
],
"abstract": "The Transformer-based approaches to solving natural language processing (NLP) tasks such as BERT and GPT are gaining popularity due to their ability to achieve high performance. These approaches benefit from using enormous data sizes to create pre-trained models and the ability to understand the context of words in a sentence. Their use in the information retrieval domain is thought to increase effectiveness and efficiency. This paper demonstrates a BERT-based method (CASBERT) implementation to build a search tool over data annotated compositely using ontologies. The data was a collection of biosimulation models written using the CellML standard in the Physiome Model Repository (PMR). A biosimulation model structurally consists of basic entities of constants and variables that construct higher-level entities such as components, reactions, and the model. Finding these entities specific to their level is beneficial for various purposes regarding variable reuse, experiment setup, and model audit. Initially, we created embeddings representing compositely-annotated entities for constant and variable search (lowest level entity). Then, these low-level entity embeddings were vertically and efficiently combined to create higher-level entity embeddings to search components, models, images, and simulation setups. Our approach was general, so it can be used to create search tools with other data semantically annotated with ontologies - biosimulation models encoded in the SBML format, for example. Our tool is named Biosimulation Model Search Engine (BMSE).",
"keywords": [
"Transformer",
"BERT",
"biosimulation model search engine",
"semantic annotation",
"CASBERT",
"Physiome Model Repository",
"composite annotation",
"information retrieval"
],
"content": "Introduction\n\nMany natural language processing (NLP) tasks have seen significant performance improvements since the introduction of the Transformer1 and the derived technology such as BERT2 and GPT.3,4 The Transformer is an encoder-decoder structure and was originally designed for natural multi-language translation. Its advantages lie in the attention mechanism and position coding to memorise long source sentences and carry out training efficiently in parallel. Then, GPT explores the decoder section by creating pre-training models from extensive data using unsupervised learning to further fine-tune the models for specific NLP tasks using supervised learning. BERT works on a similar fine-tune concept but specifically uses the encoder section to train in parallel and recognise the context of words bidirectionally. These positive attributes draw our attention to implement the Transformer, specifically BERT, in developing a search tool for data compositely annotated using ontologies.\n\nBiosimulation models are examples of data that are largely annotated using ontologies, e.g. those written using the CellML5,6 and Systems Biology Markup Language (SBML)7 standards. Structurally, the biosimulation model is composed of constant or variable that form more complex entities such as mathematical equations, components or reactions and in overall represent the model. To give expressive and complete descriptions, it is recommended to provide semantic annotations even compositely with multiple ontology instances.8 Now, entities can be rediscovered for various purposes, such as new model composition, initial variable search, and model verification. Furthermore, this way of annotation is encouraged by the Computational Modeling in BIology NETwork (COMBINE) community as a standard to ensure interoperability and sharing between different platforms.9,10\n\nSPARQL helps to find entities and has been recommended as a standard by W3 Community. However, creating SPARQL is difficult as it requires good knowledge of annotation structure, syntax, and ontology terms. Tools to help generating SPARQL from natural languages, such as NLIMED,11 are helpful. Still, it is more suitable for experts who already know the target entity, not for those doing exploratory searches like using commercial search engines. Furthermore, annotations are mainly for the lowest and highest entities; as in biosimulation models, there are rarely component and image annotations. Consequently, finding these unannotated entities using SPARQL is impossible.\n\nBERT is a cross-encoder that takes a pair of sentences as input and generates a classification embedding and a set of token embeddings. The classification embedding is used to calculate the probability that the last sentence is a continuation of the first sentence. Although the implementation for information retrieval has high accuracy, its efficiency is low because it has to generate embeddings of pairs of a query to all sentences. Reducing the number of embedding creations, several studies have used BERT as a re-ranker by initially retrieving sentences using traditional methods such as bag of word; the top n results are considered as relevant.12–14 However, the formation of one embedding that represents each sentence will be more convenient, resulting in more efficient computation and simpler data management. BERT can receive a sentence and then output token embeddings. The average of token embedding is considered as a sentence embedding. Still, the results are not satisfactory, because the BERT paradigm is a cross-encoder for the next sentence prediction task. Therefore, Sentence-BERT implements a siamese architecture to train language models using BERT so it can generate sentence embedding.15 Sentence-BERT is a bi-encoder that does not preserve the query context in the target sentence. It is much more efficient, although its effectiveness may be lower than other approaches implementing a cross-encoder. The poly-encoder modify BERT to maximise performance by accommodating both encoders and tweaking the cross-encoder.16 Although it is more efficient than original BERT, it is still not comparable to Sentence-BERT. Then, ColBERT uses a polling approach by calculating the similarity of each query token embedding with each sentence token embedding.17 The maximum scores are taken and then summed, and the sentences with the higher total score are given a higher rank. Due to the simplicity of Sentence-BERT, Composite Annotation Search Using BERT (CASBERT) uses it to represent ontology classes and predicates in composite annotations.18 The composite annotations are converted into embeddings representing entities in biosimulation models.\n\nIn this paper, we demonstrate the practical use of a Transformer-based approach to build a search tool on a biosimulation model stored in the Physiome Model Repository (PMR)19 using CASBERT. There are five entity levels in ascending order: variables/constants, components, models (CellML), images, and simulation setups (SED-ML). Initially, we created embeddings for variables/constants where most of the composite annotations are available. Variables/constants are the fundamental entities that make up the components and further form the model, while at the same time, images and simulation setups can be equivalent to models. Therefore, combining embeddings from the lowest to the highest level will form embeddings at each entity level. The availability of text-based annotations that are unique to an entity, such as the model authors and filename, are also useful to make the embedding more distinctive. Further, we also used these text-based annotations to create high-level entity embedding whose constituent entities are not annotated. Now the entity search simply converts the query to an embedding using CASBERT and then calculates its similarity against embeddings organised by level and displays the results in order. The search tool we created is named Biosimulation Model Search Engine (BMSE).\n\nAccessing SBML models from the BioModels database20 to BMSE is possible due to the similar annotation procedures and data formats, and this will be our future work. Other domains with semantic annotations such as gene experiments in the ArrayExpress21 and food microbiology models in ComBase22 could similarly implement our approach in their searching tools.\n\nOur implementation, dataset, indexes, and source code are publicly available [1].\n\n\nMethods\n\nWe developed a search tool to find entities in the PMR19 organised by entity levels. The PMR primarily consists of biosimulation models encoded in the CellML format.5,6 Composite annotations explaining entities in the CellML were extracted and converted to entity embeddings using CASBERT.18 Then, entity embeddings were managed by their levels in a list-like structure to simplify the creation, replacement, update, and deletion (CRUD) processes. Our tools are built in a modular manner to improve reusability and to help aid sustainability by making maintenance easier.\n\nCellML is a standard format for encoding mathematical models related to biological systems.5 Structurally, a model is composed of components which are the smallest units that can be reused to form other models.23 The component contains one or more mathematical equations composed of variables or constants. Then, all these entities together with supplemental or derived entities, e.g. schematic diagrams or simulation plots, are needed for various purposes such as checking initial values of variables, reuse of constants, model composition, and reproduction of experiments. Here, we used entities consisting of 4652 variables/constants, 1987 components, 980 models, 295 simulation setups and 980 images. Our approach allows for inexpensive addition and modification of entities and will be described in the next subsection.\n\nFigure 1 shows the example of composite annotations in the model of brain energy metabolism24 encoded using CellML model available in the PMR [2]. There are two components, GAPg and F6Pn, where each component having four variables, and structurally is similar. Concerning GAPg, three variables, i.e. GAPg_GAPg, GAPg.Vg_Pgk, and GAPg.Vg_Pfk, are annotated to Ontology of Physics for Biology (OPB),25 Foundational Model of Anatomy (FMA),26 and Chemical Entities of Biological Interest (ChEBI).27 GAPg_GAPg is the main variable and is the output of the component, providing information about the rate of glyceryldehyd-3-phosphate concentration change in an astrocyte. To give a complete and expressive description, this variable is compositely annotated with OPB_00340:Concentration of chemical, FMA:54537:Astrocytes, and CHEBI:17138:glyceryldehyd-3-phosphate complete with relationship predicates such as isVersionOf, isProperyOf, and isPartOf. Other variables are the input arguments obtained from the other components and annotated with OPB_00593: Chemical concentration flow. A similar annotation pattern is performed for most other CellML files where primarily at the variable/constant entities. At the same time, other annotations are mainly for model entities as descriptive metadata such as title, abstract, and author (see Figure 1).\n\nThe model is about brain energy metabolism; the two components, GAPg and F6Pn, are related to glyceraldehyde-3-phosphate and fructose-6-phosphate, consecutively.24\n\nWe used CASBERT to create variable/constant embeding. CASBERT18 is a tool for converting the composite annotation of an entity into an embedding by applying Sentence-BERT.15 Sentence-BERT is used to convert textual properties related to ontology classes (e.g. CHEBI:17138, OPB_00340) and predicates (e.g. isPropertyOf, isVersionOf) to embeddings. Then, the embeddings is merged to create an embedding representing variable/constant.\n\nTechnically CASBERT can implement other approaches such as ColBERT17 and poly-encoder16 with the increase in computational and indexing complexity; the use of Sentence-BERT is preferred because of its practicality while still providing good performance. Other alternatives are Onto2Vec28 and OPA2Vec29 which use Word2Vec30 to translate the words in the ontology class to embeddings, and then merge them as an ontology embedding. However, a word embedding approach only considers word co-occurrence in the training data, so the embedding of a particular word will be the same for all sentences. Moreover, it does not consider the context of the sentence.\n\nHere we describe our approach to build a search tool for biosimulation models encoded using CellML in the PMR. The tools consists of hierarchical entity embedding collection where the entity embeddings are organised based on their level. Query evaluation was carried out to determine the ranking of entities according to level based on their similarity to the query.\n\nHierarchical entity embedding collection\n\nEntity embeddings are grouped vertically, and collectively called a hierarchical entity embedding collection. With this grouping, users can search for entities specific to their level and possibly get a better searching experience. Figure 2 shows the process of creating the collection, starting from the lowest-level entity, variable/constant, and then combined to gradually create higher-level entity embeddings, i.e. constant, model (CellML), simulation setup (SED-ML), and image. Initially, CASBERT converts the composite annotations of the variables/components, resulting in the variable/constant embeddings. Then, one or more variable/constant embeddings are combined to form component embedding. Combining embeddings can be done by concatenation or merging. Concatenation can represent the combined embedding well, while merging may reduce information. However, merging is advantageous for the uniform embedding size, making it easier to measure similarity. Moreover, Coates and Bollegala31 demonstrated that merging by averaging could retain most information because high-dimensional embeddings are considered nearly orthogonal; therefore, we used this approach. We implemented Equation 1 for averaging by removing duplication and dividing the sum of embeddings E by the number of embeddings |E|. Using this averaging, SED-ML plot embeddings were also created; nevertheless, the generated entities are few and therefore, BMSE did not include them.\n\nModel (CellML) embeddings are created based on the component embeddings and additional metadata describing the model. The metadata mostly contains the reference article information such as filename, title, authors, and abstract. The short metadata, i.e. filename, title, and authors, are converted directly to embeddings; in contrast, the long metadata, i.e. abstract, is summarised first by taking the important phrases using SciSpacy.32 These phrases are put together as one text and then converted into embedding. The summarisation is to overcome the BERT input limit of 512 tokens. Tokens are generated using WordPiece33 so abstracts with a maximum of 250 words will likely have more than 512 tokens. Then, all metadata embeddings are merged, and the result is combined with the merged component embeddings, all using Equation 1 (see Figure 3). Image and simulation setup (SED-ML) embeddings are the same as model embeddings; however, an image usually has a caption. Therefore, the image embedding is a combination of caption embedding and model embedding. More than half of CellML files in the PMR are not annotated, leading to incomplete results when searching on model semantics alone. With metadata embeddings, most unannotated models can be represented.\n\nModel and image embeddings are enriched with metadata embeddings. The metadata includes title, author, filename, abstract summary, and image caption.\n\nQuery evaluation\n\nThe query used to search for entities is converted to embedding using CASBERT. The process in CASBERT involves both macro embedding and micro embedding. Macro embedding is the entire query text converted to embedding, whereas micro embedding is a combination of phrase embeddings. Then the addition of macro and micro embeddings forms a query embedding.\n\nFigure 4 shows the hierarchical entity search process, where a query embedding is measured against each entity embedding at each hierarchical level. The measurement uses cosine similarity,34 which is suitable for non-normalised Sentence-BERT-based embedding. The results are displayed based on the hierarchical levels, so it helps users to find entities by types, such as initial values for variables, reaction formulas, and model images.\n\nThe query is converted to embedding using CASBERT; then, the similarity is measured against the embedded entities at each level. The results are presented in order and displayed by level.\n\nHierarchical entity embedding collection enables modular data management and we further developed the search tool in a modular fashion. This modularity speeds up the development, deployment, and maintenance processes where the modules created have a consistent interface, so algorithm and data changes do not affect other modules.\n\nData organisation\n\nWe defined the embeddings and other related data for each entity level in EntityEmbeddings and EntityData objects, respectively. The EntityEmbeddings is a two-dimensional tensor created using PyTorch35 where each element is an embedding representing an entity. This tensor, along with PyTorch, is efficient in calculating and sorting the similarities of query embedding to each entity embedding. Data organisation, i.e. CRUD, are quite fast because the tensor data format is simple and resembles a list. CRUD operation in the high entity level should not affect the lower level but not the other way around. To facilitate entities propagation when there is a CRUD operation in lower level entity, pointers to the higher level entities are encoded in EntityData. In addition to pointers, EntityData stores other information according to its level, for example at the variable/constant level there are initial values and equations, while at the model level there are workspace links and other related models. Furthermore, the EntityEmbeddings and EntityData of each entity level are stored in the form of files so that they are easy to implement and deploy on different platforms.\n\nModular development\n\nBMSE modularity is generally divided into frontend and backend. The frontend implements a JavaScript Framework providing an interface for interactive use of BMSE in the web browser. Users can search for entities by keywords; then, with the search results, they can perform advanced activities such as comparing entities, searching for images and dependent equations, and copying LaTeX code for equations. Results presented by the frontend are provided by the backend performing tasks such as query processing, similarity measurement, entity retrieval, and data formatting. Accessing the backend is standardised, as are the return formats, so there is a guarantee that changes to the backend do not interfere with the frontend. Regarding the CRUD processes of EntityEmbeddings and EntityData, the backend will not be affected as the processes can be done without shutting down the service.\n\nModel cluster\n\nWe found a large number of structurally similar models in the PMR due to model composition and modification. They differ in completeness of information, e.g. images, titles, annotations, and some low-level entity details. Sharing information in such a model can provide a more comprehensive description. To do this, we extracted three types of structures from each CellML file, namely the XML document as a whole (all-structures), the entity as a whole (deep-structure), and the path from the entity root to the leaf (wide-structure). Then, these structures are converted into a term frequency (TF) and Inverse Document Frequency (IDF) matrix and finally clustered using hdbscan.36\n\nBMSE requires Docker 20.10.x for deployment on a local machine or cloud instance. The local machine does not need specific specifications; however, the cloud instance should be Linux based, where we use Ubuntu, with 4 VCPUs and 8GB RAM. We provide the BMSE pipeline in the GitHub repository [3] and the archive in Zenodo [4].\n\n\nExperiments and results\n\nIn this section, we present Biosimulation Model Search Engine (BMSE), a web-based search tool, to find model entities (variables/constants, components, models, simulation setups, and images) in the Physiome Model Repository (PMR). Queries in BMSE are keywords consisting of phrases, abbreviations, and formulas, so it provides flexibility of search expression and effortless refinement.\n\nUsers search for entities by submitting queries as keywords, and then BMSE presents results organised by level. Using keywords allows users to access information just like in a commercial search engine. Keywords are structured intuitively and can be modified by generalisation, specification or reformulation. Later, users can customise the results, such as displaying at a certain level only, sorting by attributes, and filtering based on ontology classes. The customised results then are ready for knowledge extraction, e.g., the variable initial values, simulation plots, entity comparison, and model authors. Hence, different information needs may lead to different workflows which users freely describe.\n\nFigure 5 is an example of the results at the variable/component level for the query ‘concentration of triose phosphate in astrocytes’ where triose phosphate is the synonym of glyceryldehyd-3-phosphate. Variable/constant entities are arranged based on similarity values and are described with the name, initial value, type, unit, and mathematical equation attributes. For the query example, GAPg/GAPg with glyceryldehyd-3-phosphate is correctly presented in the top position, followed by G6Pg/G6Pg with Robison ester, both of which are about the chemical concentration in astrocytes. Expanding entities can access detailed information about these chemical compounds, images, and models. At the component level, the top-ranking entities are usually those containing the top variables at the variable/constant level. Most components present mathematical equations representing the variables that carry out the process or reaction. The results at the model level are quite different, where models with higher ranking variables or components can be in a lower order. However, this makes sense because the sample query is suitable for low-level entity search. Models can contain many variables and components with various annotations; thus, queries require more general keywords such as article authors and title. Simulation setup and image levels follow the model level. The simulation setup shows the resulting plot with the initial values of the associated variables. Due to caption embedding, image level results may differ slightly from model level.\n\nThe results show entities with variable initial values, types, units, and mathematical equations. Each entity is expandable to get more detailed information such as related images, models, and ontology classes.\n\nBiosimulation models in the PMR are mainly based on published articles. These articles may discuss the same object with different assumptions and approaches and present new biosimulation models combining the available models. Therefore, there are many similar entities at all levels; they differ in the content of particular attributes such as initial variable values, formulas, authors, and approaches used. BMSE provides an interface to compare entities and spot differences so that users can select the suitable entities.\n\nSuppose a user is looking for the initial value of voltage-gated sodium channels and then makes a query ‘sodium channel voltage’. Of the entities shown, the variable ENa in the fast_sodium_current component is the suitable one and is described with the voltage-gated sodium channel activity (GO:0005248) and complex (GO:0001518). However, there are nine variations of ENa initial value, all of them with the same mathematical formula, type, and units, found in models from five articles.37–41 Even the same variable from the same article may have a different initial value such as 62.748 mV, 62.904 mV, 70.495 mV, and 55.377 mV in Ref. 41. The user can further analyse these variations by comparing the model, image, and mathematical equation attributes (see Figure 6) and then selecting one of the initial values.\n\nFurther differences are analysed to select the one suitable for user needs.\n\nNow with BMSE, it is possible to reuse entities over a broader range of physiology. Entities in different models can be found and presented together with the relevant information. Tools such as the Epithelial Modeling Platform (EMP)42,43 can use the BMSE web service to explore candidate entities and ensure their compatibility quickly and accurately. The EMP is used to assemble a new model using public entities, and compatibility checks are essential in guaranteeing a plausible new model. For the ENa variable in the previous subsection, for example, if the assembled model is mammalian with sodium overload-induced, the variable in Ref. 41 might be the most appropriate.\n\n\nDiscussion\n\nWe have demonstrated a practical approach to building a search tool using a Transformer-based approach for compositely annotation entities in models in the PMR. Here we discuss the advantages of using Transformer and the potential use of the developed search tool (BMSE). The last subsection examines limitations and future works for BMSE.\n\nOur approach to using CASBERT offers the organisation of entity embeddings vertically and modularly. Creating embeddings is incremental from the lowest to the highest level, so it is simple and fast. Then, the embeddings are organised in a simple data structure, assuring efficient management without compromising system performance when performing CRUD operations. Each embedding at different levels is arranged in a modular manner, allowing for the application of modular designs when developing the tool. While not mandatory, separating data, models, and views is suitable for future continuous tool development.\n\nIn the biosimulation model community, there are standards and tools to describe models and entities using composite annotations, e.g., SemGen.44 The tools make the annotation consistent, and consequently the number of the annotated entities are increased. The consistent annotation was demonstrated to be valuable for new model compositions such as in the Epithelial Modelling Platform (EMP)43 and bond-graph based hierarchical composition.45 Here, BMSE can be an intermediary tool serving entities for further reuse, and facilitate the FAIR data principles in the biosimulation model domain.\n\nWe see the potential use of our approach in other domains by applying semantic annotations such as the experimental gene datasets in ArrayExpress21 and predictive models of food microbiology in the ComBase22 repositories. Our approach is designed to accommodate composite annotations and hierarchical entities but is not mandatory. In the absence of hierarchical entities, entities can also be grouped according to specific criteria independently as needed. ArrayExpress is now equipped with Expression Atlas,46 an interface for exploring experimental results, which displays information organised by organism, anatomy, and gene expression. The query is assisted with the autocomplete and suggestion features. While the results are sophisticated, we thought our approach would help enable more expressive queries.\n\nWe use CASBERT, which is Transformer-based as well as embedding-based. As an alternative, our approach allows for adapting other embedding systems such as word-based,30,47,48 GPT-based,3,4 and other BERT-based.15–17 In the future, we could rapidly implement a new embedding-based system with better performance; this is an essential side of our practice.\n\nWe identify limitations in our work that, when done, may improve performance and user experience; this will be our future work. The Sentence-BERT model for converting text to embedding has not been fine-tuned for models in the PMR. Fine-tuning could use ontology classes involved in the composite annotation or the entire ontologies. We expect that the fine-tuned model will allow queries using more general terms not used for existing annotations in the PMR, such as ‘macroglial’ to find entities with either of the more specific terms ‘astrocytes’ or ‘oligodendrocytes’.\n\nWe suggest that lower-level entity embedding should also store information about higher-level entity embedding, just as variable/constant embedding should contain information about its model. This hold will allow, for example, to search for variable/constant entities by the article author. Combining higher-level entity embedding with lower-level embedding can use a weighted average. However, this is not covered here as we focus on the process of developing hierarchical entity embeddings.\n\nCurrently, BMSE does not consider user intent and only treats queries equally against all entity levels. By identifying the user intent, we could apply entity-level selection to the query (vertical selection) and customise the results by aggregating information from multiple entities (aggregate view). To achieve this, however, data about user behaviour in searches on BMSE is required, which is currently unavailable. In future, the data could be collected as user query logs and analysed to find correlations between queries and information needs. Finally, the search is expected to accommodate natural language in the form of questions and answers.\n\nExtending BMSE to integrate with model repositories including content similar to the PMR (e.g., the BioModels database) is possible due to the harmonised manner for annotating models compositely. The combination of these repositories provides the most extensive biosimulation model collection supporting a more comprehensive range of entity reuse and robust model verification. By integrating suitable translation tools, such as Tellurium49 for CellML to SBML and SBML to CellML translation, it is possible to envision extending BMSE to guide the reuse of models independent of the source model repository.\n\n\nConclusions\n\nWe have presented the use of a Transformer-based approach in building a retrieval tool for data annotated compositely. In this case, we used biosimulation models encoded with CellML standard deposited in the Physiome Model Repository (PMR). Each model is arranged hierarchically from the variable/constant entities to the model entity. Our efficient approach can construct embeddings representing these entities and organise them in a simple data structure. Therefore, this makes it possible to implement the same strategy in other domains. Our searching tool is named Biosimulation Model Search Engine (BMSE). People in the biosimulation model community can explore entities specific to their level, i.e. variable/constant, component, model, simulation setup, and image. Finding these entities is crucial for the following activities: model composition, verification, and reproduction, therefore, supporting the FAIR data principles. In this paper, we presented the necessary steps to develop the tool and have identified some opportunities for future developments.",
"appendix": "Data availability\n\n\n\n• The PMR models indexed by BMSE: https://models.physiomeproject.org/\n\nLicense: Attribution 3.0 Unported (CC BY 3.0)\n\n• The PMR model used as an example in this manuscript: https://models.physiomeproject.org/workspace/5af/\n\nLicense: Attribution 3.0 Unported (CC BY 3.0)\n\n\n\n• The method used, CASBERT, to convert queries and entities to embeddings and search entities: https://github.com/napakalas/casbert/ (https://doi.org/10.5281/zenodo.7549557). 50\n\n• BMSE documentation and tutorials to implement and reproduce query examples: Figshare: BMSE Documentation and Tutorials, https://doi.org/10.17608/k6.auckland.21679394.v1\n\n\nReferences\n\nVaswani A, Shazeer N, Parmar N, et al.: Attention is All you Need. Advances in Neural Information Processing Systems. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nShahidi N, Pan M, Safaei S, et al.: Hierarchical semantic composition of biosimulation models using bond graphs. PLoS Comput. Biol. May 2021; 17(5): e1008859. Publisher: Public Library of Science. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nPapatheodorou I, Moreno P, Manning J, et al.: Expression Atlas update: from tissues to single cells. Nucleic Acids Res. January 2020; 48(D1): D77–D83. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPennington J, Socher R, Manning C: Glove: Global Vectors for Word Representation. Proceedings of the 2014 Conference on Empirical Methods in Natural Language Processing (EMNLP), Doha, Qatar. Association for Computational Linguistics. October 2014; pp. 1532–1543. Publisher Full Text Reference Source\n\nBojanowski P, Grave E, Joulin A, et al.: Enriching word vectors with subword information. Trans. Assoc. Comput. Linguist. 2017; 5: 135–146. Publisher: MIT Press. Publisher Full Text\n\nChoi K, Medley JK, König M, et al.: Tellurium: An extensible python-based modeling environment for systems and synthetic biology. Bio. Systems. September 2018; 171: 74–79. tex.ids= choi_tellurium_2018-1. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMunarko Y: napakalas/bmse: BMSE 1.0.0.January 2023. Publisher Full Text\n\n\nFootnotes\n\n1 https://github.com/napakalas/bmse/\n\n2 https://models.physiomeproject.org/workspace/5af/\n\n3 https://github.com/napakalas/bmse/\n\n4 https://doi.org/10.5281/zenodo.7549557"
}
|
[
{
"id": "163793",
"date": "10 Mar 2023",
"name": "Socrates Dokos",
"expertise": [
"Reviewer Expertise Computational modelling of biological systems",
"neuroscience",
"electrophysiology",
"biomedical engineering"
],
"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 a search tool for biological computational models in the Physiome Model Repository based on a Composite Annotation Search Using BERT (CASBERT) Transformer approach. The main advantage of the approach is that composite annotations can be efficiently searched for in entities ranging from author/title, variables, model components, images to simulation setups. The article is well-written: I have only minor typographical corrections to suggest, as per below.\nMinor Corrections\nPage 3, paragraph 2: replace “composed of constant or variable” with “composed of constants or variables”.\n\nPage 3, paragraph 3: replace “by W3 Community” with “by the W3 Community”.\n\nPage 3, paragraph 4: replace “The poly-encoder modify BERT” with “The poly-encoder modifiesBERT”.\n\nPage 4, paragraph 5: delete “where” from “A similar annotation pattern is performed for most other CellML files were primarily at the variable/constant entities”.\n\nPage 4, paragraph 6: replace “Then, the embeddings is merged to create an embedding representing variable/constant” with “Then, the embeddings are merged to create an embedding representing avariable/constant”.\n\nPage 4, paragraph 8: replace “The tools consists of hierarchical entity embedding collection” with “The tools consists of a hierarchical entity embedding collection”.\n\nPage 5, figure 1 caption: replace “an CellML file” with “a CellML file” and “consecutively” with “respectively”.\n\nPage 9, paragraph 3: replace “for compositely annotation entities in models in the PMR” with “for compositely-annotated entities in models in the PMR”.\n\nPage 10, figure 6 caption: replace “but with a different initial values” with “but with different initial values”. Also, replace “user needs” with “user need”.\n\nPage 10, paragraph 3: replace “and other BERT-based” with “and other BERT-based approaches”.\n\nPage 10, paragraph 4: replace “but with a different initial values” with “but with different initial values”. Also, replace “user needs” with “user need”.\n\nPage 10, paragraph 3: replace “We identify limitations in our work that, when done” with “We identify limitations in our work that, when addressed”.\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": []
},
{
"id": "205266",
"date": "12 Oct 2023",
"name": "Garima Malik",
"expertise": [
"Reviewer Expertise Natural Language Processing (NLP)",
"Machine Learning and Large Language Models (LLMs)",
"Weak Supervision",
"Data Programming."
],
"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 of research:\nThe authors developed a search tool called CASBERT using BERT technology. This tool helps search through data annotated using ontologies. They used biosimulation models encoded with CellML standard from the Physiome Model Repository (PMR) as their dataset. The tool can highlight various entities such as variables/constants, components, models, simulation setups, and images. It also creates embeddings for these entities and organizes them in a simple data structure.This article provides detailed technical information on building the tool, including the GitHub code. To enhance the article, my minor suggestions for improvement are outlined below.\nSuggestions:\nThe article could provide more detailed insights into the applications of the word embeddings generated by the tool.\n\nThe introduction lacks a smooth flow in language.\n\nAdditionally, it's important to explicitly state the contributions of the research at the end of the introduction section.\n\nThe results section lacks discussion on metrics, which are crucial to validate the effectiveness of the proposed tool.\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? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-162
|
https://f1000research.com/articles/12-158/v1
|
10 Feb 23
|
{
"type": "Systematic Review",
"title": "Preparedness for contingencies: a systematic review of the factors that influence the crisis resilience of project managers",
"authors": [
"Ching Wen Kok",
"Kamran Shavarebi",
"Iffah Farhana Binti Abu Talib",
"Walton Wider",
"Elsie Nga",
"Ching Wen Kok",
"Kamran Shavarebi",
"Iffah Farhana Binti Abu Talib",
"Elsie Nga"
],
"abstract": "Background: The goal of this review paper is to investigate factors that contribute to project managers' crisis resilience through a systematic review of the literature and bibliometric analysis using VOXviewer. Methods: Using the PRISMA framework for systematic literature, 55 peer-reviewed articles published between 1993 and 2022 that met our criteria were identified through a structured keyword search in the Scopus and WoS databases. Results: The systematic review and bibliometric analysis reveal eight clusters, which we further categorise into four determinants. In the context of the roles of project managers, the results of a comparative analysis reveal four prominent factors for enhancing crisis resilience: 1. leadership; 2. interpersonal skill; 3. agility; 4. risk management and vulnerability . These factors are essential for developing project managers who are less susceptible to future crises and disasters. This study has exhaustively characterised the possibilities and capacities of crisis resilience in terms of competency, integration, collaboration, and novelty; however, the search was restricted to a small number of databases and a short period of time, which could be explored in future research. Conclusions: According to the findings, most previous research on crisis resilience focused on emergency preparedness and was primarily conducted in Western and American studies. There is a lack of a holistic perspective on crisis resilience, which will be developed. We believe that international collaboration efforts to establish a platform for the exchange of knowledge between Western and American nations and ASEAN members are necessary.",
"keywords": [
"Preparedness",
"Contingencies",
"Awareness",
"Crisis Resilience",
"Project Manager"
],
"content": "Introduction\n\nThe Centre for Research on the Epidemiology of Disasters (CRED, resUClouvain) reported in 2021 that climate-related disasters accounted for 389 events, 15,080 deaths, 98.4 million people affected, and economic losses of at least US$ 171.3 billion in 2020 (CRED, 2021). More and more places on Earth are being hit by natural disasters regularly. The term “project manager” is widely used in many different fields, including but not limited to manufacturing, construction, information services and publishing, IT/IS, finance and insurance, management and professional services, utilities, oil and gas, governmental departments (such as defence), and many others. The Project Management Job Growth and Talent Gap 2017–2027 study by Anderson Economic Group (AEG) reveals extremely optimistic projections. Until 2027, businesses will need to fill an estimated 22 million new project-based positions annually (PMI, 2017). In addition to their unique leadership or individual roles, project managers also play a crucial part in boosting society’s resilience by building the resilience of their teams (Karlsen and Berg, 2020). It is critical for those working in project management (PM) to build resilience (as both a trait and a process) and acquire a strong capacity to respond rapidly to crises and tasks requiring participation.\n\nThe ways in which crises occur are unforeseen, sudden, and unpredictable. Unpredictability is a primary contributor to poor performance as well as the inability to successfully complete a project. Traditional techniques for mitigating unpredictability in projects centre on risk identification and risk responses (avoidance, transfer, mitigation, and acceptance). These risk-based techniques can protect projects against identified threats. In highly unpredictable circumstances, however, the success or failure of a project cannot be guaranteed. The urgency of a paradigm shift from risk-based to resilience-based techniques has been heightened as a result. A resilience-based strategy focuses on enhancing project resilience as the capacity to withstand known and unknown uncertainty (Rahi, 2019; Rahi et al., 2019, 2021). The reality is that project management during crisis events is complex and stressful (Ismail, Majid, Roosli, & Samah, 2014). There is scant information and scant research on crisis resilience and the qualifications of Project Managers. Lack of competence and inadequate crisis resilience and preparedness awareness (Chang-Richards et al., 2017, Rahi, 2019; Wilkinson et al., 2016; Loosemore and Teo, 2000) has resulted in project manager failure in managing crises and establishing team trust (McLaren & Loosemore, 2019). In Poland, researchers (Goniewicz & Burkle, 2019) have noted that one of the most fundamental antecedent goals of the Sendai Framework for Disaster Risk Reduction (SFDRR) is to increase crisis resilience and preparedness awareness in order to effectively manage crises. However, Poland has yet to adopt SFDRR goals adequately due to a lack of preparedness awareness. The Polish government continues to prioritise the emergency response and recovery phases of the disaster risk management life cycle, and its preparedness remains reactive. The same situation occurs in the Netherlands, as Imperiale and Vanclay (2021), concur. They conducted a heuristic analysis and concluded that cultural and political barriers influence implementation failures in disaster risk reduction. A paradigm shift from “assessing the impacts” to “reducing the resilience risk” is necessary due to an insufficient understanding of society’s resilience and the community’s perception of risk, the absence of a strategy to engage and entrust resilience in the community, and the recurrent impediments to the implementation of effective DRR and community adaptive capability preparedness policies (Imperiale & Vanclay, 2021). Hence, the purpose of this paper is to investigate the concrete factors of crisis resilience that project managers should consider when dealing with disruptions and ensuring project success as outcomes of crisis resilience and preparedness awareness.\n\n\nMethods\n\nWe conducted a comprehensive systematic review of relevant articles in inter-disciplinary fields, utilising established methodologies and protocols. We developed a search strategy to identify relevant literature for this systematic search. This search strategy was created to include a computerised literature search of two databases using the library services provided by Scopus and Web of Science. Instead of publishers or journals, we utilised library services to obtain two comprehensive databases of academic publications on peer-reviewed journals and to cross-check the findings of our investigation. In addition, the multidisciplinary nature of the concept of resilience and crisis preparedness, as well as its applicability across multiple sectors, supported the decision to search for relevant papers through a library service rather than through publishers or journals. In our systematic paper search, we combined the term “resilience” with the Boolean operator and the following search terms: “individual resilience”, “project manager” AND “resilience”, “crisis preparedness”, “project resilience”, “team resilience”, and “construction resilience”. All searches covered the period from the database’s inception in 1993 to 2022 and included journal articles, review papers, and only English-language publications.\n\nThe PRISMA Statement served as the foundation for the criterion for selection (Moher et al., 2009). The primary goal of the search was to map current literature on individual resilience in the fields of social sciences, environmental sciences, business, and economics. The topics were then narrowed down to environmental science, multidisciplinary, social science, psychology, arts and humanities, and earth science. The time period covered by the search was from 1993 to 2022. No articles published prior to 1993 were included in the search results. The search focuses primarily on the nations of ASEAN, Europe, and the United States. As a result, any articles from another country were excluded. The keyword search strategy was carried out twice to add credibility to the study, as per our inquiry to the library services regarding keywords. Accordingly, we compiled a list of 1539 articles that could be relevant and performed a preliminary screening using a title/keyword and summary check, eventually eliminating 1494 articles and inquiring about 45. Each author independently reviewed and analysed the remaining 45 articles to determine their applicability to the subsequent analysis steps based on a set of predetermined inclusion and exclusion criteria.\n\nIn this study, only original research articles and review articles were used. All duplicates were meticulously examined to ensure the quality of the review. To ensure the quality and relevance of the academic literature included in the review process, the abstracts of the papers were thoroughly evaluated. Each research project was subsequently subjected to a thorough evaluation. The second criterion for exclusion was restricting the papers to those that had been published in English-only journals. Thirty-four (34) articles that were written in a language other than English were excluded from the study (15 German, 5 Spanish, 4 Russian, 2 Croatian, 4 French, 1 Norwegian, 1 Turkish, 1Afrikaan, 1 Russian). After eliminating duplicate records, another publication was removed from the analysis. After applying the aforementioned criteria for acceptance and rejection, we narrowed the pool of potential papers down to 45.\n\nThe bibliographic references of the included papers were then examined to confirm the study’s veracity and rule out the possibility of omissions. Because of this, we hand-selected 10 papers that we felt answered our research question and met our other inclusion criteria. Because of their prevalence in the reviewed papers, the following contributions were chosen for consideration. The systematic review procedure that we used to compile our final dataset of 55 studies.\n\n\nResults\n\nWhile there has been an overall increase in crisis resilience and preparedness research publications over the research period (1993–2022), there have been significant shifts in the publication distribution between time series phases, as shown in Figure 1. The time series distribution of resilience and crisis preparedness research papers can be divided into three phases. The first period covers the years 2000–2015; during this time, there were only about 22% of all publications in the field of resilience and crisis preparedness, and the average annual number of publications in this area was less than two. This period is characterised by a slow rate of development. The second phase of the crisis resilience and preparedness research, lasting from 2016 to 2021, is a part of the rapid expansion phase. During this time, new publications on crisis resilience and preparedness research appeared, indicating an increased interest in these topics among global researchers. This phase is part of the rapid growth phase of resilience and crisis preparedness research. The third phase runs from 2021 to 2022, indicating that research on resilience and crisis preparedness has reached a stable development phase. This trend indicates that global researchers are becoming increasingly interested in resilience and crisis preparedness research. We can conclude and forecast that the number of publications will continue to increase beginning in the first quarter of 2022. The completion date of this strategy search is 18th May 2022.\n\nBoth the countries from which the articles were sourced and the total number of articles published are considered in this analysis of the geographic distribution of materials on disaster resilience and preparedness. The global coverage of the terms “crisis resilience” and “preparedness” is displayed in Figures 2 and 3. First place goes to the United States (12). According to a number of reports, the United States has been hit the hardest by this phenomenon, with a large number of citizens experiencing the effects of a number of different natural disasters. Canada and Australia are ranked second and third, with eight each, among nations where disaster resilience and preparedness measurement tools have recently advanced in development. As a result, policymakers at the national, district, and municipal levels are concerned and have taken decisive action, focusing on the Sendai Framework for Disaster Risk Reduction (SFDRR).\n\nThe United Kingdom has four publications; China, Hong Kong, Israel, Malaysia, New Zealand, Norway, and Singapore each have two. They are ranked lower than the rest of the world’s countries. “Crisis resilience” and “preparedness” develop more slowly here. Studies on disaster risk management have been conducted on a global scale, with the majority of studies focusing on either developed or developing countries.\n\nThe chosen 55 papers were published in 18 different interdisciplinary journals as depicted in Figure 4. This diversity reflects the immense fragmentation of expertise and scientific disciplines involved in crisis resilience and preparedness at present. To make logical sense of what is already known, a focused investigation is required to make sense of the vast number of publications.\n\nGroup and Organizational Management, International Journal of Disaster Resilience in the Built Environment, International Journal of Information Systems and Project Management, International Journal of Mass Emergencies and Disasters, International Journal Sustainable Construction, Journal of Engineering, Design, and Technology, and Market Trziste are the journals with the highest average number of citations per year (2). The previous publication is primarily concerned with IS/IT, project management, and sustainable construction. Case studies conducted by academics and patricians are included. Using an academic approach, the second section examines the reasons behind crisis resilience. In addition, it addresses disaster resilience indexes and built environment capacities. The topics and content are centered on spreading awareness of preparedness for crisis resilience.\n\nThis study also employed bibliometrics to examine the content of publications (titles and abstracts) found in the scientific databases Scopus and Web of Science (ISI). VOSViewer version 1.6.18 were utilised in the process of carrying out the analyses. Bibliometric analysis is utilised to categorise clusters of related publications discovered by a co-citation analysis utilising textual data. This bibliometric study, which continues the analysis of the first three decades of resilience and crisis preparedness research, aims to (1) create a map based on bibliographic data to create co-authorship, co-occurrence, citation, and bibliographic coupling in the period between 1993 and 2022; and (2) create a term co-occurrence map based on bibliographic data. The research reveals that there are seven distinct trajectories for future development. By comparing the most recent literature on resilience and crisis preparedness, the development paths and underlying strategic principles uncovered by this bibliometric analysis are then contrasted. Overall, this provides a systematic review of the research on resilience and preparedness conducted between 1993 and 2022, and it further reveals the divisions within its intellectual structure. The dichotomous nature of the development paths of resilience and crisis preparedness that each thematic cluster relates to creates a division.\n\nIn this study, VOSViewer was used to analyse the co-authorship by countries’ co-occurrence network of crisis resilience and preparedness research. Figure 5 is a network visualisation map showing author cooccurrence, which was generated by selecting co-authorship as the type of analysis, countries as the unit of analysis, full counting as the counting method, and three as the minimum number of documents per author. Figure 5 (5A, 5B, and 5C) shows the number of authors and their home countries for studies on crisis resilience and preparedness. The names of the countries were labelled with circles. What was represented by the space between the two circles was the degree of their connection. In this diagram, the coauthorship between two countries was represented by the thickness of the connecting curve lines. Each country’s total number of citations was used to calculate its share of the circle’s area. The bar in the lower right corner of the graph indicated the average year of the studies, and the circles’ colours reflected that. The range of colours represented the typical publication year in each nation. There are significant relationships between the distance between nodes and the thickness of connecting lines, both of which reflect the extent to which authors have worked together. If two authors have a strong connection and are geographically close together, they are more likely to work together on future projects.\n\nFigure 7 depicts the term co-occurrence map based on text data for the clusters of crisis resilience and preparedness research. The node size is proportional to the number of times a term appears in the titles and abstracts of publications; the larger the node, the greater the word count. In light of this, this paper explored the distribution of hotspots in resilience and crisis preparedness research by visually analysing the cooccurrence of keywords in resilience and preparedness research using VOSViewer. It selected cooccurrence as the analysis type, keywords as the unit of analysis, full counting as the counting method, and a minimum of three occurrences per keyword.\n\nAccording to Figure 6, the research hotspots for resilience and crisis preparedness are organised into eight keyword clusters, with the distinct clusters representing the distribution of resilience and crisis preparedness research in various domains. Cluster 1 (red region) represents relationship-related research on resilience and crisis preparedness. Cluster 1 contains ten keywords, including conflict, work, physical safety outcome, strategic resilience, adversity, effect, attribute, economic hardship, employee resilience, acceptance resilience, and policymaker, and is the largest cluster in the distribution of resilience and crisis preparedness research hotspots. According to the distribution of nodes, high-frequency keywords such as strategic resilience and adversity are relatively close and their connecting lines are relatively thick. One of the most promising new avenues of research in resilience is the application of complex adaptive systems (CAS) theory (Cavallo & Ireland, 2014). A “blessing in disguise” is a capability that emerges and grows in response to a systemic threat, whether real or imagined. Ability to persevere and maintain one’s essential traits and sense of self while also growing stronger, wiser, and more capable is what we mean when we talk about resilience. The approach itself is not revolutionary. Through the promotion of local genetic adaptation, the generation of spatial and temporal heterogeneity, the maintenance of local biodiversity, and the development of an ecosystem that is more resistant to future shocks, researchers studying ecological resilience are identifying the self-organizing processes that create self-regeneration and natural regeneration. Researchers have used this term to explore the intricate connection and tactic of resilience and crisis preparedness by, for example, looking at resilience antecedents in different settings. For concepts and resilience in particular, the close proximity of their nodes and the thickness of their connecting lines indicate a high degree of cooccurrence. In addition, the keywords in cluster 1 are spread out more than in any other cluster, as shown by the distribution of nodes. The dispersed nature of the research hubs in this cluster reflects the breadth of the topic of resilience and crisis preparedness in the context of interpersonal relationships (Andrianu, 2020; Calvente & Smicker, 2019).\n\nCluster 2 (orange region) represents team-related research on resilience and crisis preparedness. Cluster 2 consists of six keywords: trust, project team resilience, evidence, signature strength, creative problem, and project management. Compared to Cluster 1, this cluster has a shorter distance between nodes and a relatively close network connection, indicating that research on team resilience and crisis preparedness is relatively concentrated. According to the distribution of keywords in Cluster 2, the research hotspots for resilience and crisis preparedness in the field of teams include trust, project management, and creative problem solving, among others. Among them, regarding the study of strategy, some scholars propose the team’s core (Figure 6: Term co-occurrence map network visualization). It is interesting to note Cluster 2’s keyword strategy, which is central and close to Cluster 1 (relationships). Moreover, the frequency of project team resilience is relatively high, making it one of the research hotspots in the field of teams. It is reasonable to conclude that the resilience of project teams is correlated with trust in a cluster of teams (Pavez et al., 2021; Carmeli et al., 2021; Chapman et al., 2020).\n\nCluster 3 (region in light blue) represents resilience and crisis preparedness research in the field of project management. Cluster 3 contains nine keywords, including influence, challenge, strategy, project, success, competency, leadership, and project success. Compared to other clusters, the nodes in Cluster 3 are relatively close, with the exception of influence, and the connecting lines between some nodes are relatively thick, such as the connecting lines between project manager and competency and project manager and leadership, indicating that the research on resilience and crisis preparedness in the field of project managers is less scattered and more focused, and that the keywords are closely related. Focusing on the distribution of keyword nodes in Cluster 3, the resilience and crisis preparedness research hotspots in the field of project management centre on competency and leadership. Concerning a project manager’s research, organisational crises are low-probability, high-impact events that undermine an organization’s competitiveness and sustainability. It is a managerial and leadership responsibility to design and implement an organisational framework capable of dealing with these traumatic events (Carmeli et al., 2021; Aruta, 2021; Douglas, 2021).\n\nCluster 4 contains nine keywords: leader in disaster management, climate change, responsibility, risk, disaster resilience, sense, flood, flood disaster, Malaysian city. Compared to the first three clusters, the keywords surrounding vulnerability in cluster 4 are relatively concentrated, the distance between them is relatively close, and the connecting lines are relatively longer, such as vulnerability and flood, as well as flood crisis, indicating that the research hotspots of resilience and crisis preparedness in the field of vulnerability exhibit the characteristics of concentration and general dispersion. This cluster contains one of the largest numbers of keywords, indicating that the research on resilience and crisis preparedness in the field of vulnerability spans a broad spectrum and that the research hotspots are relatively concentrated and focused on vulnerability (Crosweller & Tschakert, 2021; Karki, 2019; Hickman, 2018).\n\nCluster 5 (brown region) represents resilience and crisis preparedness research conducted within the concept domain. Cluster 5 consists of ten keywords, including project resilience, lack, conceptual framework, disruptive event, project agility, comparative analysis, linearity, crisis subjectivity, multiple levels, and vulnerability management. Compared to other clusters, the nodes in cluster 5 are relatively distant from one another, with the exception of project agility, disruptive events, and project resilience, and the connecting lines between some nodes are relatively thinner, such as the connecting lines between lack and multiple level, indicating that the research on resilience and crisis preparedness in the field of concepts is relatively dispersed and less focused, and that the connection of keywords is less closely related. Focusing on the distribution of keyword nodes in Cluster 5, the research hotspots of resilience and crisis preparedness in the field of concept are centred on the adaptability of the project (Shenhar & Holzmann, 2017; Calvente & Smicker, 2019).\n\nCluster 6 (green region) represents resilience and crisis preparedness research in the preparedness field. Nine keywords are included in Cluster 6: perception, COVID-19, exposure, crisis preparedness, organisational preparedness, higher level, difference, organisation, and construction industry. Compared to the first five clusters, the keywords surrounding measure in cluster 6 are relatively dispersed, and the distance between the keywords surrounding them is relatively short, such as stress, mental health, and factor, indicating that the research hotspots of resilience and crisis preparedness in the field of measure exhibit partial concentration and general dispersion. Despite the fact that crisis experience and technical risk in an industry were not the most significant predictors of crisis preparedness, high-performing organisations reported greater levels of crisis preparedness (Carmeli et al., 2021; Carmeli & Schaubroeck, 2008; Labaš, 2017). Crisis-prepared organisations are perceived to be more capable of forecasting, recognising, managing, and making effective decisions during times of crisis (Asheim et al., 2020). Therefore, crisis preparedness within an organisation is strategic and has a substantial impact on the organisation. In contrast, highly successful organisations are crisis-ready to a significant degree (Mokline & Ben Abdallah, 2021; Chen & Zhang, 2021; Bardoel & Drago, 2021; Andrianu, 2020).\n\nCluster 7 (the purple region) represents resilience and crisis preparedness research in the measurement field. Eight keywords are included in Cluster 7: factor, workplace, mental health, depression, stress, tradesman, psychological distress, and self. Compared to the first six clusters, the measure keywords in cluster 7 are relatively concentrated, the distance between them is relatively close, and the connecting lines are relatively thick and long, such as mental health and psychological distress, indicating that the resilience and crisis preparedness research hotspots in the field of measure exhibit the characteristics of concentration and high co-occurrence. In the field of measurement (Asheim et al., 2020), the research hotspots for resilience and crisis preparedness are stress, psychological distress, and mental health. This is well supported in the findings by Miller-Graff (2022), Nwaogu et al. (2022), First & Houston (2022), Nwaogu et al. (2021) and Aruta (2021).\n\nCluster 8 (yellow region) represents research in the field of entrepreneurship pertaining to resilience and crisis preparedness. There are nine keywords in Cluster 8: business success, entrepreneur, entrepreneurial success, organisational crisis preparedness, persistence, disaster preparedness, guidance, training, and conceptualization. Compared to the first seven clusters, the keywords surrounding entrepreneurs in cluster 8 are relatively concentrated, the distance between the keywords surrounding them is relatively close, and the connecting lines, such as training and guidance, are relatively thick, indicating that the research hotspots of resilience and crisis preparedness in the field of entrepreneurship exhibit concentration characteristics. In the field of entrepreneurship, the research hotspots for resilience and crisis preparedness are organisational persistence and crisis preparedness (Renko et al., 2021; Anwar et al., 2021; Mokline & Ben Abdallah, 2021; Smith et al., 2022; Fisher et al., 2016; Matin & Taylor, 2015).\n\nFigure 7 is a visual representation of the co-occurrence map overlay. VOSViewer analysed 55 papers on crisis resilience and preparedness, with co-occurrence of terms determining the size of the circle. Using the icon in the lower right corner, the colours of the circles represented the average frequency of the study. The distance between circles indicates their interconnectedness. The thickness of the connecting lines indicated the degree of co-occurrence between two terms. The various hues of the circles represented clusters separated by co-occurrences. The area of each circle indicated the frequency with which each term occurred. Visualization of term co-occurrence map overlay illustrates the evolution of research domains and identifies potential hotspots and frontiers, such as vulnerability and risk, leadership, and emotional intelligence, among others. This laid the foundation for future scholarly inquiry.\n\nFigure 8 is a density visualisation graph generated in order to gather additional information about these keywords. Similar to the network visualisation, items are indicated by their label in the item density display. Each point on a map is coloured based on the item density at that location. This colour is midway between yellow and blue by default. When a point’s colour is closer to yellow, more objects are located near it, and the objects’ combined weights are larger. On the other hand, the closer a point’s colour is to blue, the fewer objects there are in its vicinity and the lighter their weights. The keywords Project Manager, Competency, Relationship (interpersonal), Risk & Vulnerability, Concepts, Preparedness, Measure, and Entrepreneur are highly densely concentrated, indicating a close relationship between these This figure was extracted from the VOSviewer, which do not need permission.keywords and other keywords. And it is acceptable to conclude that the higher the density, the more mature and thoroughly developed the theme’s research (Hu and Zhang, 2015). However, we could not overlook the fact that there are fewer terms in the yellow area than in the blue-green area. It is revealed that there are fewer fundamental research domains on organisational crisis preparedness, leadership (disaster management), failures and that many of these disciplines are underdeveloped.\n\nTable 1 shows the results of counting how often the 25 most frequently occurring keywords occurred within the context of resilience and crisis preparedness research.\n\n\nDiscussion\n\nThe above systematic review and bibliometric analysis highlight a few potential research hotspots from eight (8) clusters, and the following factors shape the project manager’s crisis resilience: Determinant 1 of leadership (individual resilience, influence, team trust, emotional intelligence), determinant 2 of agility (proactive, coping capacity, adaptive capacity), determinant 3 of interpersonal skill (conflict management, persistence, crisis preparedness), and determinant 4 of risk management and vulnerability (perception, awareness).\n\nSome of the most important skills for a project manager to have are leadership (Moradi et al., 2020; Alvarenga et al., 2019); transformational leadership (Fareed et al., 2021); and soft skills (Moradi et al., 2020). Construction projects are at risk of failing when led by incompetent managers. The failure or poor performance of construction projects is often attributable to a lack of a visible project manager and the management of relationships with team members and stakeholders (Kapogiannis et al., 2021). This was empirically shown to be the case in Indonesia, where the success of complex projects was directly tied to the transformational leadership and soft skills of the project managers overseeing them (Rogo et al., 2020). Poor leadership is the main cause of the failure of 80% of Pakistan’s projects, say Fareed et al. (2021). Furthermore, their data shows that a balance of IQ and EQ is essential for project success. Additionally, public sector project success is greatly influenced by transformational leadership. A study by Moradi et al. (2020) used Norway and Finland as test cases and argued that there is currently very little research-based knowledge on different environments that appear to require certain types of competencies from project managers; this reflects the maxim that “one size does not fit all.” To a large extent, the situation in Poland is similar, as Podgórska & Pichlak (2019) have remarked. They went into depth about the findings’ empirical support for the impact of the project manager’s leadership competencies and emotional and managerial skills on the project’s success. Furthermore, they argued that the results analysis proved that different competencies are required for the success of different projects. Based on empirical evidence, it has been established that a project manager’s direction is crucial to an organization’s success, especially in highly fluid settings. Research by Alvarenga et al. (2019) and others in Brazil confirms the rising importance of soft skills and underlines the importance of expanding project knowledge and bridging the gap between theory and practice. The studies that investigate the link between a project manager’s leadership and the outcome of the project cover a wide range of projects and place special emphasis on the conditions under which this link is formed, particularly in economies that are still developing.\n\nWhen it was first published in 2001, the Agile Manifesto for Software Development advocated for swift and simple approaches to developing software (Conforto et al., 2016; Hobbs & Petit, 2017). When compared to the waterfall method, which places an emphasis on the sequential completion of project phases, the Agile methodology still stands as the most practical alternative when managing software projects. For instance, there’s requirement gathering, then development, testing, and finally deployment (Hobbs & Petit, 2017). Since its inception in 1995 (Hobbs & Petit, 2017), SCRUM has grown into one of the most widely used agile development frameworks. Lean, Kanban, and Extreme Programming (XP) are a few other frameworks out there. Agile software development is an evolutionary (iterative and incremental) method that uses a value-driven life cycle to reliably deliver high-quality, low-cost, and on-time software (Ambler, 2009). Stakeholders play an integral role in this process, which is carried out in a highly collaborative, disciplined, and self-organizing manner to guarantee that the team fully grasps and satisfies the stakeholders’ ever-changing requirements. By adjusting their rituals to the specifics of the situation, agile software development teams are able to produce consistent results (Ambler, 2009). It wasn’t long after the Agile Manifesto was published in 2001 that the term “Agile” began to appear in a wide variety of project management literature. In spite of this, the vast majority of studies on the subject remain focused on the software engineering sector (Hobbs & Petit, 2017).\n\nAfter reviewing the literature on the topic, Conforto et al. (2016) concluded that “definitions of agility found in the project management (PM) and agile project management (APM) disciplines are inconsistent, incomplete, and lack clarity” (Conforto et al., 2016). Researchers analysed 171 projects and identified this management concept as “the project team’s ability to rapidly modify the project plan in response to customer or stakeholder needs, market or technology demands in order to achieve better project and product performance in an innovative and dynamic project environment” (Conforto et al., 2016). This definition clarifies a number of points. Agility is typically viewed as a talent at first (or a quality). The second is that the project team is the most crucial part of the whole, while the project plan is the one that needs the most tweaking. Agility, in sum, necessitates a shift in response to the needs of customers or stakeholders, or the demands of the market and technology, and this shift need not be a disruptive one. On the other hand, Rahi (2019) argues that agility is more about responsiveness (actions taken during or after a disruptive event occurs) than proactiveness (activities undertaken before a disruptive event occurs). It stresses adaptability to change quickly, especially in response to the requirements of stakeholders and customers. Risks that may arise as a result of catering to the wants and needs of customers and other stakeholders are already implicitly addressed by agile methods. When it comes to risk management, agile approaches tend to gloss over crucial details like the creation of rules and processes, mitigation plans, risk repositories for keeping track of hazards, and so on. This demonstrates how Agile systems don’t have any failsafes built in.\n\nEven with these advances in the idea of agility, there are still many other research avenues to explore. It would be interesting, for instance, to look into how agility could be used on massive undertakings. In fact, agility has proven useful for small projects because the client can actively participate in making adjustments and has a close personal connection to such endeavours (may be physically present). On the other hand, “there are a number of barriers to scaling these processes (Agile practises) in large multi-site, multi-customer, and multi-project businesses,” as Hobbs and Petit (2017) put it. This point of view is often disregarded in the academic literature. Investigating how to apply enterprise-level agility to projects is another fascinating area of study. Consultancy firms have developed a plethora of frameworks for just this purpose (Hobbs & Petit, 2017). Although other frameworks [including Agile Scaling Model (ASM) and Disciplined Agile Deliver (DAD)] do exist, Scaled Agile Framework (SAFe) has seen the most widespread adoption. To help businesses expand their use of Agile methods beyond a single project team, this framework compiles best practises for doing so. Its purpose is to ensure that organisations can continue to reap the benefits of Agile practises (Leffingwell, 2015). Agile principles are great for smaller projects, but Leffingwell (2007) points out that it’s incredibly difficult to implement them at a large organisation. There are two main types of difficulties. The main problem stems from the principles of the Agile methodology (e.g., difficulty of continuous involvement by the client, difficulty of analysing needs and demands, etc.). Second, there are internal factors that work against introducing new approaches like Agile, such as a conservative company culture and an aversion to change. As the company continues to expand, this idea must be refined and developed further to ensure its agility.\n\nIn conclusion, from a project management perspective, focusing solely on agility could make a project vulnerable (Rahi, 2019; Rahi et al., 2021) because events outside the scope of customers’ and stakeholders’ expectations as well as market and technology demands can interrupt a project. Consequently, it would be intriguing to investigate new avenues that focus on coping with disruptive events and enhancing a project’s capacity to manage occurrences that may cause it to deviate from its primary objectives. These paths illustrate the objective of this research, which is to make projects more robust. It is evident that current project management methodologies and the knowledge and skills of project managers are insufficient to contribute to crisis events in a vulnerable environment. Consequently, it is essential to equip project managers and project team members with the resilience and preparedness skills necessary for the success of projects locally and globally, especially crisis recovery projects (Amaratunga et al., 2018; Chang-Richards et al., 2017). Adaptive resilience (Shenhar & Holzmann, 2017), professionalism, project managers’ crisis resilience (Bowers et al., 2017), and preparedness (Staupe-Delgado & Kruke, 2017; Bowers et al., 2017) would be great additions to disaster risk reduction and resilience capacity development procedures, particularly for project managers who will manage high-stress, complex, and dynamic vulnerable environment projects (Pavez, Gómez, Laulié, & González, 2021; Ismail, Majid, Roosli, & Samah, 2014; Ismail, Majid, Roosli, & Samah, 2014). The built environment stakeholders in New Zealand (Chang-Richards et al., 2017) and the UK (Amaratunga et al., 2018) both agreed that the main deficiencies were crisis resilience and preparedness, skill, and knowledge. Observations and extensive research conducted in developed countries indicate a lack of crisis resilience and preparedness. There is an immediate need to shift the paradigm from disaster recovery and response to crisis preparedness (Whittaker, Khalfan & UlHaq, 2020). From the available literature, it is worthwhile to investigate crisis resilience and preparedness awareness in the context of project management professionals.\n\nPodgórska and Pichlak (2019) claim that there is a growing body of uncertainty about what constitutes competence in project management due to the fact that researchers and professional bodies have developed a patchwork of knowledge in this area. According to their findings, a project manager’s competency outline is made up of 81 different skills and traits spread across 11 different categories, including the ability to persuade and communicate effectively, as well as to manage projects effectively and professionally, and to have a firm grasp of the ins and outs of project management (Podgórska & Pichlak, 2019). In each phase of the project life cycle, interpersonal/communication, leadership, and dedication are the most important skills (Bowers et al., 2017; Alvarenga et al., 2019). To manage and enable the completion of the complex task, which was based on a layer of systems integration, it was necessary to communicate and coordinate with a large number of diverse stakeholders whose interests and priorities varied (Alvarenga et al., 2019; Shenhar & Holzmann, 2017). Its success was built on a clear vision, inspiring leadership, and well-managed project communication and documentation procedures (Bowers et al., 2017; Alvarenga et al., 2019). The ability to interact with other teams or members of the organisation or project is primarily required to improve the project manager’s skills (Kapogiannis, Fernando, & Alkhard, 2021). This engagement enhances communication and collaboration (Alvarenga et al., 2019) and fosters trust (McLaren & Loosemore, 2019; Kapogiannis, Fernando, & Alkhard, 2021) between the project manager and the teams. In addition, by enhancing and developing the aforementioned critical factors, the acquisition of relationships will be facilitated and efficient (Kapogiannis et al., 2021).\n\nThere are always things that could go wrong with a project, but there are also things that could go right, and these are what we call risks and opportunities, respectively (Project Management Institute, 2017; Ward & Chapman, 2003). Therefore, the primary goal of risk management from the perspective of project management is to lessen the impact of undesirable risks while making the most of desirable risks in order to accomplish project goals (Chapman & Ward, 2007; Project Management Institute, 2017). There are two main schools of thought when it comes to assessing risk, and they are what Zhang (2011) refers to as the “risk as an objective fact” school and the “risk as a subjective construct” school. There is a school of thought in risk assessment known as “Risk as an Objective Fact,” which maintains that potential harm exists apart from how people feel about it. The process of identifying, assessing, mitigating, and controlling risks is conducted in accordance with scientific methodologies and transparent procedures (Zhang, 2011). Therefore, we can classify the outcomes of using this strategy for risk management in two ways. Without caring about what the stakeholders think, the first group approaches the project as a system with well-defined goals. As a result, reasonable and systematic risk management processes and methodologies are put into place to deal with the evidential and empirical results of dangers (e.g., the works of Baccarini, 1996; Huchzermeier & Loch, 2001; etc.). Those who hold the view that risk management is a matter of opinion form the second camp. So, people can have varying reactions to the same real-world risks. Factors such as the individual’s background, skillset, and knowledge, as well as psychological and institutional contexts, strongly impact the effectiveness of one’s chosen approach (Ward & Chapman, 2003; Zhang, 2007). Because “uncertainty management is not only about managing perceived threats, opportunities, and their implications,” the approach described by Ward and Chapman (2003), which focuses on managing uncertainty rather than risks, is one of the most important ways to address this type of risk. It necessitates an awareness of, and strategy for dealing with, the myriad of uncertainties that combine to form our individual risk and reward assessments (Ward & Chapman, 2003). The “Risk as a Subjective Construct” school of risk analysis argues that individuals’ perceptions of risk are fundamentally flawed. Individuals recognise threats and devise countermeasures based on their own assessments. In addition, people who experience the world in vastly different ways may select and implement various risk management strategies. As a result, the interplay between causes and effects makes it easier to spot and assess potential dangers (Zhang, 2011). Kutsch and Hall (2005) provide a clear explanation of this viewpoint (“risks as a subjective construction”), which holds that project stakeholders fail to logically recognise risks because they ignore, deny, or avoid them. Ignorance, denial, and avoidance are all linked to external factors that affect how project stakeholders view risks, the efficacy of measures taken to mitigate those risks, and the ultimate success of the endeavour. The concept of vulnerability was first developed in the social sciences, but it has since found use in other disciplines, including economics, information systems, organisational management, politics, and project management (Crosweller & Tschakert, 2021; Podgórska & Pichlak, 2019; Zhang, 2007).\n\nFüssel and Klein (2006) distinguished three major models for conceptualising and defining vulnerability: (1) the “risk-hazard framework,” in which vulnerability represents the relationship between hazard and its detrimental effects on a system; (2) the “social constructivist framework,” in which vulnerability is a prior condition of a system determined by socio-economic and political factors; and (3) a school of thought that views vulnerability as a system function. In his analysis of vulnerability as a re-definition of the project risk process, Zhang (2007) looks to the third school of thought in project management, as presented by Füssel and Klein (2006). He shows the vulnerability of a project from two angles: exposure and capacity. The first dimension is the effect of organisational activities on the occurrence of risk events. According to the second dimension, a project’s susceptibility lessens as its ability to deal with risk events grows. An improvement in risk management is possible through an understanding of vulnerability. To better explain and clarify, “this procedure ignores the layered interactions and feedback between risk events and project systems” (Zhang, 2007). The susceptibility of a project to causing interruptions is what is meant by the term “vulnerability” (Vidal & Marle, 2012; Zhang, 2007). As a result, the presence of threats is not necessary for the existence of vulnerabilities. A weakness in a project could be that there isn’t enough capable people to finish it. It’s possible that this weakness will result in lower output. Thus, a vulnerability (“lack of skilled personnel”) can cause a risk (“poor-quality work”) to materialise, but a vulnerability does not automatically result in a disruptive occurrence (a risk that actually materialized). That is to say, the less susceptible a project is to disruptions, the longer it will last. On the other hand, the greater the project’s vulnerability, the greater the likelihood that it will be negatively affected by disruptions (Aleksic et al., 2017; Zhang, 2007). Vulnerability is defined as “the characteristic of a project that makes it susceptible to being subject to negative events and, if they occur, that makes it incapable of coping with them, thereby allowing them to degrade the project” by Vidal and Marle (2012), who build on Zhang’s (2007) work and perspective on the concept of vulnerability. They also proposed a four-stage process for managing project vulnerabilities, including vulnerability identification, analysis, the creation of a response plan for dealing with vulnerabilities, and vulnerability monitoring and control. Zhang’s (2007) approach is improved by the vulnerability perspective of Vidal and Marle (2012). Vulnerability, from Zhang’s point of view, is any aspect of a project that leaves it open to being negatively impacted by outside forces. Additionally, resilience to disruptive events is correlated with project vulnerability. Factors’ ability to adapt to and recover from disruptions are therefore vulnerable. Another author, Proag (2014), said something along these lines: “the concept of vulnerability indicates a measure of risk associated with the physical, social, and economic components and repercussions stemming from the system’s capacity to respond to the ensuing crisis” (Proag, 2014).\n\n\nLimitations\n\nThis investigation has several limitations. For instance, the selection of journals to represent the crisis-resilient scholarly output is one of them. In addition to journals, crisis resilience knowledge can also be disseminated through books, conference papers, and book chapters. Also, it is important to remember that, because crisis resilience transcends disciplines and fields of study, articles pertaining to crisis resilience are published in journals that do not specialise in crisis resilience (e.g., sociology, anthropology, geography, marketing, etc.). In addition, this study focuses on only nine non-English-speaking systems (German, Spanish, Russian, Croatian, French, Norwegian, Turkish, Afrikaan and Russian), which are not representative of other non-English-speaking countries.\n\n\nConclusion and future research\n\nThe Project Manager witnessed an astonishing panorama of crisis resilience throughout the incident (Karlsen & Berg, 2020). Individuals must make important decisions about whether to resist, absorb, adapt, or recover quickly after a disaster. Individuals’ preparedness and awareness (StaupeDelgado & Kruke, 2018; Sutton & Tierney, 2006), risk management (Imperiale & Vanclay, 2021), vulnerability knowledge (Füssel & Klein, 2006), as well as disaster management skills and leadership, all have an impact on how effectively they discover and recover from a disaster (Crosweller & Tschakert, 2021; Rahi et al., 2021). Understanding the evolution of multidimensional resilience research, from individual resilience to community resilience, is critical at both the individual and community levels (Kapogiannis et al., 2021; McLaren & Loosemore, 2019; Mokline & Ben Abdallah, 2021; Tasic et al., 2020; Thibodeaux, 2021). This review was conducted to assess the breadth and depth of the crisis resilience preparedness variables. The study patterns were also examined in order to provide the most comprehensive perspective on the dynamic complexities of crisis resilience. The limitations of this review, like those of other studies, are unclear. The lack of empirical research into the relationship between project success and its variables limits this study. The main components of this study are a PRISMA-based systematic review and bibliometric analysis of previous studies on crisis preparedness and resilience. Future research could look into how to measure or identify indicators of project management competency indices related to crisis resilience and preparedness.",
"appendix": "Data availability\n\nZenodo: Preparedness for Contingencies: A Systematic Review of the Factors that Influence the Crisis Resilience of Project Managers, https://doi.org/10.5281/zenodo.7519157 (Kok et al., 2022).\n\nThis project contains the following underlying data:\n\n• combined scopus (all)280522.csv\n\nZenodo: Preparedness for Contingencies: A Systematic Review of the Factors that Influence the Crisis Resilience of Project Managers, https://doi.org/10.5281/zenodo.7519157 (Kok et al., 2022).\n\nThis project contains the following extended data:\n\n• PRISMA checklist.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\nI am extremely appreciative to Dr. Khalil Rahi, Assistant Professor at Abu Dhabi University, United Arab Emirates, for his consistent direction and assistance.\n\n\nReferences\n\nAleksic A, Puskaric H, Tadic D, et al.: Project management issues: vulnerability management assessment. 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}
|
[
{
"id": "173995",
"date": "26 May 2023",
"name": "Mohammad Ichsan",
"expertise": [
"Reviewer Expertise Project management",
"Operations Management",
"Resilience and sustainability"
],
"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\nIn general this paper is interesting and well structured. I would recommend that the PRISMA Structure is also explained in the section 'Results', so we can see how the articles are filtered from 1494 to 45, as I am curious to see how the articles are extremely reduced.\nAside of the qualitative analysis, I would love to see literature review as a basis of concept of the phenomenon highlighted in these research.\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? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-158
|
https://f1000research.com/articles/12-157/v1
|
10 Feb 23
|
{
"type": "Research Article",
"title": "Socio-demographic correlates and trends in the timing of the onset of parenthood among women of reproductive age in Ghana: evidence from three waves of the demographic and health surveys",
"authors": [
"Ololade Julius Baruwa",
"Yaw Acheampong Amoateng",
"Yaw Acheampong Amoateng"
],
"abstract": "Background: Childbearing is one of the central events in a woman’s life and the age at which this event occurs has important health, socioeconomic and fertility implications for her.\n\nMethods: We used three waves of the Ghana Demographic and Health Surveys (GDHS) from the individual files of married women aged 15 to 49 years old to explore the trends in the timing of the onset of parenthood among women in Ghana. The Cox proportional hazard model was used to assess the effect of socio-demographic factors on the birth experience of women.\n\nResults: Results showed the median age of the women increases from 17 years in 1998 to 19 years in 2014. Further, results showed that women with secondary education had 0.67, 0.89- and 0.77-times lower hazard risk of early birth than women without any formal education in 1988, 1998, and 2014 respectively. The hazard risk of early childbirth consistently decreased as age increased in all the years of surveys except in the case of the age group 40-44 in 1988, 1998 and 2014.\n\nConclusions: This study showed that the timing of first childbirth is changing in the direction of a late childbirth regime in Ghana and could facilitate improvement on individual health, job stability and higher level of education. Efforts should be channeled to sensitizing women on the importance of delaying childbearing.",
"keywords": [
"onset of parenthood",
"sociodemographic",
"childbearing",
"Ghana",
"Demographic and Health Surveys",
"Cox proportional hazard Women"
],
"content": "Introduction\n\nChildbearing is one of the central events in a woman’s life course and the age at which this event occurs has important health, socioeconomic and fertility implications for her. For instance, the age at which a woman has her first birth is a risk factor for poor maternal health throughout the life course (Schiücker and Blumenfelder 2014; Blanc, Winfrey, and Ross 2013). Childbearing at adolescence may also lead to physiological dysfunctions that may lead to chronic diseases and physical disability in later life (Cho et al. 2012). In settings where resources are limited, early age at first birth has been associated with higher maternal mortality (Gupta and Mahy 2003) and has adverse effects on child health and child survival because of low birth weight and pre-term births which lead to infant mortality (Wendt et al. 2012; Gibbs et al. 2012). Other reported effects of early age at first birth are truncated education which has ramifications for the socioeconomic wellbeing of women and their children (Akella and Jordan 2015; Leung, Groes, and Santaeulalia-Llopis 2016; Gibbs et al. 2012; Jutte et al. 2010).\n\nBecause of the above-mentioned effects and implications of the timing of first birth, the existing literature is replete with studies examining the problem of how social, economic, and demographic conditions impact the way in which women have their first child in both developed and developing societies (e.g. Aksan 2014; Ayiga 2015; Bongaarts and Ann 2015; Gibbs et al. 2012; Karabo and Ayiga 2014; Rabbi and Kabir 2013; Statistics South Africa 2015; Tadesse 2014; Takyi and Addai 2002). In Ghana, there is strong evidence that age at first birth has a strong impact in explaining the fertility of contemporary cohorts. That is, the timing of the first birth is essential in determining the completed fertility among Ghanaian women (Obeng Gyimah 2003). Recent evidence shows that fertility transition is notable in Ghana. For instance, the 1988, 1998 and 2014, Ghana Demographic and Health Survey (GDHS) statistics shows that the median age at first birth increased from 17 in 1988 to 19 in 2014. However, as the brief review of studies has clearly shown, studies that look at the socio-demographic trend in the timing of first birth are almost non-existent. Invariably, almost all the studies on timing of first birth have been examining the problem at a single point in time, ignoring the question of trend over time. Although a previous study in Ghana reported that more than half (51.4%) of women of reproductive age have given birth at the age of 19 (Amoateng 1991) while another study revealed the median age at first birth in Ghana is 20 years (Obeng Gyimah 2003). However, these studies are rather too old (Amoateng 1991; Obeng Gyimah 2003). Besides, evidence linking the sociodemographic factors of women and timing of age at first birth over a period is lacking in Ghana.\n\nIt is against the backdrop of the foregoing effects of the timing of first birth that we undertake the present study. The aim of the present study is to examine the effect of selected socio-demographic factors on the age at which women have their first child in Ghana. The present study becomes important in addressing the void in the existing body of knowledge, the study goes beyond these existing studies by using three waves of the demographic and health survey data on Ghana to examine trend in age at first birth. Consistent with the study’s aim of examining change over time, we use a process-oriented theoretical framework-the family life course perspective to examine trends in the timing of first birth over three waves of the Ghana Demographic and Health Survey data.\n\nThe present study used the Life Course Theory, theorized by Glen Elder (Elder, 1998). The Life Course Theory helps in understanding how the individual interfaces social institutions (e.g., education, economy, occupation, place of residence etc.) through rational choices as he/she goes through life. The theory directs attention to the powerful connection between individual lives and the historical and socioeconomic contexts in which these lives unfold. As a concept, a life course is defined as “a sequence of socially defined events and roles that the individual enacts over time” (Giele and Elder 1998). Since a household is basically a confluence of people at different points in their life courses, age becomes a crucial factor in the analysis of family change because the cumulative experiences of these individuals help to define the family as a social institution (De Vos 1995).\n\nThe life course perspective emphasizes the importance of time, context, process, and meaning on human development and family life (Bengtson and Katherine 2009), while the family is perceived as a micro social group within a macro social context. The life course reflects the intersection of social and historical factors with personal biography and development within which the study of family life and social change can ensue (Elder 1998).\n\nIn most developing countries, especially in sub-Saharan Africa, where early childbirth is common, there has been visible transition in this pattern of family building as a result of modernizing influences such as urbanization and education (Gibbs et al. 2012), and improvements in child health and survival (Aksan 2014). The existing literature is replete with studies that have identified the effects of education and urbanization on the age at which women have their first child. For example, a study found that lack of education or low education does not only lead to early marriage, but it also impedes access to contraception leading to unintended pregnancy and thus early age at first birth for women (Bongaarts and Ann 2015). On the other hand, better educated women initiate childbearing at older ages, mainly because education delays age at first birth since being in school is not compatible with childbearing (Karabo and Ayiga 2014). Moreover, education increases age at first birth through engendering favorable attitudes towards and uptake of contraception.\n\nPlace of residence has also been found to be a predictor of age at first birth through its indirect influence on the age at first union (marriage or cohabitation) and ease of access to contraceptive use by sexually active women in urban areas. Existing studies in sub-Saharan Africa suggest that the age at marriage is early in rural areas because the return to education, an important factor that increases age at birth is low in rural areas (Tadesse 2014), while the relative lack of access to contraceptives in rural areas increases the risk of early pregnancy and childbearing (Ayiga 2015). In South Asia, where the age at first birth is early (less than 18 years), Rabbi and Kabir (2013) observed that it was also attributable to the early age at marriage and poor access to contraceptives in rural areas.\n\nBesides education and urban living, life course events such as changes in the age at marriage have been observed worldwide as one of the important proximate determinants of age at first birth (Gupta and Mahy 2003). For example, the generally early age at first marriage regime in sub-Saharan Africa has been found to be a factor influencing the high fertility rates in these countries since childbearing begins soon after marriage and continues for a long time thereafter (Khan et al. 2008). Conversely, if marriage occurs at an older age, the age at first birth will also be much higher (Chung et al. 2006).\n\nAge at first birth has been found to be affected by socio-cultural factors such as religion, ethnicity and region of residence. As far as religion is concerned, some studies have found that women who subscribe to a more pro-natalist religious doctrine, i.e. religions that reinforce family values and prohibit contraception or abortion such as Catholicism, are more likely to have earlier first births (McQuillan 2004). However, in a study of Ugandan women aged 15-49 years old, Mugarura, Kaberuka and Atuhaire (2016) found religion to be an important determinant of age at first birth. They found that Muslim women were 1.67 times more likely to give birth at an early age compared to Catholic women, Pentecostal women 1.49 times more likely to have an early birth compared to Catholic women, and Seventh Day Adventist (SDA) women 1.8 times more likely to have a child at an early age compared to Catholic women.\n\nIn Tanzania, Ngalinda (1998), found that Muslim women were more likely to get their first child earlier than any other religious denomination in Tanzania (Ngalinda 1998). However, unlike many previous studies, Ngalinda (1998) found Catholic women in Tanzania to have a higher mean age at first birth (18.6 years) compared to Protestants (18.5 years). However, this is contrary to findings by Logubayom & Luguterah (2015) who found that religious affiliation was not a significant determinant of Ghanaian women’s waiting time to first birth. In terms of region, the Ghana Statistical Service (2009) found that the median age at first birth across regions showed earlier first births for women in Northern Ghana (i.e., 19.5 years in the Upper East and Upper West regions) compared to their Southern counterparts (e.g. 23.2 years in Greater Accra).\n\nEthnicity which reflects an individual’s cultural background has been found to be associated with reproductive decisions or family formation, although its effects on age at first birth has not received much attention in the literature. In Nepal, ethnicity was found to have large impact on early motherhood (Choe, Thapa & Mishra 2005), while in Ghana, Takyi and Addai (2002), using data from the early 1990s, did not find ethnicity to be an important predictor of family formation in Ghana. Using Census 2011 data and language as a proxy for ethnicity in South Africa, it was found that Xhosa, Zulu, SiSwati, Tshivenda and Tsonga speaking women aged 45–49 had a lower median age at first birth compared to English speaking and Afrikaans speaking women (Statistics South Africa 2015).\n\nTo the best of our knowledge of the existing literature, there are no studies conducted on the socio-demographic factors of the timing of age at first birth in Ghana. However, the availability of several DHS in Ghana conducted between 1988 and 2014 provides us with an opportunity to use these data sets to examine trends in age at first birth in Ghana. Therefore, the aim of the present study is to examine the effect of selected socio-demographic factors on the age at which women have their first child in Ghana.\n\n\nMethods\n\nThe present study employs data from the Ghana Demographic and Health Surveys (GDHS) from the women individual files of ever married women aged 15 to 49 years old for the survey periods 1988, 1998 and 2014 (4481, 4843 and 9396 respectively). There is no methodological or substantive reason why the present analysis is limited to only three out of the six waves of the survey other than the fact that we try to look at the trends that have occurred with an interval of at least 10 years. Ten years is the benchmark the United Nations has set in the decennial census programme as it is considered long enough to measure changes in both the independent and outcome variables.\n\nData collected across the three surveys included background characteristics such as education, ethnicity, religion, place of residence, region of residence, age at first sexual intercourse, age at first marriage or cohabitation, age at first birth, marital duration, total number of children ever born, health service providers, communities, household health expenditures of women as well as information on young adults.\n\nThe outcome variable for this study is onset of parenthood (age at first birth), while the explanatory variables of interest are variables that have been found to be associated with age at first birth. These explanatory variables include age (measured as 15-19, 20-24, 25-29. 30-34, 35-39, 40-44, and 45-49), place of residence (measured as rural and urban), ethnic group (measured as Akan, Ga-adangbe, Ewe, Guan, Mole-dagbani, and other), education (measured as no education, primary, secondary, and tertiary), marital status (measured as never married and ever married), religion (measured as no religion, Catholic, other Christian, Muslim and traditional), region (measured as western, central, greater/Accra, Eastern, Volta, Ashanti, B/A and northern.\n\nThe GDHS used a two-stage sample design and was intended to provide estimates of key indicators at the national, urban, and rural levels, as well as for each of Ghana’s ten administrative regions. The first step was to select sample points (clusters) made up of enumeration areas (EAs). The second stage involved systematic household sampling. Even though there were slight variations in the sampling designs over the years, invariably, all the surveys used clusters from which representative samples of women were selected. The EAs consisted of three strata, namely, Coastal Savannah, Forest and Northern Savannah, and within each stratum, urban, semi-urban and rural EAs were identified giving an average of about 400 EAs. The combined effective sample size for the three data sets is 18,727 women aged 15-49 years.\n\nThree questionnaires were used in the GDHS: the Household Questionnaire, the Woman's Questionnaire, and the Man's Questionnaire. These questionnaires were adapted from standard Demographic and Health Survey (DHS) questionnaires to reflect the population and health issues relevant to Ghana. Various stakeholders representing government ministries and agencies, nongovernmental organizations, and international donors were asked to provide feedback on the questionnaires. The final questionnaires were written in English first, then translated into the major local languages of Akan, Ga, and Ewe.\n\nThe women’s questionnaire was used to gather information from all eligible women aged 15-49 years. These women were questioned on the following topics; background characteristics, birth history and child mortality, knowledge and use of family planning, fertility preference, marriage and sexual activities, antenatal and delivery among others. Staff members from the Ghana Statistics Services (GSS) and the Ghana Health Service (GHS) supervised and coordinated the fieldwork. Data collection took place at the respondents’ houses. For 1988 GDHS, data collection and fieldwork began in March and lasted until June 1988. For 1998 GDHS, data collection began in November 1998 and ended in February 1999. For the 2014 GDHS, data collection took place between August and December 2014. The GDHS are mostly self-reported, while the fieldworkers did the data entry.\n\nBefore the commencement of statistical analyses, the data were weighted using the data sampling weight to account for the differentials in the sample design and response rate. A descriptive analysis was conducted using univariate analysis to describe the median age, which gives a better picture of age distribution at first birth and the background characteristics, while Cox proportional hazard model was employed for the multivariate analyses (Cox 1972). In the DHS survey, age at first birth is given as the woman’s age (at her last birthday) at the time of her first birth.\n\nThe Cox proportional hazard model assesses the effect of socio-demographic factors on the birth experience of women in a multiple regression framework. Following Cox (1972), the Cox model is defined as:\n\nWhere the hazard function ht is the dependent variable, which is dependent on a set of p covariates x1x2…xpwhose impact is measured by the size of the respective coefficients b1b2…bp. The term h0 is the baseline hazard, which gives the value of the hazard if all the xi are equal to zero. Empirically, estimating the Cox regression involves the status, time and covariate variables. The status variable is the dependent variable in the regression is a binary response, which is the birth experience of a woman. Therefore, the dependent variable is whether or not first birth has occurred. The responses are coded 0 for those women who indicate that they have never had a child, and 1 for those who have ever been a parent.\n\nIn the present analysis, we disaggregated the result for each survey by year of survey in order to observe the effects of the independent variables on the dependent variables over the period of each survey. The results are presented as hazard risk, showing for example, the relative likelihood of a woman in a given educational category having a first birth compared to a woman with tertiary education that is used as the reference category. A variable has a significant effect on age at first birth if the associated relationship is significant at p<0.05.\n\nThis research utilized secondary information that was collected from 1988, 1998, and 2014 GDHS. Ethical authorization to utilize this information was granted by ICF Macro through the DHS programme site (dhsprogram.org). The DHS fieldworkers were trained on how to obtain informed consent from the participants, and ensured that the participants knew they could withdraw from the survey at any time. Hence, the dataset used in this study doesn’t include identifying or other confidential information about the respondents. In this manner, obscurity and privacy of the study participants were ensured.\n\n\nResults\n\nThe socio-demographic characteristics of women aged 15-49 years are presented in Table 1. The table shows that the distribution of the women by five-year age intervals is a normal bell-shaped curve with a peak at the 20-24 and 25-29 age group in 1988 and thereafter declines monotonically to 45-49 years age group. However, for 1998 and 2014, the majority of the women are 15-19 years of age and the proportion of this age group declines linearly thereafter to age group 45-49. The distribution of women by place of residence shows that although the proportion of women in urban areas increased to 49% in 2014, the women remained predominantly rural residents in all the survey years.\n\nTable 1 also shows an improvement in the overall level of education of the women. For example, the proportions of women with secondary education increased from 7% in 1988 to 52% in 2014, while the proportion of women with tertiary education increased from under 1% (0.9%) in 1988 to 5.5% in 2014. The proportion of married women decreased from 80.2% in 1988 to 67.4% in 2014. Table 1 also shows that in terms of ethnic identification, the most dominant group is the Akan ethnic group and the Guan followed by Ga/Adangbe who constitute the smallest and second smallest ethnic groups respectively in the three surveys.\n\nAs far as religion is concerned, other Christians (Protestants) are in the majority, followed by Catholics, while women who profess traditional religion and women with no religion constitute the lowest proportion. Women who reside in the Ashanti and Northern regions are the majority across the three survey periods. Women in Ashanti region were the highest in 1988 and Northern region in 1998 and 2014. Table 1 also reveals that most women married between the ages of 15-19 years in all the three surveys.\n\nFigure 1 shows the median age at first birth among women. The figure shows that the median age of the women is in a narrow range of 17 to 19 for the three survey years. Overall, the figure shows that trends in the median age at first birth increased by one year between 1988 and 1998 and by one year again between 1998 and 2014.\n\nFigure 2 shows the trends and differentials in median age at first birth by the socio-demographic characteristics of the women. For women in the age group 40-44 years, there was a two-year increase in the age at first birth from 18 years in 1988 to 20 years in 2014. Figure 2 also shows that the median age at first birth was lowest (17 years) among women of the youngest (15-19) age cohorts for all the three surveys.\n\nThere is a positive relationship between the level of urbanization and the timing of first birth in Ghana. For example, there was a gradient increase in the median age at first birth from 19 years in urban areas in 1988 to 20 years in 2014. In rural areas, the median age at firth birth also increased by only one year over the survey period.\n\nAs far as the effect of education is concerned, Figure 2 shows that although the median age at first birth increased from 23 years in 1988 and 1998 among women with tertiary education to 25 in 2014, it remained relatively unchanged for the other educational groups. The differentials in age at first birth by level of education show that age at first birth increased with the level of education except for women with secondary education for whom the mean age dropped from 21 in 1988 to 19 in 1998, and then to 20 years in 2014. Women with no education and primary education had the lowest age at first birth, while women with tertiary education continue to have the highest age at first birth for all the survey years.\n\nAs far as marital status is concerned, Figure 2 shows that the median age at first birth for ever-married women increased marginally by 1 year for each survey year. There was an increase in age at first birth for ever-married women from 19 in 1998 to 20 in 2014. The age at first birth also increased among all ethnic groups between 1988 and 2014. However, as shown in Figure 2, the Ewe and Ga/Adangbe ethnic groups delayed the longest in transitioning to parenthood, while the Mole/Dagbani ethnic group reported the lowest increase in age at first birth over the survey period.\n\nIn terms of religion, there was a median increase of two years in age at first birth for all religious groups from 19 years in 1988 to 21 years in 2014, except for women with no religion and women in other religious groups. Specifically, for each survey year, Catholics, other Christians and Muslims experienced higher and similar increases in age at first birth from 19 years in 1988 to 20 years in 1998 and 21 years in 2014.\n\nGenerally, there is an increase in the median age at first birth for all regions except for the “Northern regions” where the median age at first birth increased from 19 years in 1988 to 20 years in 1998. In the northern regions, there was a decrease to 19 years in 2014, while the Volta region had the highest increase in the median age at first birth from 19 years in 1988 to 20 years in 1998 and remained at 20 years in 2014.\n\nThe age at which a woman marries affects the timing of the onset of parenthood in Ghana. Figure 2 shows that as a woman postpones the age at first entry into a marital union, there is a tendency to postpone the onset of parenthood. For example, the median age at first birth for women who married before 15 years of age in 1988 is 15 years compared to a median age at first birth for women who married at above 25 years and above. Moreover, in 2014, the median age at first birth for women who married at above 25 years increased from a median age of 26 years in 1988 to a median age of 27 years in 1998 and 2014.\n\nThe results of the multivariate analysis of the risk and protective factors of the timing of birth for the three waves of the data in Ghana are presented in Table 2. The table shows that almost all the selected social and demographic factors (age, education, ethnicity, region and age at first marriage) were significantly associated with age at first birth across the three surveys. However, the only factor that had a strong, consistent impact on the timing of first birth in Ghana is the age of a woman. As the table shows, the hazard risk of early childbirth consistently decreased as age increased in all the years of the surveys except in the case of age group 40-44 in 1988, 1998 and 2014. For instance, the hazard risk of early childbirth was 0.47, 0.46, and 0.47 times lower among women between the ages of 40-44 years compared to women between the ages of 15-19 years in 1988, 1998 and 2014 respectively.\n\n* Significant results.\n\nThe effect of education on the onset of parenthood was not always linear as the theory of modernization would predict, even though on the whole, educational attainment appeared to exert a negative influence on age at first birth. The inconsistent effect of education on age at first birth is shown by the fact that in 1988 there was no significant difference between women with education and those with primary education and tertiary level of education, on the other hand. Moreover, in 1988, women with secondary education were more likely to delay parenthood compared to their counterparts with tertiary education and those without education which is the reference category.\n\nBut, as the table clearly shows, over time, the effect of education on the timing of parenthood is unmasked as evidenced by the fact that women with primary, secondary and tertiary education were all more likely to initiate parenthood later than those without education. For example, women secondary education had 0.67, 0.89- and 0.77-times lower hazard risk of early birth than women without any formal education in 1988, 1998, and 2014 respectively. Furthermore, women with tertiary education had 0.77 times lower hazard risk of early childbearing compared to women without education in 1998 compared to women with no education.\n\nCultural values and norms largely shape the attitudes and behaviors of individual members of ethnic groups towards social institutions like the family in terms of their structure and process. As Table 2 shows, ethnicity affects the timing of the onset of parenthood in Ghana in significant ways. With the exception of the Ewe ethnic group which is not significantly different from the Akan ethnic group (the reference category), all the remaining ethnic groups, initiated parenthood later than the Akan ethnic group, but the statistical significance varied across the three surveys. For instance, women from the Ga-Adangbe ethnic group had 0.83 times lower hazard risk of early childbirth compared to women from the Akan ethnic group in 1998. This finding is similar to that of women of the Guan ethnic group who had 0.66 lower times the hazard risk ratio of initiating parenthood early than their counterparts from the Akan ethnic group in 1988. Moreover, women from the Mole-Dagbani ethnic group had 0.75 and 0.82 lower hazard risk of early birth compared to their counterparts from the Akan ethnic groups in 1988 and 2014 respectively.\n\nWhile as a geographic entity region largely reflects local social, economic, and demographic conditions, it often has an independent effect on various social phenomena as shown clearly by the findings in Table 2 although this effect is not consistent over time. For example, even though women in the Eastern and Brong/Ahafo regions all had higher hazard risks of early birth regimes compared to women in the Western region, these effects are not consistent over the three surveys. While women in the Eastern region started birth early in 1988 and 2014 (HR; 1.22 and 1.13) respectively, this tendency is observed for women in the Brong/Ahafo region (HR; 1.16) only in 2014.\n\nWhile age at first marriage may reflect changing social and economic conditions in the society, Table 2 shows that after factoring in such socio-economic factors as education and residence, the age at which a woman first married had the most impact on the age at which she had her first child as shown by the findings for the 1998 survey. For example, women who married at 15-19, 20-24, and above 25 years had lower hazard risk of 0.32, 0.11, and 0.05 respectively to times to have early childbirth compared to women who married before 15 years.\n\n\nDiscussion\n\nThe present study sought to examine the effect of selected social and demographic factors on the timing of the onset of parenthood among women in Ghana using three waves of the Demographic and Health Survey data. Specifically, we employed the Cox proportional Hazard Model to examine the effects of place of residence, educational attainment, ethnic background, region of residence, religious affiliation, and age at first marriage, and age at first birth of women aged 15 to 49 years old. The results of this study have shown that socio-demographic factors (especially age, education, ethnicity, region and age at first marriage) are important in predicting age at first birth.\n\nOur results are consistent with the life course theory. The life course theory provides a useful means of illuminating changes in age at first birth in Ghana over time. This theoretical perspective allows the link between social context and age at which a woman first gives birth. This link occurs in the interactions of women in contexts in which she lives such as schools, family, employment, and religion in which she lives. We found that the transitions into motherhood varied among the ethnic groups and regions of residence. A possible explanation of this variation could be the traditional norms and values that govern the formation of family or childbearing.\n\nOur finding regarding the association of region and age at first birth is similar to the findings of Gurmu and Etana (2014) conducted in Ethiopia and with the outcomes of Fagbamigbe and Idemudia (2016) in a study conducted on survival analysis and prognostic factors of timing of first childbirth among women in Nigeria.\n\nThe finding that women between the ages of 15-19 years have the highest risk of early childbirth compared to all other age groups is consistent with the findings of a Nigerian study which reported that majority of women in the study have had their first birth before the age of 20 years (Fagbamigbe and Idemudia 2016), and another study in Bangladesh which observed that 72.8% of the women in the study had their first child before the age of 20 years (Aminu Haque and Sayem 2009). It is possible that younger women may not have the power to negotiate safe sex practices and they may not be able to partake in fertility decision making in a case where they marry at a younger age.\n\nEarly marriage is a strong predictor of age at first birth. Consistent with a previous study in Ghana on Statistical distribution and determinants of mother’s age at first birth (Logubayom and Luguterah 2015), this finding that the earlier a woman is first married, the earlier she bears her first baby. This is because early marriage increases the risk of early sexual initiation that is likely to increase the risk of pregnancy. This is in line with our results that show that marrying before the age of 15 years increases the risk of early age at first birth compared to marrying after the age of 15 years. This finding is also consistent with the findings of Mohammad Manjur Alam (2015) on marriage to first birth interval and its associated factors in Bangladesh.\n\nOur results suggest that having higher education is consequential for women’s age at first birth. Higher level of education delays the timing of age at first birth. We found that women with no former education have higher risk of early childbirth, a finding which is consistent with the findings in Ghana (see e.g., Logubayom and Luguterah 2015), Ethiopia (Gurmu and Etana 2014), and Brazil (Marteleto and Dondero 2013). The negative association between education and age at first birth is possibly because education is a competing activity to childbirth. In addition, education empowers women in terms of arming them with knowledge about the importance of contraception and a greater say in fertility decisions in the household.\n\nThe present study has provided empirical evidence on the age at first birth in Ghana. Despite the findings and the contribution of this study to reproductive health, some important limitations should be considered while interpreting the findings of this study. The cross-sectional form of this study, which makes it challenging to infer causation with some of the variables under investigation, is a glaring weakness. The socio desirability of the surveys is another restriction that should be taken into account. Social desirability may have reduced reporting or led to inaccurate responses on the questionnaire about age at first birth.\n\n\nConclusion\n\nIn conclusion, the present study has shown that in tandem with broader transformation of the Ghanaian society as a result of such modernizing forces as education, urbanization and their concomitant attitudinal and demographic changes, the timing of first childbirth is changing in the direction of a late childbirth regime. This change in the age at which a woman has her first child is bound to affect the structure of the Ghanaian family through its effect on fertility levels.",
"appendix": "Data availability\n\nData used in this study are from the cross-sectional individual women dataset of the Ghana 1988, 1998, and 2014 demographic and health surveys, available from the Demographic and Health Survey (DHS) website https://dhsprogram.com/. Access to the dataset requires registration and is granted only for legitimate research purposes. A guide for how to apply for dataset access is available at: https://dhsprogram.com/data/Access-Instructions.cfm.\n\n\nReferences\n\nAkella D, Jordan M: Impact of Social and Cultural Factors on Teen Pregnancy. J. Health Dispar. Res. Pract. 2015; 8(1): 41–62.\n\nAksan A-M: Effects of Childhood Mortality and Morbidity on the Fertility Transition in Sub-Saharan Africa. Popul. Dev. Rev. 2014; 40(2): 311–329. Publisher Full Text\n\nAlam MM: Marriage to first birth interval and its associated factors in Bangladesh. Asian J. Soc. Sci. Humanit. 2015; 4(4): 36–47.\n\nAminul Haque M, Sayem AM: Socioeconomic Determinants of Age at First Birth in Rural Areas of Bangladesh. Asia Pac. J. Public Health. 2009; 21(1): 104–111. Publisher Full Text\n\nAmoateng AY: Social structure and the timing of first birth: The case of Ghana. S. Afr. Sociol. Rev. 1991; 29–39.\n\nAyiga N: Explaining Trends of Premarital Childbearing among Young Women in Uganda. Etude de La Population Africaine. 2015; 29(2). accessed September 15, 2017.Reference Source\n\nBaizán P, Aassve A, Francesco CB: Cohabitation, Marriage, and First Birth: The Interrelationship of Family Formation Events in Spain. Eur. J. Population. 2003; 19(2): 147–169. Publisher Full Text\n\nBengtson VL, Katherine RA:The Life Course Perspective Applied to Families over Time. Sourcebook of Family Theories and Methods. Springer;2009; pp. 469–504. accessed September 15, 2017. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nGiele JZ, Elder GH: Methods of life course research: Qualitative and quantitative approaches. Sage;1998. Publisher Full Text\n\nGupta N, Mahy M: Adolescent Childbearing in Sub-Saharan Africa: Can Increased Schooling Alone Raise Ages at First Birth? Demogr. Res. 2003; 8: 93–106. Publisher Full Text\n\nGurmu E, Etana D: Age at first marriage and first birth interval in Ethiopia: analysis of the roles of social and demographic factors. Afr. Pop. Stud. 2014; 28(3): 1332–1344. Publisher Full Text\n\nJutte DP, Roos NP, Brownell MD, et al.: The Ripples of Adolescent Motherhood: Social, Educational, and Medical Outcomes for Children of Teen and Prior Teen Mothers. Acad. Pediatr. 2010; 10(5): 293–301. Publisher Full Text\n\nKarabo M, Ayiga N: Rates and Predictors of School Pregnancy among Black Women in the North West Province, South Africa. Etude Popul. Afr. 2014; 28(1): 636. Publisher Full Text\n\nKhan S, Bradley SE, Fishel J, et al.: Unmet Need and the Demand for Family Planning in Uganda. Further Analysis of the Uganda Demographic and Health Surveys 1995-2006.2008. accessed September 18, 2017.Reference Source\n\nLeung MY, Mallory FG, Santaeulalia-Llopis R: The Relationship between Age at First Birth and Mother’s Lifetime Earnings: Evidence from Danish Data. PLoS One. 2016; 11(1): e0146989. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLogubayom AI, Luguterah A: The Statistical Distribution and Determinants of Mother’s Age at First Birth. Am. J. Theor. Appl. Stat. 2015; 4(2): 41–52.\n\nMarteleto LJ, Dondero M: Maternal age at first birth and adolescent education in Brazil. Demogr. Res. 2013; 28: 793–820. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcQuillan K: When does religion influence fertility? 30. Popul. Dev. Rev. 2004; 30: 25–56. Publisher Full Text\n\nMugarura A, Kaberuka W, Atuhaire R: Factors determining the age at first birth in Uganda. Issues Sci. Res. 2016; 1(5): 61–66.\n\nNgalinda I: “Age at First Birth, Fertility, and Contraception in Tanzania”, Doctoral dissertation, Humboldt University of Berlin, Germany.1998.Reference Source\n\nObeng Gyimah S: A cohort analysis of the timing of first birth and fertility in Ghana. Popul. Res. Policy Rev. 2003; 22(3): 251–266. Publisher Full Text\n\nRabbi AMF, Kabir MHMI: Factors Influencing Age at First Birth of Bangladeshi Women-A Multivariate Approach. Am. J. Public Health Res. 2013; 1(7): 191–195. Publisher Full Text\n\nStatistics South Africa: Census 2011: Fertility in South Africa. Pretoria:Statistics South Africa;2015.Reference Source\n\nTakyi BK, Addai I: Effects of Ethnicity on the Onset of Parenthood in a Developing Country: Some Evidence from the Early 1990s. J. Comp. Fam. Stud. 2002; 33(1): 57–71. Publisher Full Text\n\nSchiücker FU, Raphaela Blumenfelder AEffects of Age at First Birth on Health of Mothers Aged 45 to 56. Zeitschrift Für Familienforschung-Journal of Family Research. 2014; 26(3). accessed April 18, 2017.\n\nTadesse M: Assessment of HIV Discordance and Associated Risk Factors among Couples Receiving HIV Test in Dilla, Ethiopia. BMC. Res. Notes. 2014; 7(1): 1.\n\nWendt A, Gibbs CM, Peters S, et al.: Impact of Increasing Inter-Pregnancy Interval on Maternal and Infant Health. Paediatr. Perinat. Epidemiol. 2012; 26(s1): 239–258. PubMed Abstract | Publisher Full Text | Free Full Text"
}
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[
{
"id": "185520",
"date": "20 Jul 2023",
"name": "Adriana A E Biney",
"expertise": [
"Reviewer Expertise Sexual and reproductive health",
"health systems"
],
"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 well written manuscript that assesses the sociodemographic correlates and trends in the timing of the onset of childbearing among women in Ghana. I have listed below a few comments for the authors that I believe will help improve the manuscript.\nAbstract The sample size(s) should be included in the abstract as this provides useful information for those simply reviewing abstracts.\nIntroduction In the second paragraph, line 12, the sentence begins with the word ‘Although’ however as you read on this does not fit and should be revised.\nAnother subsection under the Introduction should be included providing some contextual background on childbearing in Ghana, so readers can understand the Ghanaian context regarding fertility.\n\nIn their discussion of the problem warranting the study, the authors do not clearly state why it is important to assess trends in onset of childbearing time, and why it is important to assess the correlates of age at first birth. We understand that the age at first birth comes with certain consequences and fertility implications but clear statements as to why it is important to know the socio-demographic trends in the age at first birth of women are needed. Perhaps it could be that this is not an important thing to know hence studies on this being non-existent.\nAs the manuscript reports on what has been done and not done on the topic, the Introduction could also include some other references that discuss the topic of transitioning to adulthood and the onset of childbearing. For example, Beguy et al. (2011)1. Most of the papers cited are quite old, those for Ghana, especially, which was even mentioned by the authors. They should attempt to include a few more current papers.\nTheoretical framework At the end of the discussion on the theory and the various factors the literature has indicated as being linked to age at first birth, it could be helpful to end the section with a brief paragraph summarizing the key variables based on the review of the literature. Readers would then understand your justification for including these variables in the study. The authors could again tie this back to the life course theory.\nIn paragraph 4 – the authors refer to the Ghana Statistical Service (2009). I suggest they mention to the DHS report or just report the information and provide the citation after (GSS, GHS and ICF Macro, 2009). I also wonder why not all the GDHS reports for which their data were analysed were included in the references but only the 2008 GDHS was cited.\n\nMethods The authors could include a statement that they solely used the women’s file for their analysis. This is so that readers are not confused as all the questionnaires – women’s, men’s and household were initially mentioned.\nAs the authors describe their sociodemographic variables, they report marriage and refer to it as a dichotomous variable of marital status, however, later on the variable on age at first marriage is used for the bivariate graphs and multivariate analysis. Age at first marriage is also not described along with the other measures.\nThe authors should write B/A in full and capitalize the first letters for the Western, Central, Greater Accra, and Northern regions.\nThe readers should report in their Statistical Analysis section how they conducted the analysis to report the trends they presented in graphs. This was not explained.\nReaders may benefit from a sentence under the Statistical Analysis section explaining whether the assumptions for use of the Cox proportional hazard model were met.\nResults The authors should clarify the samples used for the different analyses conducted. More specifically, in order to compute the median ages at first birth across the three years, were all women – even women with no births – included? I understand they were included in the regression analysis as this variable was dichotomized to include those with and without births, but I do not understand what was done to obtain the median ages for the different variables if these women do not have an age at first birth.\nOther Christians are not all Protestants, as some are Latter Day Saints and Jehovah’s Witnesses and are not historically from the same line of Christianity.\nFor the various graphs indicating trends in age at first birth by sociodemographic variables, the data values could be indicated. Also, some graphs indicate the Year of Survey as the x-axis when it is not. This occurs in figure 2 for age group of women (on page 8), and all graphs in Figure 2 continued (on page 9). Also, age at first marriage graph has been titled wrongly indicating region instead.\nThe authors need to explain the rationale for the different line graphs in Figure 2, so that readers can better understand the results being displayed on the graphs. Some graphs do not indicate the trends across the three DHS waves but rather changes in the categories by the year of survey. Explanations are given but the authors should have another look especially at the graphs that display nominal data (religion, ethnic group, and region graphs) but present these in a trend format. Perhaps bar graphs would be best to represent these data instead of the line graph.\nOn Table 2 – the authors use the term hazard ration instead of ratio.\nThe final paragraph under the multivariate results explaining the age at first marriage variable reports that after age and education were factored in, it had an impact on age at first marriage. This statement indicates that some sort of stepwise analysis was done as variables were included in the model. If so, this must be stated.\nI wonder about some control variables being included in the model. I understand the authors were only considering important sociodemographic variables which were in line with their theoretical framework as the main correlates. However, a variable such as wealth quintile could be included as a control and not a correlate in the study.\nThe final paragraph in the Results section reports age at first marriage findings. On line 4 in that paragraph, the sentence says “…had a lower hazard of 0.32, 0.11, and 0.05 respectively to times to have…”. This should be revised.\nDiscussion The results on findings with the age at first marriage variable indicate only 1998 results were significant. Can the authors posit as to why the 1988 and 2014 results were not also significant despite indicating very similar ratios.\nFinal conclusions about the trends need to be included since this was a major aim of the study. What can the authors tell readers about the changes over time concerning age at first birth and the different correlates.\nAre there any recommendations the authors can suggest? The results on education and early marriage may be important for policymakers and programmers.\nThe first reference to socio desirability should also be social desirability.\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? Partly",
"responses": []
},
{
"id": "185522",
"date": "25 Jul 2023",
"name": "Christine Chawhanda",
"expertise": [
"Reviewer Expertise Sexual and reproductive health",
"fertility",
"teenage pregnancy",
"migration",
"public health policy and systems"
],
"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 references cited in the literature are from the 1990s to 2016. Perhaps the authors could include most recent references (2019, 2020, 2021, 2022)?\nUnder results on continuation of figure 2 titled median age at first birth by region, the last figure to the left the regions are not shown in the figure (the figure does not show age at first birth by region), however, the figure after this (to the right) is the one that shows age at first birth by region.\nThe multivariate results on region, kindly revisit the results that you have marked as significant.\nUnder discussion, The Life course theory allows for analysing people's lives within structural, social, and cultural contexts. In your discussion, perhaps you could acknowledge the importance or the role of culture (societal expectations) in the timing of pregnancy. Once married, the society may expect the woman to get pregnant and discourage family planning soon after marriage.\nBased on your findings and discussion, what recommendations can you provide for Ghana to consider.\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? Partly",
"responses": []
},
{
"id": "181169",
"date": "31 Jul 2023",
"name": "Babatunde Gbadebo",
"expertise": [
"Reviewer Expertise Reproductive health",
"Child mortality",
"Applied Demography",
"Female genital cutting"
],
"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 comment:\n\nThere are a few typographical and editorial errors that should be carried out. For instance, towards the end of the introduction, a statement reads: ’Other reported effects of early age at first birth are truncated education which has ramifications for the socioeconomic wellbeing of women and their children’ instead of ‘Other reported effect of early age at first birth is truncated education which has ramifications for the socioeconomic wellbeing of women and their children’.\nSimilarly, the word “socio-demographic” is included in the title of the article but there were occasions that the authors wrote sociodemographic instead of socio-demographic; there is need for consistency.\nIn the sixth paragraph of the discussion, 'former education' should be written as formal education.\nAbstract: Results - kindly specify the age of the women you were reporting. Is it the age of respondents or the median age at the onset of birth/parenthood?\nKeywords: Keywords should be between 3 and 5: you can delete sociodemographic, Demographic and Health Surveys, and Cox proportional.\nIntroduction: Don't start the second paragraph with 'because'.\nObjective of the study: Kindly delete lines 1 to 4a; it is more or less part of the study's justification, rather than the objective of the study.\n\nResearch tools and data collection: Kindly specify clearly which of the questionnaires you used for your study - or did you use all the questionnaires for your study?\nStatistical analysis: Specify the univariate analysis tool used.\nResults: Don't start your report with 'as far as'; kindly recast those statements that start with 'as far as'.\nDiscussion: Kindly recast paragraph 5 of your discussion. The discussion should start from the general principle (if there is a need), your findings, how it relates to previous findings, and the implication of your findings\nReferences: Kindly check your fourth reference. Reference should be written as: surname first, followed by the initial(s).\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/12-157
|
https://f1000research.com/articles/12-156/v1
|
10 Feb 23
|
{
"type": "Systematic Review",
"title": "Association of physical activity and heart rate variability in people with overweight and obesity: A systematic review",
"authors": [
"Sinha Mukesh Kumar",
"Vaishali K.",
"Arun G. Maiya",
"Shivashankar K.N.",
"Shashikiran U.",
"Ravi Shankar N.",
"Sinha Mukesh Kumar",
"Arun G. Maiya",
"Shivashankar K.N.",
"Shashikiran U.",
"Ravi Shankar N."
],
"abstract": "Background: Obesity is a major public health issue globally which is intrinsically linked to reduced heart rate variability (HRV). Physical inactivity and reduced resting HRV are linked to an increased risk of coronary heart disease, while athletes have a greater HRV. However, the exact correlation between physical activity and HRV remains uncertain. This systematic review aims to collect, report, and critically assess the current scientific literature about the association between physical activity and HRV in individuals with higher weight and obesity. Methods: A systematic search was carried out in electronic databases (Medline/PubMed, SCOPUS and CINAHL Plus) to retrieve studies that evaluated the relationship between physical activity and HRV in individuals with higher weight and obesity. Case-control, longitudinal/cohort, cross-sectional and observational studies were included. Using a critical narrative approach, information about the HRV, and physical activity was extracted and synthesized. The study was registered in PROSPERO: CRD42020208018 on October 9 2020. Results: After removing duplicates, 980 title/abstract records were checked for eligibility, and 12 papers were finally included in the narrative synthesis. The included studies contained physical activity as well as HRV in adults with higher weight or obesity with or without comorbidities. A negative relationship between moderate to vigorous physical activity and HRV indices had been found in two studies. There was also a negative relationship between sedentary time and HF (p = 0.049) and LF/HF (p = 0.036), as well as a positive relationship between sedentary time and LF (p = 0.014). Also dose-response association was found between vigorous exercise and higher SDNN, LF power, and HF power in one of the studies. Conclusions: This systematic review revealed a wide range of responses to physical activity and HRV; however, the current evidence uses a variety of approaches to objectively assess physical activity and measure HRV with different equipment.",
"keywords": [
"exercise",
"cardiac autonomic function",
"cardiorespiratory endurance",
"aerobic exercise",
"resistance exercise"
],
"content": "Abbreviations\n\nHRV: Time-domain variables of Heart rate variability\n\nSDNN: Standard deviation of NN intervals (ms)\n\nRMSSD: Root mean square of successive RR interval differences (ms)\n\npNN50: Percentage of successive RR intervals that differ by more than 50 ms (%). Frequency domain variables of Heart rate variability\n\nVLF: Absolute power of the very-low-frequency band (0.0033–0.04 Hz)– milli-second square\n\nLF: Power in the low-frequency range (0.04–0.15 Hz)\n\nHF: Power in the high-frequency range (0.15–0.4 Hz)\n\nLF/HF ratio: Ratio of LF [ms2]/HF [ms2], Ln, the natural logarithm of the absolute value in ms2\n\nBMI: Body mass index\n\nWC: Waist circumference\n\nST: Sedentary time\n\nBF%: Body fat %\n\nGPCS: Global physical capability score\n\nPA: Physical activity\n\nLPA: Light-intensity PA\n\nVPA: Vigorous-intensity PA\n\nVVPA: Mean daily very vigorous physical activity\n\nWHR: Waist-hip ratio\n\nHR: Heart rate\n\nMVPA: Moderate-to-vigorous physical activity\n\nCRF: Cardiorespiratory fitness\n\nMBQOA: The Modified Baecke Questionnaire for Older Adults\n\nPAEE: Physical activity energy expenditure\n\nIPAQ: International Physical Activity Questionnaire\n\n\nIntroduction\n\nHaving higher weight or obesity is characterized by abnormal or excessive fat accumulation that poses a health concern leading to chronic medical issues and a greater risk of disability.1,2 Obesity affects about 40% of young adults aged 20-39 years, 44.8% of middle-aged adults (aged 40-59 years), and 42.8 % of people aged ≥ 60 years globally.2 The World Health Organization estimated the global economic impact of obesity to be around 2.8% of the world’s gross domestic product. However, despite its widespread prevalence, and the accompanying cost, disease burden, and complications, obesity is often ignored as a disease.3 In the low-and-middle-income nations, uncontrolled urbanization and a shift in eating patterns from traditional to western-style diets are leading to an alarming rise in the incidence of obesity. It is reported that a curvilinear relationship between relative weight and mortality begins after the age of 18 years.1\n\nSeveral diseases like diabetes, hypertension, cancer, stroke, osteoarthritis, liver, renal disease, sleep apnea, and depression are linked to obesity, and the association increases with age and the presence of comorbidities.4–21 Another notable dysfunction associated with obesity is the disruption of cardiac autonomic function leading to alterations in the normal parasympathetic and sympathetic regulation, which can be detected using heart rate variability (HRV).22–25 HRV is a non-invasive tool for evaluating autonomic function by measuring beat-to-beat differences in R-R intervals.26 It is known that low HRV is an independent predictor of cardiovascular mortality and sudden cardiac death, is related to higher skinfold thickness, higher body mass index (BMI), higher body fat percentages, and lower levels of physical activity.27–29 Furthermore, reduced physical activity and cardiorespiratory fitness are also potential risk factors contributing to cardiovascular diseases30 which are worsened by higher associated adiposity indices.31 Research shows that increased epicardial fat thickness is related to a lack of physical activity, impacting the autonomic nervous system.32–34 Despite these facts, the relationship between physical activity and the autonomic cardiac function as measured by HRV has not been explored well. Accordingly, this systematic review aimed to collate, review and critically assess current scientific and clinical knowledge on the relationship between physical activity and HRV in adults with either higher weight or obesity.\n\n\nMethods\n\nThe study was registered in PROSPERO: CRD42020208018 on October 9 2020.\n\nSearch strategies were developed related to physical activity and HRV with the use of boolean operators “AND,” and “OR” to allow logical interconnections between concepts. Synonyms or Medical Topic Heading (MeSH) keywords and the title and abstract text for each of the terms were searched. Multiple databases, Medline, SCOPUS, Cumulative Index to Nursing, and Allied Health Library (CINAHL Plus) [Ebscohost], were searched from their earliest record to January 2021. Before adaptation for the other databases, the search strategy was initially built in Medline. For any additional studies, the reference list entries of the included studies and systematic reviews were inspected. We used the following keywords in the quest–exercise, physical activity, incidental physical activity, aerobic fitness, fitness, habitual physical activity, obese, overweight, healthy people, older adults, cardiac autonomic function, autonomic nervous system, heart rate variability, autonomic function, sympathetic function, and parasympathetic function. Table 1 presents the search strategy in detail.\n\nOnly case-control, longitudinal/cohort, cross-sectional, and observational studies about physical activity (occupational, transportation, and leisure) and HRV in people with higher weight and obesity with or without any comorbidity were included in this review. A reported mean or median BMI value of ≥ 25 kg/m2 was also considered for inclusion. The physical activity assessment in the studies could be either subjectively or objectively evaluated. The HRV considered for inclusion was either normalized unit or log-transformed data of time domain or in frequency domain measures; all time-domain measures were reported in ms and frequency domain measures in ms2. Studies that failed to examine the results of interest by using only healthy subjects or not including the overweight and obese group were excluded from the analysis.\n\nMKS screened all study titles after removing duplicates. Then, MKS and VK independently assessed all relevant titles and abstracts for eligibility, and the full texts of all potentially qualifying papers for independent review were retrieved. Any disputes were addressed by dialogue with the third reviewer, AGM. Articles considered suitable were further processed for data extraction and quality assessment.\n\nThe following data were extracted from each qualifying article: study design, study setting, funding source, ethical approval, study population characteristics (age, gender, BMI, body fat percentage), inclusion criteria, obesity grading, sample size, objectives, outcome measures, and compiled in a data-recording table. Initially, MKS and VK piloted the data extraction and qualitative evaluation methods on three papers. MKS conducted data extraction and it was checked by VK. Any conflicts were resolved by contacting the third reviewer, AGM, SK, SU and RS.\n\nA narrative synthesis of the studies was performed while accounting for the differences in the individual investigations regarding their design, findings, and objectives. A meta-analytical approach was not feasible in this analysis due to variations in the measurement of physical activity and HRV and the different study designs.\n\n\nResults\n\nWe retrieved 1,902 published papers following a database search based on the keywords described above. After removing the duplicates, 980 records of titles/abstracts were screened for eligibility, of which, 12 studies were finally included in the narrative synthesis of this systematic review. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for the inclusion process is presented in Figure 1. A summary of the 12 studies is presented in Table 2.23,35–45\n\n\n\n• MVPA was independently associated with cardiac autonomic function in both men and women.\n\n\n\n• Body fat was independently associated with cardiac autonomic function in both men and women.\n\n• A negative association was found between MVPA and rMSSD when including CRF, MVPA, and Fat% in the same regression model.\n\n• Body Fat% was not significantly related to rMSSD.\n\nThe quality of the studies was determined by the quality index score.46 For the present review, the score for the included studies ranged from 16 to 23; however, a few of the points were not scored because they were specific to the intervention study (Table 3). Furthermore, the majority of the included studies did not contain adequate information to understand the role of potential confounders in their relationship with HRV.\n\nThe participants were aged between 18 and 83 years and all studies included both men and women, except Tonello et al.37 who included young non-menopausal women with higherweight but in good health. Three of the included articles focused on only people with obesity,23,35,38 one study had recruited only people with higher weight (Mean BMI = 26.3 ± 4.1 kg/m2)37, and another included people with higher weight and obesity36. In the remaining six studies, it was unclear if participants were with higher weight or obesity, but their mean BMI was >25 kg/m2 (40-45 kg/m2), and one study included people with a BMI both less than and more than 25 kg/m2.39 Physical activity status of the participants is depicted in Table 4.\n\nThe included studies' levels of physical activity were presented in the following, moderate, vigorous, and moderate to vigorous. Figures 2, 3, and 4 provide specifics of the meta-analysis.\n\nA brief overview of the studies assessing relationships between HRV and physical activity is presented in Table 5.\n\n\n\n\n\n\n\n\n\n\n\nTwo studies had reported a negative association between moderate to vigorous physical activity and rMSSD.23,40 One of these also described a negative correlation between sedentary time and HF (p = 0.049) and LF/HF (p = 0.036), as well as a positive association between sedentary time and LF (p = 0.014).23 Likewise, Föhr et al.41 observed that both moderate and vigorous physical activity is linked to rMSSD and the LF/HF ratio.\n\nThe GCPS, a method to assess physical activity, was reported to be moderately correlated with ln SDNN and ln HF, with correlation coefficients values of 0.61 (p = 0.001) and 0.59 (p = 0.001), respectively.35 In other three studies, significant correlations were observed between vigorous physical activity (VPA) and rMSSD.36,37,43 VPA is associated with SDNN: βstd= 0.06 [0.03, 0.10]; and rMSSD: βstd = 0.08 [0.05, 0.12] according to Pope et al.36 and light physical activity (LPA) is associated with only rMSSD (βstd = 0.05 [0.01, 0.08]. Tonello et al.37 also found correlations between VPA and rMSSD (r = 0.449, p = 0.041), and VPA and HF (r = 0.520, p = 0.016) in their analysis.\n\nOne of the studies reported a dose-response relationship between vigorous exercise and higher SDNN, LF power, and HF power (p = 0.05, p = 0.01, and p = 0.01, respectively).39 Leisure-time behavior was cross-sectionally linked to higher SDNN (ptrend=0.001) and higher ULF (ptrend<0.0001) according to a study by Soares-Miranda et al.44 On the other hand, Kluttig et al. found no consistent or statistically significant connection between physical activity and HRV variables.45\n\n\nDiscussion\n\nThis systematic review elucidated the link between physical activity and HRV-derived cardiac autonomic function. We found that rMSSD is negatively correlated to moderate to vigorous physical activity, and sedentary time has a positive relationship with LF. A dose-response relationship between vigorous exercise and frequency-domain HRV measures has been documented (LF and HF). Although the evidence for the effect of age, sex, and diet remains inconclusive, all studies measured physical activity differently and used different equipment to determine HRV. These variables could be obscuring the evidence.\n\nThe included studies used both objective and subjective methods to measure physical activity. Oliveira et al.23, Pope et al.36, Tonello et al.37, Kiviniemi et al.40, and Föhr et al.41 all utilized an objective method which included an accelerometer, polar device, or HRV-based physical activity measurement. The remaining studies35,38,39,42–45 employed questionnaires to assess physical activity. The studies reported that regular physical activity had a positive effect on autonomic control of the heart in adults by decreasing the resting heart rate and an increase in HRV. Further, regular physical activity and aerobic fitness improve a range of health outcomes and lower mortality from all causes. Nevertheless, the use of objective tools to assess physical activity and thorough body composition measurements has been less frequent.\n\nThe included studies used a variety of equipment to record HRV–V800 Polar, ANS watch monitor, GE MC1200 for resting electrocardiography (ECG); RS800CX Polar heart rate monitor, Polar R-R recorder, 12-lead electrocardiogram, Firstbeat Bodyguard device for ambulatory HRV recording; ECG Holter, BIOPAC MP-36 system, 24-hour Holter and Modular ECG Analysis System. However, the use of different equipment to measure HRV in the included studies limits the scope of comparison of results between the studies. Many confounding factors for HRV were identified which included the level of physical activity, recording time, room temperature, individual stress or nutrition, gender, and several hormones.23,35–45 The reporting may also be influenced by the HRV data or log transformation of the data.\n\nOliveira et al.23 stated that physical activity and HRV-derived cardiac autonomic activity, rMSSD, have a negative relationship with moderate to VPA and higher levels of MVPA were associated with reduced LF; however, their participants were with severe obesity with only minimal time spent on MVPA (98.92 ± 41.00 min/week). Another important finding was the association between WC and the deterioration of vagal tone.23 In the same article, sedentary time was linked to all of the frequency domain indices, with a negative correlation with the parasympathetic component and sympathovagal HRV balance, and a positive association with cardiac sympathetic modulation.23 This suggests that PA may protect the heart, as opposed to increased sympathetic tone. Higher levels of PA are also associated with a favourable modulation of the cardiac sympathetic nervous system in severely obese individuals. As a result, PA reduces the risk of cardiovascular disease associated with obesity through enhancing autonomic function.23 Similarly, De Liao et al.32 reported higher cardiac frequency and a decrease in the HF index in elderly persons with higher weight, and a lower HRV in the poor physical capacity group compared to the high physical capacity group.\n\nOn analyzing further, Kiviniemi et al.40 found a negative relationship between rMSSD and MVPA where physical activity was monitored continuously over two weeks, which can be considered representative of the overall current physical activity level. However, the authors stated that cardiorespiratory fitness was a better predictor of cardiac autonomic function than MVPA.\n\nPope et al.36 found independent associations between accelerometer-estimated VPA, MPA, and LPA and time-domain HRV measures. Their findings suggested that LPA participation is affordable to a large portion of the population regardless of disease status or age, arguing for more LPA participation to replace sedentary time, highlighting the benefits of LPA. When compared to sedentary subjects, Buchheit et al.42 found that those with the greatest self-reported MVPA had greater SDNN and rMSSD values as well as higher HF power. According to Soares L et al.44 prospective study, walking and leisure activities are connected to improved HRV. Additionally, older people who increased their walking distance or pace over a five-year period of follow-up had a more favourable HRV than those who decreased it. Kleiger RE et al.47 also observed the benefits of physical activity and significant correlations between physical activity and higher SDNN and ULF.47 Likewise, Kluttig et al.45 observed that physical activity was inconsistently related with HRV and HRV were closely linked to biomedical risk factors, resulting in a high predictive capacity for potential cardiovascular events like diabetes and obesity.\n\n\nConclusion\n\nThis review found that physical activity and obesity indices were both independently associated with changes in the cardiac autonomic modulation of obese individuals. Improved cardiac autonomic function has been shown to have positive effects on health outcome, it is crucial to promote it because PA greatly impacts adipocity indices. In this systematic review, we observed a wide range of responses to physical activity and HRV (time and frequency domain variables); however, the existing literature contains a variety of methodologies and equipment for quantifying physical activity and measuring HRV. Furthermore, the evidence for a definite association between different levels of physical activity and HRV is insufficient. Future studies should aim to delve deeper into the influence of intensity and type of physical activity on cardiovascular parameters accounting for all potential regulated confounders. Also, the variability in the equipment used to determine HRV makes it difficult to draw objective conclusions, thereby limiting generalizability.\n\n\nEthical approval\n\nFormal ethical approval is not required as this article is a review paper.",
"appendix": "Data availability\n\nAll of the data that underlies the results are included in the article and no additional source data are required.\n\nFigshare: PRISMA_2020_checklist for ‘Association of physical activity and heart rate variability in people with overweight and obesity A systematic review’. https://doi.org/10.6084/m9.figshare.21119554.v1. 48\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nBray GA, Kim KK, Wilding JP, et al.: Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation. Obes. Rev. 2017 Jul; 18(7): 715–723. PubMed Abstract | Publisher Full Text .\n\nPronk N: Weight Bias and Discrimination in the Workplace: Addressing a Diversity and Inclusion Issue. ACSMs Health Fit J. 2021 May 1; 25(3): 54–56. Publisher Full Text\n\nEndalifer ML, Diress G: Epidemiology, predisposing factors, biomarkers, and prevention mechanism of obesity: A systematic review. J. Obes. 2020 May 31; 2020: 1–8. PubMed Abstract | Publisher Full Text\n\nSchnurr TM, Jakupović H, Carrasquilla GD, et al.: Obesity, unfavourable lifestyle and genetic risk of type 2 diabetes: a case-cohort study. Diabetologia. 2020; 63: 1324–1332. PubMed Abstract | Publisher Full Text\n\nBarnes AS: The epidemic of obesity and diabetes: trends and treatments. Tex. Heart. Inst. J. 2011; 38(2): 142–144. PubMed Abstract\n\nPraso S, Jusupovic F, Ramic E, et al.: Obesity as a risk factor for artherial hypertension. Materia socio-medica. 2012; 24(2): 87–90. PubMed Abstract | Publisher Full Text\n\nWilson PW, D“Agostino RB, Sullivan L, et al.: Overweight and obesity as determinants of cardiovascular risc: the Framingham experience. Arch. Intern. Med. 2002; 162: 1867–1872. Publisher Full Text\n\nZhang J, Wan S, Dong F, et al.: Secular Trends of the Impact of Overweight and Obesity on Hypertension in Yi People: Yi Migrant Study, 1996–2015. Int. J. Hypertens. 2020 Mar 29; 2020: 1–9. PubMed Abstract | Publisher Full Text\n\nde Pergola G , Silvestris F: Obesity as a major risk factor for cancer. Journal of Obesity. 2013; vol. 2013: 11 pages. Article ID 291546.\n\nCampbell PT: Obesity: a certain and avoidable cause of cancer. Lancet. 2014 Aug 30; 384(9945): 727–728. PubMed Abstract | Publisher Full Text\n\nOesch L, Tatlisumak T, Arnold M, et al.: Obesity paradox in stroke–Myth or reality? A systematic review. PLoS One. 2017 Mar 14; 12(3): e0171334. PubMed Abstract | Publisher Full Text\n\nReyes C, Leyland KM, Peat G, et al.: Association between overweight and obesity and risk of clinically diagnosed knee, hip, and hand osteoarthritis: a population-based cohort study. Arthritis Rheum. 2016 Aug; 68(8): 1869–1875. PubMed Abstract | Publisher Full Text\n\nZheng H, Chen C: Body mass index and risk of knee osteoarthritis: systematic review and meta-analysis of prospective studies. BMJ Open. 2015 Dec 1; 5(12): e007568. PubMed Abstract | Publisher Full Text\n\nHarris R, Card TR, Delahooke T, et al.: Obesity is the most common risk factor for chronic liver disease: results from a risk stratification pathway using transient elastography. Am. J. Gastroenterol. 2019 Nov 1; 114(11): 1744–1752. PubMed Abstract | Publisher Full Text\n\nKovesdy CP, Furth SL, Zoccali C, et al.: Obesity and kidney disease: hidden consequences of the epidemic. Am. J. Nephrol. 2017; 45(3): 283–291. Publisher Full Text\n\nRhee CM, Ahmadi SF, Kalantar-Zadeh K: The dual roles of obesity in chronic kidney disease: a review of the current literature. Current opinion in nephrology and hypertension. 2016 May; 25(3): 208–216. Publisher Full Text\n\nSchwartz AR, Patil SP, Laffan AM, et al.: Obesity and obstructive sleep apnea: pathogenic mechanisms and therapeutic approaches. Proc. Am. Thorac. Soc. 2008 Feb 15; 5(2): 185–192. PubMed Abstract | Publisher Full Text\n\nRomero-Corral A, Caples SM, Lopez-Jimenez F, et al.: Interactions between obesity and obstructive sleep apnea: implications for treatment. Chest. 2010 Mar 1; 137(3): 711–719. PubMed Abstract | Publisher Full Text\n\nHung CF, Rivera M, Craddock N, et al.: Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study. Br. J. Psychiatry. 2014 Jul; 205(1): 24–28. PubMed Abstract | Publisher Full Text\n\nLuppino FS, de Wit LM , Bouvy PF, et al.: Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Archives of general psychiatry. 2010 Mar 1; 67(3): 220–229. Publisher Full Text\n\nGarg R, Saxena SK, Bashir S: Is obesity a risk to depression? A cross-sectional study. Ind. Psychiatry J. 2019 Jan; 28(1): 130–134. PubMed Abstract | Publisher Full Text\n\nRossi RC, Vanderlei LC, Gonçalves AC, et al.: Impact of obesity on autonomic modulation, heart rate and blood pressure in obese young people. Auton. Neurosci. 2015 Dec 1; 193: 138–141. Publisher Full Text\n\nOliveira C, Silveira EA, Rosa L, et al.: Risk Factors Associated with Cardiac Autonomic Modulation in Obese Individuals. J. Obes. 2020 Apr 1; 2020: 1–8. PubMed Abstract | Publisher Full Text\n\nFidan-Yaylali G, Yaylali YT, Erdogan Ç, et al.: The association between central adiposity and autonomic dysfunction in obesity. Med. Princ. Pract. 2016; 25(5): 442–448. PubMed Abstract | Publisher Full Text\n\nMondal DH: Evaluation of cardiac autonomic function in overweight males: A cross-sectional study. Adv. Hum. Biol. 2017; 7: 23–26. Publisher Full Text\n\nElectrophysiology TF: Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation. 1996 Mar 1; 93(5): 1043–1065. Publisher Full Text\n\nChen LY, Zmora R, Duval S, et al.: Cardiorespiratory fitness, adiposity, and heart rate variability: the CARDIA study. Med. Sci. Sports Exerc. 2019 Mar; 51(3): 509–514. PubMed Abstract | Publisher Full Text\n\nTian Y, Huang C, He Z, et al.: Autonomic function responses to training: correlation with body composition changes. Physiol. Behav. 2015; 151: 308–313. Publisher Full Text\n\nKaravirta L:Electrophysiological adaptations to endurance and strength training. Sex and Cardiac Electrophysiology. Academic Press;2020 Jan 1 (pp. 311–321). Publisher Full Text\n\nRoss R, Blair SN, Arena R, et al.: Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign: a scientific statement from the American Heart Association. Circulation. 2016 Dec 13; 134(24): e653–e699. PubMed Abstract\n\nDavison K, Bircher S, Hill A, et al.: Relationships between obesity, cardiorespiratory fitness, and cardiovascular function. J. Obes. 2010 Jan 1; 2010: 1–7. PubMed Abstract | Publisher Full Text\n\nLee DC, Artero EG, Sui X, et al.: Mortality trends in the general population: the importance of cardiorespiratory fitness. J. Psychopharmacol. 2010 Nov; 24(4_suppl)): 27–35. PubMed Abstract | Publisher Full Text\n\nBairapareddy KC, Maiya AG, Kumar P, et al.: Effect of aerobic exercise on echocardiographic epicardial adipose tissue thickness in overweight individuals. Diabetes, metabolic syndrome and obesity: targets and therapy. 2018; 11: 303–312. Publisher Full Text\n\nKim MK, Tanaka K, Kim MJ, et al.: Epicardial fat tissue: relationship with cardiorespiratory fitness in men. Med. Sci. Sports Exerc. 2010 Mar 1; 42(3): 463–469. Publisher Full Text\n\nLiao CD, Tsauo JY, Hsiao DJ, et al.: Association of physical capacity with heart rate variability based on a short-duration measurement of resting pulse rate in older adults with obesity. PLoS One. 2017 Dec 21; 12(12): e0189150. PubMed Abstract | Publisher Full Text\n\nPope ZC, Gabriel KP, Whitaker KM, et al.: Association between objective activity intensity and heart rate variability: cardiovascular disease risk factor mediation (CARDIA). Med. Sci. Sports Exerc. 2020 Jun; 52(6): 1314–1321. PubMed Abstract | Publisher Full Text\n\nTonello L, Reichert FF, Oliveira-Silva I, et al.: Correlates of heart rate measures with incidental physical activity and cardiorespiratory fitness in overweight female workers. Front. Physiol. 2016 Jan 6; 6: 405. PubMed Abstract | Publisher Full Text\n\nKaikkonen KM, Irmeli Korpelainen R, Tulppo MP, et al.: Physical activity and aerobic fitness are positively associated with heart rate variability in obese adults. J. Phys. Act. Health. 2014 Nov 1; 11(8): 1614–1621. PubMed Abstract | Publisher Full Text\n\nRennie KL, Hemingway H, Kumari M, et al.: Effects of moderate and vigorous physical activity on heart rate variability in a British study of civil servants. Am. J. Epidemiol. 2003 Jul 15; 158(2): 135–143. PubMed Abstract | Publisher Full Text\n\nKiviniemi AM, Perkiömäki N, Auvinen J, et al.: Fitness, fatness, physical activity, and autonomic function in midlife. Med. Sci. Sports Exerc. 2017 Dec 1; 49(12): 2459–2468. PubMed Abstract | Publisher Full Text\n\nFöhr T, Pietilä J, Helander E, et al.: Physical activity, body mass index and heart rate variability-based stress and recovery in 16 275 Finnish employees: a cross-sectional study. BMC Public Health. 2016 Dec; 16(1): 1–3.\n\nBuchheit M, Simon C, Charloux A, et al.: Heart rate variability and intensity of habitual physical activity in middle-aged persons. Med. Sci. Sports Exerc. 2005 Sep 1; 37(9): 1530–1534. PubMed Abstract | Publisher Full Text\n\nMay R, McBerty V, Zaky A, et al.: Vigorous physical activity predicts higher heart rate variability among younger adults. J. Physiol. Anthropol. 2017 Dec; 36(1): 1–5. Publisher Full Text\n\nSoares-Miranda L, Sattelmair J, Chaves P, et al.: Physical activity and heart rate variability in older adults: the Cardiovascular Health Study. Circulation. 2014 May 27; 129(21): 2100–2110. PubMed Abstract | Publisher Full Text\n\nKluttig A, Schumann B, Swenne CA, et al.: Association of health behaviour with heart rate variability: a population-based study. BMC cardiovascular disorders. 2010 Dec; 10(1): 1–1.\n\nDowns SH, Black N: The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J. Epidemiol. Community Health. 1998 Jun 1; 52(6): 377–384. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKleiger RE, et al.: Heart rate variability: Measurement and clinical utility. ANEC. 2005; 10: 88–101. Publisher Full Text\n\nSinha MK:PRISMA_2020_checklist for Association of physical activity and heart rate variability in people with overweight and obesity A systematic review.docx. figshare. [dataset].2022. Publisher Full Text"
}
|
[
{
"id": "163549",
"date": "24 Feb 2023",
"name": "Jaya Shanker Tedla",
"expertise": [
"Reviewer Expertise Physical Therapy",
"Rehabilitation",
"Neurology",
"Pediatrics"
],
"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 documented. The authors have done an excellent job of accumulating evidence for their hypothesis. Overweight and obesity are burning common problems throughout the world, and physical activity has a very high impact on this. The manuscript follows proper technique and is well presented. It is an interesting article. These kinds of articles are important in the current situation. This paper can be accepted with a few minor suggestions which need to be addressed.\nThe current obesity recommendation for physical activity should be highlighted in the introduction section. Regular physical activity has also been shown to help control and prevent non-communicable diseases.\n\nDespite the many confounders, HRV is a promising marker of cardiac autonomic function. If those confounders like diet and sleep were taken into account in the included study, the authors need to mention them in the discussion section.\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",
"responses": []
},
{
"id": "163550",
"date": "28 Feb 2023",
"name": "Rajat M. Singh",
"expertise": [
"Reviewer Expertise Physical activity",
"Obesity and Health promotion fitness"
],
"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 topic is interesting, and the manuscript is well-written. The abstract, methodology, results, discussion, and conclusion are all well-written sections of the manuscript. The overall quality of the writing makes the manuscript acceptable. Few suggestions from my end:\nDiscussion section - HRV Measurement: Describe the HRV measurement in detail and discuss its usefulness.\n\nDiscussion section - Physical activity and HRV: Discuss physical activity and RMSSD, PNN50, and physical activity and LF, HF, and LF/HF ratio.\n\nProvide details of the confounding measures if it is reported in the included studies.\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",
"responses": []
},
{
"id": "163548",
"date": "02 Mar 2023",
"name": "Aishwarya Nair",
"expertise": [
"Reviewer Expertise Rehabilitation",
"Physical Fitness",
"Cardiac performance",
"Exercise Physiology",
"Physical acitivity"
],
"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 has been well drafted with a thorough literature search.\n\nGeneral:\nThe grammar of the overall manuscript can be upgraded especially the Introduction.\n\nAbstract:\nBackground for overweight can be mentioned in the abstract along with the distinction between obesity and overweight since these words are mentioned in the title. In a few places, the terms higher weight/overweight/obesity have been used interchangeably. This has been observed throughout the manuscript. A uniformity can be incorporated for the same.\n\nIntroduction:\nNo comments.\n\nMethods:\nNo comments.\n\nDiscussion:\nIn understanding the association between heart rate variability and physical activity, it is advised to add more points in the discussion that give an understanding regarding the mechanism behind it.\n\nConclusion:\nThe impact of PA on obesity and overweight can be elaborated as a summary. Limitations and future scope can be mentioned in terms of obesity, overweight, PA as well in addition to HRV and PA.\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",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-156
|
https://f1000research.com/articles/12-152/v1
|
09 Feb 23
|
{
"type": "Research Article",
"title": "Risk factors of COVID-19 clinical worsening: A retrospective cohort study in COVID-19 referral hospital in west Java, Indonesia",
"authors": [
"Arto Yuwono Soeroto",
"Ade Yudisman",
"Nabila Nauli Asriputri",
"Hendarsyah Suryadinata",
"Ade Yudisman",
"Nabila Nauli Asriputri",
"Hendarsyah Suryadinata"
],
"abstract": "Background: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is marked as one of the highly pathogenic viruses, resulting in millions of deaths worldwide. Management of COVID-19 in limited resources requires appropriate decisions. Clinical considerations along with simple laboratory parameters that can predict the worsening are needed to determine which patients should be treated more intensively.\n\nMethods: This is a retrospective cohort study based on the Research Electronic Data Capture (REDCap) registry of COVID-19 patients in Hasan Sadikin General Hospital from April to December 2020. Patients were divided into worsening and non-worsening groups within a 14-day follow-up. Factors affecting these conditions were analyzed. Results: A total of 537 patients were included in this study, of which 72 patients suffered deterioration. Multivariate analysis showed the significant factors affecting the worsening of COVID-19 patients were age > 60 years (aOR 4.207, 95% CI 2.13-8.32), heart disease (aOR 2.802, 95% CI 1.12-6.99), diabetes mellitus (aOR 3.107, 95% CI 1.43-6.74), respiratory rate > 23x/minute (aOR 3.71, 95% CI 1.87-7.38), and NLR > 3.8 (aOR 2.51, 95% CI 1.21-5.21). Conclusions: Older age, chronic heart disease, diabetes mellitus, tachypnea, and higher neutrophil-to-lymphocyte ratio (NLR) are risk factors for the clinical worsening of COVID-19 and can be useful to predict the worsening outcome and poor prognosis.",
"keywords": [
"COVID-19",
"predictors",
"comorbidity",
"severity",
"worsening"
],
"content": "Introduction\n\nSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a new type of coronavirus which causes respiratory infections and is currently becoming the center of attention in global health.1 The clinical course of Coronavirus disease 2019 (COVID-19) ranges from asymptomatic to critically ill conditions with severe pneumonia and acute respiratory distress syndrome (ARDS), leading to death.2 Rapid worsening is one sign of intense viral replication and uncontrolled inflammatory response.3 Systemic inflammatory response, immune system disorder, and dysfunction of the renin-angiotensin-aldosterone system (RAAS) can trigger a cytokine storm causing ARDS and leading to increased mortality.4–7\n\nManaging COVID-19 in limited resources requires a quick decision as to whether initiating antiviral or supportive treatment may lead to different outcomes and prognoses.8 Certain parameters, along with the patient's clinical appearance, may predict the worsening of COVID-19.9 Therefore, patients who tend to worsen need to be prioritized and require early aggressive treatment.10 Prompt and appropriate medical treatment can improve the prognosis of COVID-19 patients.11 Several factors such as age, gender, comorbidities, and laboratory parameters may predict the occurrence of worsening.6,12 On the other hand, some factors initially linked to the poor outcome of the disease but proven contrarily, such as asthma.13\n\nA comprehensive understanding of the characteristics of COVID-19 patients and the risk factors for progression is fundamental. The findings of this study may be helpful not only in determining the prognosis but also in establishing appropriate treatment policies to prevent poor outcomes. Therefore, our study was conducted to assess whether male, elderly, several comorbidities and laboratory parameters could affect the clinical worsening in COVID-19 patients at the tertiary referral hospital in one of the most densely populated provinces in Indonesia, Hasan Sadikin General Hospital in Bandung, West Java, which can be used to determine the priority and predict the clinical outcome of the patients.\n\n\nMethods\n\nThis is an analytic observational study with a retrospective cohort design. Secondary data were obtained through the Research Electronic Data Capture (REDCap) registry of COVID-19 patients in Hasan Sadikin General Hospital, Bandung.14 The inclusion criteria in this study are patients aged 18 to 80 years old and confirmed with a diagnosis of mild or moderate COVID-19 based on World Health Organization (WHO) criteria when the patient was first admitted to the hospital between March to December 2020. The study size was arrived at by calculating the minimum sample size the formula for the multivariate regression analysis.15–18 As our study included 33 independent variables to be analyzed, the minimum sample size required was 330 (our study sample was 537 subjects). Therefore, obtaining the necessary minimum sample. The exclusion criteria are patients aged less than 18 years, patients with severe or critical symptoms on admission, patients who died less than 24 hours after admission, patients with less than ten days of follow-up care, and patients with incomplete data. Samples that met the inclusion criteria were followed within 14 days of treatment and were grouped into two major groups, the group with worsening of COVID-19 disease and the group without worsening of COVID-19 disease. From the 689 subjects obtained from the REDCap register, 152 subjects were excluded from the study because when they were initially admitted to the hospital as severe, critical, or deceased COVID-19 patients.\n\nThe diagnosis of COVID-19 was confirmed by real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) examination from the nasopharynx and oropharynx swab sample. Sansure Biotech Novel Coronavirus (2019-nCoV) Nucleic Acid Diagnostic Kit was used to confirm the diagnosis in this study. A cycle threshold (Ct) value less than 40 was considered positive for COVID-19. The severity classification is based on the fourth edition of the Indonesian Health Ministry COVID-19 guidelines.19\n\nMild cases were defined as symptomatic patients who met the COVID-19 case definition criteria without any signs of hypoxia. Moderate cases were defined as COVID-19 patients with clinical signs of pneumonia (fever, cough, dyspnea, rapid breathing) and no signs of severe pneumonia with SpO2 > 90% in room air. Severe cases were defined as a patient with signs of pneumonia plus one of the symptoms such as a respiratory rate > 30x/min, severe respiratory distress, or SpO2 < 90% in room air. Critical cases were defined as patients who experienced pneumonia with ARDS, sepsis, or septic shock. Worsening was defined as patients previously hospitalized as mild or moderate cases, then deteriorated to severe or critical within 14 days of follow-up. In this study, measurement bias was occurred because of the negative stigma in the community towards COVID-19, so that many patients continued to cover up their symptoms, particularly shortness of breath. To overcome the bias, we measured patients’ condition objectively.\n\nDescriptive analysis was completed by presenting the number and percentage for the categorical data and by presenting the average standard deviation of data with normal distribution in numerical data, while data that were not normally distributed were presented by the median and interquartile range (IQR).\n\nNormality of the data was tested by using the Kolmogorov-Smirnov test. For the analytical calculations, the statistical t-test was used by comparing the differences between the two means or using the Mann-Whitney test for abnormally distributed data. Determination of the cut-off point from various quantitative data measurements was used as the outcome predictors was used to calculate the Receiver Operating Characteristics (ROC) curve. The relationship between various risk factors for COVID-19 was analyzed using multiple logistic regression analysis. The significance of the statistical test results was determined based on the p-value < 0.05. For the statistical analysis, a number of programs might be utilized, including the Statistical Package for Social Sciences (SPSS), PSPP, JASP, and Rstudio; however, we used SPSS version 26.0 for Windows. The size of study sample was determined based on the rule of thumb formula for multivariate regression analysis.15–18 The minimum sample required was 330.\n\n\nResults\n\nA number of 537 subjects were included in our study, consisting of 336 patients with mild COVID-19 and 201 patients with moderate COVID-19. Analysis was carried out during the 14-day follow-up of treatment, with 72 patients had worsened, and those who did not experience worsening were 465 subjects. Further analysis revealed that 20 subjects experienced worsening from mild COVID-19 to severe or critical, and 52 subjects experienced worsening from moderate to severe COVID-19 progressed to severe and critical. Data is shown in Figure 1.\n\nCOVID-19: Coronavirus disease; REDCap: Research Electronic Data Capture.\n\nMost of the patients included were male (50.3% vs. 49.7). The median age of the subjects was 46 years old, ranging from 18 to 80 years. Median BMI was 23.1 kg/m2, and subjects with normal body mass index occupied the highest percentage (45.2%), followed by overweight (31.9%), obesity (19.1%), and underweight (3.9%). The most common comorbid in the subjects was hypertension. Chronic lung disease consisting of Chronic Obstructive Pulmonary Disease (COPD) and pulmonary tuberculosis had a percentage of 0.9%, and autoimmune disease was found in 0.5% of the patients. Asthma bronchiale was not found as a comorbid in the study subjects. The most common clinical manifestation was cough (65.0%). The demographic and clinical characteristics of the subjects are shown in Table 1.\n\nThe average time of worsening was on the fourth day of treatment. Death in the worsening group occurred in 16 subjects (17.7%) after 14 days of the treatment. In the study group that experienced worsening, 26 subjects (36.1%) died after passing the 14-day follow-up period. Subjects in the study group without worsening did not experience death until the end of hospitalization, as shown in Table 2.\n\nNon-rebreathing mask was used in 52 subjects (72%), marking it the most common means of ventilation support. Eight subjects in the deteriorating group used mechanical ventilators during the treatment (11.1%). No patient was classified in the non-worsening group that used a non-rebreathing mask and a ventilator.\n\nTable 3 presented the bivariate analysis of demographic variables, which showed that subjects aged over 60 significantly correlates with the worsening of COVID-19 (p < 0.0001). Gender, Body Mass Index (BMI), and travel history are not statistically significant in predicting the worsening of COVID-19. Hypertension (p = 0.001), heart disease (p < 0.0001), diabetes mellitus (p = 0.001), and chronic kidney disease (p < 0.0001) were significantly related to the worsening of COVID-19. Clinical manifestations showed that cough, fever, and shortness of breath were significantly associated with the aggravation of COVID-19, with a p-value of 0.0003, 0.011, and < 0.0001, respectively. Examination of vital signs at first admission showed that respiratory rate (p < 0.0001) and pulse rate (p = 0.04) were also significant. Laboratory examination revealed a significant difference between the worsening and non-worsening groups for leukocytes, eosinophils, band neutrophils, segment neutrophils, lymphocytes, monocytes, ALC, NLR, and CRP (p < 0.05). Radiological examination revealed the appearance of pneumonia on a chest X-ray showed a significant difference between the worsening and non-worsening COVID-19 groups, with p-value < 0.0001.\n\n* Statistically significant (p < 0.05)\n\nNumerical data that was statistically significant for the worsening of COVID-19, the cut-off value was determined based on the calculation of the ROC curve, as shown in Table 4 below.\n\nFigure 2 shows the factors analyzed in the ROC curve. In the analysis through the ROC curve obtained from seven variables, only pulse rate and temperature whose cut-off values were not statistically significant (p < 0.05). Multiple logistic regression was carried out to analyze what factors were related to the worsening of COVID-19 patients using multivariate analysis. The variables included in this study had a p-value of < 0.25 from the bivariate analysis results or were considered important by the researcher. Variables in multivariate analysis were age > 60 years, male, hypertension, diabetes mellitus, chronic heart disease, chronic kidney disease, body mass index, dyspnea, fever, cough, respiratory rate, pulse, body temperature, leukocyte value, ALC value, NLR, CRP value, pneumonia in the chest X-ray.\n\nAUC: Area under the ROC curve; ALC: Acute lymphocyte count; NLR: Neutrophil-to-lymphocyte ratio; CRP: C-Reactive protein.\n\nThe final model results from multiple logistic regression showed that variables significantly related to the worsening of COVID-19 patients were age, heart disease, diabetes mellitus, respiratory rate, and NLR. Age over 60 was the most significant risk of worsening COVID-19 from mild or moderate to severe or critical (aOR = 4.207, 95% CI 2.13 to 8.32). Patients with a previous history of heart disease also increase the likelihood of the disease deterioration (aOR = 2.802, 95% CI 1.12 to 6.99), followed by diabetes mellitus (aOR = 3.107, 95% CI 1.43 to 6.74), respiratory rate > 23x/minute (aOR = 3.71, 95% CI 1.87 to 7.38), and NLR > 3.8 (aOR = 2.51, 95% CI 1.21 to 5.21). Multivariate analysis is shown in Table 5.\n\n* Statistically significant (p < 0.05).\n\n\nDiscussion\n\nOur study classified the patients with and without worsening states, then retrospectively analyzed the factors affecting the outcome. Previous studies showed several factors are associated with the deterioration of the disease and the poor outcome, including older age, male, comorbidities such as obesity, hypertension, heart disease, chronic obstructive pulmonary disease, and chronic kidney disease, and also laboratory parameters such as C-Reactive Protein and NLR.3,8,10,20–24 In our study, age over 60 years old, previous history of heart disease, diabetes mellitus, respiratory rate > 23x/minute, and NLR value > 3.8 were found to be statistically significant as the factors affecting the worsening of COVID-19 in multivariate analysis. Several conditions may affect the results.\n\nSubjects aged over 60 affected the risk of worsening COVID-19 by 4.20 times higher (95% CI 2.128 – 8.320) to severe and critical degrees compared to younger ages on treatment for 14 days at the hospital. A previous meta-analysis combining various registries around the world, including China, Italy, Spain, United Kingdom, and the United States involving 611.583 patients, explained that the risk of COVID-19 worsening increases exponentially with age, especially in the elderly.25 The elderly have a higher risk of worsening because of the susceptibility to the infection and more severe clinical manifestations due to the physiological process of aging and various comorbidities that can reduce the functional capacity of the body's defense mechanism to combat the invasion of various microorganisms that enter and cause the infection.25,26\n\nPatients with comorbidities were more susceptible to COVID-19 infection and poor outcomes. Our study found that hypertension was the most common comorbid (38.9%), followed by diabetes mellitus (31.9%), chronic heart disease (18.1%), and chronic kidney disease (15.3%) in deteriorated patients. These comorbidities were significant in bivariate analysis, but only chronic heart disease and diabetes mellitus were statistically significant in multivariate analysis. A meta-analysis by Chang et al. found that hypertension, diabetes mellitus, and cardiovascular disease were the most common comorbidities associated with the severity of disease and mortality from COVID-19.27 The immune system in diabetic patients became weak and compromised, thus worsening the COVID-19 condition.28 The effect of COVID-19 on the cardiovascular system is also remarkable. Rapid release of high level of cytokines due to the COVID-19 infection causes the dysfunction of vascular endothelial cells and abnormal coagulation state, increasing the likelihood of thromboembolic events to occur.29 Therefore, patients with coronary artery disease (CAD) and COVID-19 present a greater risk of mortality. In groups of survivors against non-survivors, the incidence of CAD was 8.5% versus 21.6%, respectively.30 Conversely, the later analysis shows that hypertension and chronic kidney disease were not statistically significant. As the risk linked with hypertension is accentuated by its confounding influence on diabetes mellitus, Sun et al. discovered that hypertension was not an independent factor (95% CI 0.33 – 1.61).31 Another study also stated that there was no correlation between renal disease and aggravation of COVID-19 (95% CI 0.76 – 7.50), as renal involvement is not caused solely by one factor.32,33\n\nPatients with respiratory rate > 23x/minute at first admission had a higher risk of pulmonary deterioration. An increase in the respiratory rate indicates an early sign of disturbed airway physiology before it progressively becomes the symptom of severe COVID-19.34 Early detection of respiratory rate > 23x/minute on physical examination is a beneficial sign, as stated in the minor criteria for severe pneumonia according to ATS/IDSA, where the higher respiratory rate is an alarm sign to notify the physician to evaluate and treat effectively and immediately.35\n\nLeukocyte, lymphocyte, neutrophil, platelet, and neutrophil-lymphocyte ratio may be used to predict the worsening.1,36 Patients with severe COVID-19 symptoms should have laboratory parameters checked for hyperinflammatory markers to improve mortality rates.37 One of the causes of inflammation is infection. A severe inflammatory response contributes to a weak adaptive immune response. This causes an imbalance in the immune response.36,38 Circulating biomarkers can represent inflammatory and immune status, thus can be used as potential predictors in the prognosis of COVID-19 patients.24 Yang et al. found that patients with worsening of the disease usually have progressively lower lymphocyte, higher neutrophil, and increased NLR.36 Higher NLR was found to be independently correlated with severe COVID-19.39 The amount of the increase in neutrophil counts seen during the immunopathological phase, even in the absence of bacterial co-infection, nonetheless reflects the intensity of the inflammatory response.40 Moreover, several chronic conditions may affect NLR, such as hypertension, diabetes mellitus, and cardiovascular disease.41 Previous studies also reported that severe lymphopenia and higher WBC were linked to the poor prognosis of COVID-19.42,43 These findings align with our study result, as the severe and critical patients had higher leukocyte, more severe lymphopenia, neutrophilia, and increased NLR.\n\nOlder age is associated with elevated proinflammatory cytokines, thus contributed to prolong viral RNA shredding in COVID-19 patients.44,45 High neutrophil was observed during a cytokine storm caused by COVID-19.46 A previous study found that neutrophils will increase and enter the lungs during a cytokine storm that triggers ARDS, causing organ damage and death in COVID-19. This was found after post-mortem autopsies were carried out on COVID-19 patients.47\n\nAccording to the result of our study, the five significant factors could be used to forecast COVID-19 deterioration and determine which patients need to start receiving treatment immediately. Recent research has shown that the use of monoclonal antibodies (mAbs) like ritonavir-boosted nirmatrelvir (paxlovid), remdesivir, bebtelovimab, and molnupiravir reduce the risk of disease deterioration.48 To avoid an increase in mortality rate, our study findings can be utilized to identify which patients need to start receiving these mAbs earlier.\n\nHowever, some limitations should be noted. As the data were collected retrospectively, there were missing or incomplete data, including anosmia, ageusia, malignancy, cerebrovascular disease, and chronic liver disease. Therefore, role of these variables as risk factors for clinical worsening could not be investigated.\n\n\nConclusion\n\nFive independent variables are interrelated and can affect the deterioration of COVID-19, including older age, chronic heart disease, diabetes mellitus, higher respiratory rate, and high NLR values. These risk factors help prioritize the patients and predict treatment outcomes since these factors are routinely measured in managing COVID-19 patients.\n\nThis research has been approved by the Hasan Sadikin Hospital Ethical Committee with ethics approval number LB.02.01/X.6.5/370/2021. Our study was carried out in compliance with the Declaration of Helsinki. The ethics committee waived the requirement for informed consent since written patient consent was not necessary for this secondary use of medical data.",
"appendix": "Data availability\n\nFigshare: Baseline Data for Risk Factors of COVID-19 Clinical Worsening: A Retrospective Cohort Study in COVID-19 Referral Hospital at West Java, Indonesia, https://doi.org/10.6084/m9.figshare.21786302.v1. 49\n\nThis project contains the following underlying data:\n\n• Data of the study – Risk Factors COVID-10 Worsening.csv\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nAs an observational study, our research complies with STROBE guidelines.\n\n\nAcknowledgements\n\nThe authors convey the highest appreciation to all health professionals who were directly managing and treating COVID-19 patients at Hasan Sadikin General Hospital, especially in the Division of Respirology and Critical Care Medicine, Division of Infection and Tropical Diseases, Department of Internal Medicine and Department of Clinical Pathology Hasan Sadikin General Hospital, Bandung, Indonesia.\n\n\nReferences\n\nGuan W-J, Ni Z-Y, Hu Y, et al.: Clinical Characteristics of Coronavirus Disease 2019 in China. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nSun Y, Guan X, Jia L, et al.: Independent and combined effects of hypertension and diabetes on clinical outcomes in patients with COVID-19: A retrospective cohort study of Huoshen Mountain Hospital and Guanggu Fangcang Shelter Hospital. J. Clin. Hypertens. (Greenwich). 2021; 23(2): 218–231. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang B, Li R, Lu Z, et al.: Does comorbidity increase the risk of patients with COVID-19: evidence from meta-analysis. Aging. 2020; 12(7): 6049–6057. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSoanno Marchiori J, Athos da Silva de Oliveira M, Maria Pinheiro Bezerra I: COVID-19 and its relationship with kidney diseases: a scope review. J. Hum. Growth Dev. 2021; 31: 533–548. Publisher Full Text\n\nDhont S, Derom E, Van Braeckel E, et al.: The pathophysiology of ‘happy’ hypoxemia in COVID-19. Respir. Res. 2020; 21(1): 198. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLi HY, Guo Q, Song WD, et al.: Modified IDSA/ATS Minor Criteria for Severe Community-Acquired Pneumonia Best Predicted Mortality. Medicine. 2015; 94(36): e1474. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYang AP, Liu JP, Tao WQ, et al.: The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int. Immunopharmacol. 2020; 84: 106504. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLagunas-Rangel FA: Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis. J. Med. Virol. 2020; 92(10): 1733–1734. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMoss P: The T cell immune response against SARS-CoV-2. Nat. Immunol. 2022; 23(2): 186–193. PubMed Abstract | Publisher Full Text\n\nPimentel GD, Dela Vega MCM, Laviano A: High neutrophil to lymphocyte ratio as a prognostic marker in COVID-19 patients. Clin. Nutr. ESPEN. 2020; 40: 101–102. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKerboua KE: NLR: A Cost-effective Nomogram to Guide Therapeutic Interventions in COVID-19. Immunol. Investig. 2021; 50(1): 92–100. PubMed Abstract | Publisher Full Text\n\nQin C, Zhou L, Hu Z, et al.: Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin. Infect. Dis. 2020; 71(15): 762–768. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTong X, Cheng A, Yuan X, et al.: Characteristics of peripheral white blood cells in COVID-19 patients revealed by a retrospective cohort study. BMC Infect. Dis. 2021; 21(1): 1236. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuo XJ, Thomas PG: New fronts emerge in the influenza cytokine storm. Semin. Immunopathol. 2017; 39(5): 541–550. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCOVID-19 Treatment Guidelines Panel: Coronavirus Disease 2019 (COVID-19) Treatment Guidelines.\n\nBaseline Data for Risk Factors of COVID-19 Clinical Worsening: A Retrospective Cohort Study in COVID-19 Referral Hospital at West Java, Indonesia.2022.Publisher Full Text Reference Source"
}
|
[
{
"id": "180464",
"date": "01 Aug 2023",
"name": "Gurmeet Singh",
"expertise": [
"Reviewer Expertise My area of expertise is interventional pulmonology and non-tuberculous pulmonary infectious 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 article is clearly and accurately well presented and it cites the current literatures. As the is a new virus hence majority of the citations are not more than 5 years. Details of methods and analysis are sufficiently provided. The design used is appropriate (cohort retrospective for mild and moderate COVID-19) and work is technically sound. Details of method and analysis are clearly provided. As a cohort design it would be much better to also include a survival analysis between mild and moderate COVID-19 subjects rather than describing ROC curve, as the ROC curve in this study does not give more than 80% sensitivity.\nDemographics characteristics of mild and moderate COVID-19 can also be presented. Also, the research team can also give information regarding the medication and the mean dose for nasal canula etc, given to the all subjects and information as what were the reason for hospitalization in the mild COVID-19 group. This will give the readers more important information. Table 3 bivariate analysis can be omitted and moved to the appendix.\nAll source data underlying the results are available hence no issues for reproducibility. Conclusion are not adequately drawn as there were no analysis regarding interrelationship between the 5 variables and hence conclusion should be revised. Overall a good article for retrospective data but much better if can undergo a 3rd party proof reading before indexing.\nArticle status: approved with reservation (required further revision before indexing).\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?\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": "189950",
"date": "01 Aug 2023",
"name": "Kin Israel Notarte",
"expertise": [
"Reviewer Expertise Vaccines",
"COVID-19",
"long COVID",
"emerging infections",
"HPV",
"immunology"
],
"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 this retrospective cohort study, Soeroto and colleagues conducted an analysis using data from the Hasan Sadikin General Hospital's COVID-19 patient registry covering the period from April to December 2020. The primary aim was to identify key factors influencing the progression of COVID-19 within a 14-day follow-up period among 537 patients, of whom 72 experienced deterioration. Utilizing multivariate analysis, the researchers identified several significant risk factors for worsening COVID-19, including age over 60 years, heart disease, diabetes mellitus, respiratory rate exceeding 23x/minute, and a higher neutrophil-to-lymphocyte ratio (NLR) above 3.8. While the study successfully identified prognostic factors for COVID-19, it is important to note that these findings are consistent with existing literature and have been well-established previously. To enhance the study's contribution, the authors should clearly highlight the specific research gap their study addresses, differentiating it from previous work.\nMoreover, the discussion section of the study should emphasize the critical importance of effectively managing COVID-19 severity, as severe cases are more likely to lead to post-COVID syndrome, which is becoming a growing concern. By underscoring the need for early intervention and comprehensive care to mitigate long-term consequences, the study's implications will become more impactful and relevant.\nIn order to strengthen the credibility of the research, the authors should dedicate a section to explicitly outline the limitations of their study. Transparently addressing potential shortcomings, such as sample size, data collection methods, or other constraints, will provide context for the results and enhance the validity of the findings.\nAcknowledging these limitations also offers opportunities for future research and improvements in the field.\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? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-152
|
https://f1000research.com/articles/12-151/v1
|
09 Feb 23
|
{
"type": "Research Article",
"title": "Determination of pharmacological activity of bioactives in Allium sativum using computational analysis",
"authors": [
"Stephen Ouma",
"Richard Kagia",
"Faith Kamakia",
"Stephen Ouma",
"Richard Kagia"
],
"abstract": "Introduction: Use of natural products for management of diseases has increased widely due to the belief that natural products are less toxic than conventional medicines. Natural products have been utilised for management of chronic diseases such as diabetes and cancers. Respiratory infections have also been managed using natural products. Allium sativum is one of the natural products that has been utilised in the management of SARS-CoV infections, diabetes and cancer. Methods: This study was aimed at screening bioactive agents in Allium sativum using computational analysis. The targets of the bioactive agents were predicted using SwissTargetPrediction tools. Molecular docking followed, where the docking energies of the bioactive agents to the targets were generated. The bioactive agents were analysed for pharmacokinetics properties using SwissADME as well as toxicity profiles using the ProTox II webserver. The docking scores, toxicities and pharmacokinetics profiles of the bioactive agents in Allium sativum were compared with those of reference compounds. Results: All the bioactives showed lower docking scores than the reference compounds. The bioactives, however, showed some activity on specific receptors such as carbonic anhydrases, cyclooxygenase and ghrelin. All the bioactives showed high gastrointestinal tract absorption and none violated Lipinski’s rule of five. Diallyl trisulphide was predicted to be most lethal, with an LD50 of 100mg/kg, while Alliin was the safest, with 8000mg/kg. Conclusions: In conclusion, bioactives showed lower docking scores than the reference compounds, therefore overall pharmacological activity could be attributed to synergy between the bioactives for a particular receptor.",
"keywords": [
"Allium sativa",
"ajoene",
"alliin",
"allicin",
"diallyl sulphide",
"diallyl disulphide",
"diallyl trisulphide",
"molecular docking",
"ProTox",
"SwissADME"
],
"content": "Introduction\n\nThe rise in use of traditional medicines, mainly due to due to cost implications of conventional medicines and their availability, has led to the clarion call for their integration in treatment and prevention of diseases. The World Health Organization (WHO) estimates that up to 80% of the world’s population in one way or another uses herbal medicines in management and prophylaxis of diseases (2014–2023 WHO Traditional Medicine Strategy, n.d. (https://www.who.int/publications/i/item/9789241506096)). Herbal medicines have been used to manage a myriad of conditions that include and are not limited to cancer, respiratory conditions, diabetes, malaria and heart conditions (Vargas-Mendoza et al., 2019). In fact, the current WHO recommended regimen for acute and severe malaria contains artemisinin derived from Artemisia annua. Use of herbal medicines is thus on the rise due to high embracement among the population at large. The belief is that herbal medicines are cheap, easily accessible, and less toxic than conventional medicines.\n\nIt has been estimated that 10% of the human population in the world suffers from diabetes mellitus, since one in every 11 people have diabetes mellitus (Wszola et al., 2021). Projections estimate that, by 2025, 5.4% of human population worldwide will have diabetes mellitus (Wszola et al., 2021). Derangements in metabolism of glucose occurs due to insulin release impairment from the pancreas (Kumar et al., 2011). Natural remedies have been exploited in managing the complications associated with type 2 diabetes mellitus. Allium sativum has been exploited due to its flavonoid and antioxidant activity (Ojo et al., 2021). Moreover, Allium sativum has been exploited for its anticancer properties as well as in management of SARS-CoV-2 infection (Rajagopal et al., 2020). Allium sativum was one of the natural products exploited as an alternative to conventional medicines with an aim to curb the severity of the SARS-CoV-2 infection. Allium sativum modulates secretion of the cytokines and this is vital in regulating immunity. Bioactive agents in Allium sativum such as alliin can therefore be exploited further for management of respiratory infections (Donma & Donma, 2020).\n\nConventional medicines have been associated with high economic implications and copious adverse effects, which discourage adherence. Patients suffering from chronic illnesses require alternative therapies with less toxicities, which are easily accessible and cheap. There is thus the need to screen novel natural products to elucidate their pharmacological activities in the body in the attempt to provide safer medications. This study, therefore, aimed to screen novel bioactive molecules in Allium sativum for their pharmacological effects in the body, pharmacokinetic as well as toxicity profiles.\n\n\n\nI. To identify specific targets for bioactive agents in Allium sativum using SwissTargetPrediction.\n\nII. To identify docking scores of the bioactive agents in Allium sativum to the predicted targets and compare them to the docking scores of the standard drugs.\n\nIII. To identify pharmacokinetics properties of bioactive agents in Allium sativum using the SwissADME tool.\n\nIV. To identify toxicity properties of the bioactive agents in Allium sativum.\n\n\nMethods (Stephen et al., 2023)\n\n(https://dx.doi.org/10.17504/protocols.io.j8nlkwm95l5r/v1)\n\nBioactive agents in Allium sativum, namely z-ajoene, e-ajoene, alliin, allicin, S-allyl-cysteine, diallyl sulphide, diallyl disulphide and diallyl trisulphide, were searched in the PubChem tool and their canonical SMILES were copied. The SwissTargetPrediction (http://www.swisstargetprediction.ch/) tool was opened, and the copied canonical SMILES were pasted, allowing prediction of targets.\n\nGenerated results had specific UniProt (RRID:SCR_007071) codes. UniProt was opened using Google Chrome and codes generated in the SwissTarget page were searched in UniProt. UniProt then generated specific Protein Data Bank (PDB) (RRID:SCR_012820) codes. The PDB was searched using Google Chrome, and these specific receptor codes were searched. This generated specific receptors, which were downloaded in PDF format and saved in subfolders. Five receptors of each bioactive agents were downloaded and saved in the subfolders, with each receptor having different subfolders.\n\nThe PubChem online tool was used to download the active constituents in SDF format. Standard drugs were accessed from the GeneCards (RRID:SCR_002773) database, which generated specific ligands for specific receptors. The ligands were downloaded from PubChem and saved in SDF format to the subfolders.\n\nAuto-optimization of the ligands was done by using Avogadro (RRID:SCR_015983) Software. The ligands and the bioactives were then saved as optimized mol2 into the folders.\n\nChimera (RRID:SCR_002959) software was opened and the optimized ligands and bioactives were opened. Minimization of these molecules was done by clicking the structure, editing, then minimizing the structure. The minimized bioactives and ligands were saved as optimized–minimized mol2 compounds to the respective folders. Receptors were opened in Chimera and standardized by removing all the non-standard residues. The receptors were saved to the folders in PDB format and the session was closed.\n\nThe standardized receptor was opened first in Chimera followed by optimized–minimized bioactives and ligands, respectively. Surface binding analysis in Chimera was clicked, which brought up the popup allowing the output location to be set. The output location was then saved in PDBQT format to the same folders. The ligands and the receptors were specified. The binding site at the receptor was determined by setting random values at ‘search volumes’, which automatically generated the grid box at the receptor. The box was made to fit the receptor through frequent adjustments. Once the box fitted, the executable location was specified where ‘local’ output file was browsed and AutoDock Vina (RRID:SCR_011958) software present in each of the subfolders was clicked on and the ‘open’ button was tapped. The ‘Ok’ button was clicked, allowing docking of the ligands to specific receptors to occur. The binding results were generated as a popup and the bioactive agents in Allium sativum were compared with the standard compounds.\n\nThe SwissADME online tool (http://www.swissadme.ch/) was searched where the canonical SMILES of the bioactives in Allium sativum as well as the standard molecules were pasted. The red button was clicked to allow pharmacokinetics profile generation. The results were downloaded and saved to the folder.\n\nThe canonical SMILES of the bioactive agents as well as the reference drugs were copied from PubChem and pasted into the ProTox II (https://tox-new.charite.de/protox_II/index.php?site=compound_search_similarity) (RRID:SCR_018506) server. The predictions were carried out.\n\n\nResults\n\nAllicin was docked to 11-beta-hydroxysteroid dehydrogenase 1 and was predicted to have a lower docking score of -4.3 kcal/mol compared with tacrolimus -8.5 kcal/mol, as indicated in Table 1. Allicin was as well docked to carbonic anhydrase 9 (CAIX) and 10, carboxylesterase and muscarinic receptor 5 (M5), where allicin showed lower docking scores of -3.3, -4.4, -3.3 and -3.7 kcal/mol, respectively, compared with the reference compound methazolamide (-5.5, -6.4 kcal/mol), irinotecan -8.8 and darifenacin -9.6 kcal/mol, respectively. The docking scores of allicin were lower compared with the known reference compounds.\n\nAlliin showed the highest docking score of 5.6 kcal/mol when docked to nitric oxide synthase compared with docking to farnesoid X receptors (FXR) (-5.0 kcal/mol), gamma-aminobutyric acid (GABA) (-4.3 kcal/mol), glutamine-fructose-6-phosphate transaminase 1 (GFPT1) (-5.4 kcal/mol) and glutamate (-4.2 kcal/mol). All the reference compounds, chenodeoxycholic acid (-9.0 kcal/mol), vigabatrin (-4.6 kcal/mol), famotidine (-6.4 kcal/mol), cyclothiazide (-7.3) and doxorubicin (-9.7 kcal/mol), showed higher docking scores to the named receptors compared with alliin, as illustrated in Table 1.\n\nDiallyl sulphide, diallyl disulphide and diallyl trisulphide were docked to acetylcholinesterase receptor and the docking scores were in close range, with both diallyl disulphide and trisulphide giving a docking score of 3.9 kcal/mol and diallyl sulphide 3.8 kcal/mol. These docking scores were, however, lower than that of galantamine docking to acetylcholinesterase with -7.2 kcal/mol, as shown in Table 1.\n\nDiallyl sulphide was docked to both carbonic anhydrase 1 and CAIX, where the docking scores were 03.5 and -3.0 kcal/mol, respectively, compared with methazolamide that showed double the docking the affinity for these receptors.\n\nDiallyl disulphide and diallyl trisulphide were docked to COX 1 and 2 receptors where they showed lower docking scores to the reference ibuprofen molecule.\n\nAjoene showed relatively good results but still lower docking scores to ramelteon, when docked to both melatonin 1A and 1B receptors, with -3.6 and -4.2 kcal/mol, respectively. Ramelteon docking scores to melatonin 1A and IB were -5.6 and -5.2, kcal/mol respectively. Ajoene showed some affinity for muscarinic receptors with docking scores of -8.5 kcal/mol for the muscarinic 1 receptor (M1) and -6.6 kcal/mol for the muscarinic 3 receptor (M3), as indicated in Table 1.\n\nMethazolamide was predicted the safest when taken orally, with an LD50 of 1460 mg/kg, as shown in Table 2, compared with allicin (874 mg/kg). Irinotecan was slightly more lethal, with a lower LD50 of 765 mg/kg compared with allicin. Tacrolimus was predicted the most lethal, with an LD50 of 134 mg/kg. Allicin is, therefore, a slightly safer compound compared with the reference compounds with the exception of methazolamide.\n\nAlliin was predicted the safest when taken orally, with an LD50 of 8000 mg/kg, compared with the reference compounds chenodeoxycholic acid (2000 mg/kg), vigabatrin (3000 mg/kg), famotidine (4000 mg/kg) and cyclothiazide (5000 mg/kg), as indicated in Table 2.\n\nFlutamide was predicted to have a higher LD50 of 4000 mg/kg compared with diallyl sulphide with 2980 mg/kg. Diallyl sulphide, however, was predicted to be class VI, which translates to non-toxic, while flutamide was predicted to be class V, which translates to that the compound may be harmful when swallowed.\n\nDiallyl disulphide, diallyl trisulphide, succinylcholine, ibuprofen and phenelzine were predicted to belong to class III of toxicity classification that translates to the compounds being toxic when swallowed.\n\nAjoene was predicted to have an LD50 of 1600 mg/kg, which is higher than pirenzepine (500) and tiotropium (263). Ajoene belongs to class IV, which is ajoene may be harmful when swallowed, while pirenzepine and tiotropium belongs to class III that translates to they may be toxic when swallowed, as illustrated in Table 2.\n\nDiallyl disulphide was predicted to be carcinogenic active and tumour suppressor p53 active, with probabilities of 0.56 and 1.00, respectively. Diallyl sulphide was shown to be carcinogenic active, with a probability of 0.62. Diallyl trisulphide was predicted to have activity on tumour suppressor P53, with a probability score of 0.65. The rest of the parameters such as hepatoxicity, immunogenicity and cytogenecity were all inactive in all compounds.\n\nAll the bioactive agents in Allium sativa showed high gastrointestinal tract (GIT) absorption, as illustrated by Table 3. Allicin, diallyl sulphide, diallyl disulphide and diallyl trisulphide were predicted to permeate the blood–brain barrier (BBB) in the central nervous system (CNS). Ajoene and S-allyl cysteine does not permeate the BBB. None of the bioactive agents were P-glycoprotein efflux pump substrates.\n\nActivities of the bioactive agents to cytochrome enzyme was predicted, as indicated in Table 3. None of the compounds were predicted to be inhibitors of cytochrome P450 1A2 (CYP1A2), CYP2D6, CYP3A4 and CYP2C19. All the compounds showed a lack of activity towards CYP2C9, with the exception of ajoene, as indicated in Table 3.\n\nThe interaction of alliin’s pharmacophore and the FXR receptor is due to van der Waals, conventional hydrogen bond, carbon–hydrogen bond, cation–pi as well as pi–sulphur bonds, which indicate possible ligand and protein interactions (see Figure 1).\n\nNote: From molecular docking studies on the anti-fungal activity of Allium sativum (garlic) against mucormycosis (black fungus) by BIOVIA discovery studio visualizer 21.1.0.0 by Shaweta, S., et al. (2021), https://doi.org/10.17352/aaa.000013. Annals of Antivirals and Antiretrovirals, 028–032.\n\n\nDiscussion\n\nAllicin was docked to 11-beta-hydroxysteroid dehydrogenase 1 (11B-HSD), which regulates exposure of glucocorticoids to tissues (Hardy et al., 2018) and showed lower a docking score of 4.3 kcal/mol compared with tacrolimus, with 8.5 kcal/mol. Tacrolimus, however, was predicted to be more lethal than allicin. Tacrolimus showed an oral LD50 of 134 mg/kg compared with allicin, with 874mg/kg. Based on these results, allicin showed some potency in activating 11B-HSD and, therefore, allicin has some anti-inflammatory effects in the body with less oral toxicity than tacrolimus.\n\nCarbonic anhydrase 9 (CAIX) hydrates carbonic dioxide to bicarbonate and protons, and these reactions are vital in maintaining the acid base balance in the plasma and the cells. CAIX is a surface glycoprotein induced by hypoxia expressed mainly in cancerous cells. Expression of CAIX in non-cancerous cells such as the lining of the gallbladder, stomach and intestines is minimal. Deficiency of the CAIX in the stomach causes hyperplasia of the parietal cells, impairing basolateral regulation of pH in the stomach, causing a perforated GIT mucosal barrier and leading to chronic inflammation of the GIT (Pastorekova & Gillies, 2019). CAIX is, therefore, important in the defence mechanism of the stomach from acid overload. Allicin was docked to this enzyme and showed a lower binding score of -3.3 kcal/mol compared with methazolamide (-5.5 kcal/mol). Diallyl sulphide was also docked to this enzyme and showed a lower docking score of -3.0 kcal/mol compared with methazolamide (-6.5 kcal/mol). Based on these results, allicin and diallyl sulphide have potential activity to CAIX and, therefore, have a role in regulation of acidosis in the body. They are potentially protective against the acid and hypoxia in normal as well as in cancerous cells. Methazolamide was predicted to be safer than allicin. Methazolamide showed an oral LD50 of 1460 mg/kg compared with allicin, with 874 mg/kg. Diallyl sulphide was predicted to be safer than methazolamide. Diallyl sulphide showed an oral LD50 of 2980 mg/kg compared with 1460 mg/kg for methazolamide.\n\nThe M1 and muscarinic 3 (M3) receptors activation causes production of interleukin 6 and differentiation of B cells into plasma cells. Regulation of the immune system by the muscarinic receptors occurs at the cytokine levels (Chen et al., 2022). Inflammatory reactions in the body, such as along the GIT causing peptic ulcer disease, is mediated by M1 receptors while M3 receptors are expressed along the respiratory system. Pirenzepine and ajoene were docked to M1 receptors and they generated docking scores of -8.5 kcal/mol and -4.4 kcal/mol, respectively. Tiotropium and ajoene were docked to M3 receptors and they generated docking scores of -6.6 kcal/mol and -3.6 kcal/mol, respectively. Ajoene was shown to have considerable affinity to both M1 and M3 receptors, and therefore they have an important role in inflammatory reactions. Ajoene, pirenzepine and tiotropium were predicted for oral toxicity, and they generated an LD50 of 1600 mg/kg,500 mg/kg and 263 mg/kg, respectively. Ajoene was therefore the safest in terms of LD50.\n\nThe M5 receptor is widely restricted to the brain and is involved in regulation of dopamine in the substantia nigra as well as tegmental areas of the brain. M5 receptors potentiate accumulation and transmission of dopamine in the nucleus accumbens. M5 receptors are therefore crucial in behavioural adaptations of an individual to external cues (Razidlo et al., 2022). M5 receptors are potential agents in targeting Alzheimer’s diseases and schizophrenia. Darifenacin was docked to this receptor and showed a higher docking score (-6.7 kcal/mol) compared with allicin (-3.7 kcal/mol). Allicin was, however, predicted to be safer than darifenacin, with 874 mg/kg of allicin viz a viz 300 mg/kg of darifenacin. Allicin has potential behavioural and psychological roles in the body.\n\nCarboxylesterases are involved in hydrolysis of the exogenous products in the body such as drugs, chemicals as well as toxins. Carboxylesterases catalyse addition of water to the ester groups to generate carboxylic acids, which are polar enhancing elimination agents (Di Consiglio et al., 2021). Carboxylesterases are potentially targeted for neurodegenerative diseases. Allicin showed a -3.3 mg/kg docking score to this enzyme compared with irinotecan (-8.8 mg/kg). Allicin showed a safer oral toxicity with an LD50 of 874 mg/kg compared with irinotecan (765 mg/kg). Allicin therefore, has potential in elimination of toxins and chemicals from the body as a way of detoxification.\n\nBile acid synthesis maintains cholesterol homeostasis in the body by synthesis of bile acids from cholesterol. Bile acids interact with nuclear FXR to prevent hyperglycaemia, dyslipidaemia, obesity and diabetes. This helps in reduction of metabolic syndrome. FXR receptors are highly expressed in the GIT to maintain bile acid homeostasis by regulation of bile acid synthesis through feedback inhibition, preventing cholestasis and liver injury. The gut–liver–brain axis in bile acid synthesis and circadian rhythms are important in ensuring homeostasis as well as prevention of metabolic diseases and dysbiosis, which leads to a fatty liver and obesity. Activation of FXR receptors is important in glycaemic control through glucose metabolism as well as lipid metabolism, reducing inflammation (Chiang & Ferrell, 2020). Chenodeoxycholic acid and alliin were docked to the FXR receptor and showed docking scores of 9.0 and 5.0 kcal/mol, respectively. Alliin showed a lower docking score to the FXR receptor than chenodeoxycholic acid. Alliin and chenodeoxycholic acid were predicted for their oral toxicity, with 8000 mg/kg and 2000 mg/kg as LD50, respectively. Alliin, therefore, showed little affinity for the FXR receptor.\n\nNitric oxide (NO) is important in vasodilation, relaxation of smooth muscles as well as regulation of immune responses. NO is a free radical generated by nitric oxide synthases from oxidation of l-arginine to l-citrulline. The considerable amount of NO produced is important in defending the body against pathogens and is important in regulation of inflammatory responses. Overexpression of NO causes detrimental effects such as septic shock, pain, diabetes and cancers. Regulation of the synthesis of NO is therefore important in preventing the deleterious effects of NO (Cinelli et al., 2019). Doxorubicin and alliin were docked to NO synthase and they generated docking scores of 9.7 kcal/mol and 5.6 kcal/mol, respectively. Alliin showed substantial activity on NO synthase, and therefore has potential in decreasing oxidative stress in the body, decreasing inflammatory conditions.\n\nAcetylcholinesterase enzymes inhibit metabolism of acetylcholine in the CNS, increasing the acetylcholine in the CNS. This is essential in management of the Alzheimer’s, decreasing the chances of dementia and improving cognitive impairment (Santos et al., 2018). Galantamine, diallyl sulphide, diallyl disulphide and diallyl trisulphides were docked to the acetylcholinesterase enzyme and generated docking scores of 7.2 kcal/mol, 3.8 kcal/mol, 3.9 kcal/mol and 3.9 kcal/mol, respectively. Diallyl sulphide, disulphide and trisulphide showed lower docking scores to galantamine. Diallyl sulphide, diallyl disulphide and diallyl trisulphide were predicted for toxicity with an oral LD50 of 2980 mg/kg, 260 mg/kg and 100 mg/kg, respectively. Diallyl trisulphide was the most toxic. Galantamine oral toxicity results were not available. The butyrylcholinesterase enzyme is important in advanced Alzheimer’s disease by acting as a compensating enzyme. Succinylcholine and diallyl trisulphide were docked to the butyrylcholinesterase enzyme generating -5.3 kcal/mol and -4.1 kcal/mol, respectively. Succinylcholine was predicted to be more lethal, with 299 mg/kg oral toxicity compared with alliin, with 8000 mg/kg.\n\nMelatonin is a neurohormone produced by the pineal gland. Melatonin has physiological effects in the body such as anti-inflammatory, hypnotic, anticonvulsant, analgesic as well as sedative effects (Zhang et al., 2019). Melatonin binds to melatonin 1 and 2 receptors to cause these physiological effects. Ramelteon was docked to melatonin 1A and melatonin 1B receptors, generating docking scores of -5.6 kcal/mol and -5.2 kcal/mol, respectively. Ajoene showed lower docking scores to melatonin 1A and 1B, with docking scores of -3.6 kcal/mol and -4.2 kcal/mol, respectively. Ajoene has some affinity for melatonin 1 receptors, therefore they regulate the circadian rhythm.\n\nCyclooxygenase enzymes cause production of prostaglandins in the body. The two isoforms of cyclooxygenase include COX-1 and COX-2 enzymes. Gastroprotectivity activity is due to COX-1 enzymes (Lee et al., 2020). Ibuprofen, diallyl trisulphide and diallyl disulphide were docked to COX-1 receptors, generating docking scores of 7.5 kcal/mol, 4.0 kcal/mol and 4.2 kcal/mol, respectively. Diallyl disulphide and trisulphide showed some activity to the COX-1 receptor and therefore could have gastroprotective activity. Ibuprofen, diallyl trisulphide and diallyl disulphide were as well docked to COX-2 receptors, generating docking scores of 7.6 kcal/mol, 3.8 kcal/mol and 4.0 kcal/mol, respectively. Ibuprofen was predicted to be safer than diallyl trisulphide and diallyl disulphide. Ibuprofen was predicted to have an LD50 of 299 mg/kg compared with diallyl disulphide with 260 mg/kg and diallyl trisulphide predicted to have 100 mg/kg.\n\nAndrogen receptors repress transcription of testosterone and dehydroepiandrosterone in prostate cancer. In normal cells, the androgen receptor supplies the secretory proteins to the prostate gland. Androgen receptors are used to mediate the inflammatory processes in prostate cancer. Flutamide and diallyl sulphide were docked to the androgen receptor and generated docking scores of -8.8 kcal/mol and -3.7 kcal/mol, respectively. Diallyl sulphide was predicted to be less safe, with an oral LD50 of 2980 mg/kg compared with flutamide with 4000mg/kg.\n\nAll compounds were predicted to have high GIT absorption. All bioactives in Allium sativum were predicted to have higher BBB permeation except E-ajoene, Z-ajoene, alliin and s-allylcysteine. All compounds were predicted to lack inhibition of CYP2C9 except E-and Z-ajoene. E- and Z-ajoene when used concomitantly with warfarin and omeprazole could cause inhibition of metabolism of these drugs. All compounds complied with Lipinski’s rule of five.\n\n\nConclusions\n\nNone of the bioactives in Allium sativum had better docking scores than the standard drugs. However, all the bioactives showed considerable amounts of activity to the docked receptors. Activity of the bioactives in Allium sativum could be due to synergistic effects of the bioactives compared with the single pharmacological activity of the standard drugs.\n\nToxicity profiles indicated that allicin was less toxic than all the standard dugs except methazolamide. Alliin, E- and Z-ajoene were safer than all the standard drugs. Diallyl trisulphide was considered more lethal than the standard drugs.\n\nIn conclusion, bioactives in Allium sativum have potential physiological effects, which could be due to synergistic effects, and they are less toxic compared with the standard drugs.\n\n\n\n1. Further in vitro studies of bioactives in Allium sativum should be done.\n\n2. Further studies on synergistic effects of bioactives in Allium sativum should be done.",
"appendix": "Data availability\n\nHarvard Dataverse: Underlying data for ‘In silico study of Allium sativa bioactives. https://doi.org/10.7910/DVN/F7FONP (Ouma et al., 2023)\n\nThis project contains the following underlying data:\n\n- 2D visualization of compounds in Discovery studio\n\n- Docking scores of compounds\n\n- Pharmacokinetics properties of the bioactives\n\n- SWISS TARGET PREDICTIONS\n\n- Toxicity profile of the bioactives and standard compounds\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 researchers of this study would like to express gratitude to the developers of the software and webservers, which include Chimera, Avogadro, SwissADME, SwissTargetPrediction, GeneCards and ProTox II.\n\n\nReferences\n\nBanerjee P, Eckert AO, Schrey AK, et al.: ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res. 2018; 46(W1): W257–W263. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen A-Q, He S-M, Lv S-J, et al.: Muscarinic acetylcholine receptors regulate inflammatory responses through arginases 1/2 in zebrafish. Biomed. Pharmacother. 2022; 153: 113321. Publisher Full Text\n\nChiang JYL, Ferrell JM: Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy. American Journal of Physiology-Gastrointestinal and LiverPhysiology. 2020; 318(3): G554–G573. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCinelli MA, Do HT, Miley GP, et al.: Inducible nitric oxide synthase: Regulation, structure, and inhibition. Med. Res. Rev. 2019; 40(1): 158–189. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDaina A, Michielin O, Zoete V: SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017; 7(1). PubMed Abstract | Publisher Full Text | Free Full Text\n\nDi Consiglio E, Darney K, Buratti FM, et al.: Human Variability in Carboxylesterases and carboxylesterase-related Uncertainty Factors for Chemical Risk Assessment. Toxicol. Lett. 2021; 350: 162–170. PubMed Abstract | Publisher Full Text\n\nDonma MM, Donma O: The effects of allium sativum on immunity within the scope of COVID-19 infection. Med. Hypotheses. 2020; 144: 109934. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHardy RS, Fenton C, Croft AP, et al.: 11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis. J. Autoimmun. 2018; 92: 104–113. Publisher Full Text\n\nKumar S, Kumar V, Prakash O: Antidiabetic, Hypolipidemic, and Antioxidant Activities of Callistemon lanceolatus Leaves Extract. J. Herbs Spices Med Plants. 2011; 17(2): 144–153. Publisher Full Text\n\nLee J-O, Kim JH, Kim S, et al.: Gastroprotective effects of the nonsaponin fraction of Korean Red Ginseng through cyclooxygenase-1 upregulation. J. Ginseng Res. 2020; 44(4): 655–663. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOjo OA, Adegboyega AE, Johnson GI, et al.: Deciphering the interactions of compounds from Allium sativum targeted towards identification of novel PTP 1B inhibitors in diabetes treatment: A computational approach. Inform. Med. Unlocked. 2021; 26: 100719. Publisher Full Text\n\nOuma S, Njunge R, Kamakia F: In silico study of Allium sativa bioactives. Harvard Dataverse, V1.2023. Publisher Full Text\n\nPastorekova S, Gillies RJ: The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond. Cancer Metastasis Rev. 2019; 38(1-2): 65–77. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRajagopal K, Byran G, Jupudi S, et al.: Activity of phytochemical constituents of black pepper, ginger, and garlic against coronavirus (COVID-19): An in silico approach. Semantic Scholar. 2020; 9: 43. Publisher Full Text\n\nRazidlo JA, Fausner SML, Ingebretson AE, et al.: Chronic Loss of Muscarinic M5 Receptor Function Manifests Disparate Impairments in Exploratory Behavior in Male and Female Mice despite Common Dopamine Regulation. J. Neurosci. 2022; 42(36): 6917–6930. PubMed Abstract | Publisher Full Text | Free Full Text\n\ndos Santos TC , Gomes TM, Pinto BAS, et al.: Naturally Occurring Acetylcholinesterase Inhibitors and Their Potential Use for Alzheimer’s Disease Therapy. Front. Pharmacol. 2018; 9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShaweta S, Akhil S, Utsav G: Molecular Docking studies on the Anti-fungal activity of Allium sativum (Garlic) against Mucormycosis (black fungus) by BIOVIA discovery studio visualizer 21.1.0.0. Annals of Antivirals and Antiretrovirals. 2021; 028–032. Publisher Full Text\n\nStephen O, Muthoni F, Kagia R: Determination of pharmacological activity of bioactives in Allium sativum using computational analysis.2023.Reference SourceReference Source\n\nVargas-Mendoza N, Morales-González Á, Madrigal-Santillán EO, et al.: Antioxidant and Adaptative Response Mediated by Nrf2 during Physical Exercise. Antioxidants. 2019; 8(6): 196. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWszola M, Klak M, Kosowska A, et al.: Streptozotocin-Induced Diabetes in a Mouse Model (BALB/c) Is Not an Effective Model for Research on Transplantation Procedures in the Treatment of Type 1 Diabetes. Biomedicines. 2021; 9(12): 1790. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang Q, Gao F, Zhang S, et al.: Prophylactic use of exogenous melatonin and melatonin receptor agonists to improve sleep and delirium in the intensive care units: a systematic review and meta-analysis of randomized controlled trials. Sleep Breath. 2019; 23: 1059–1070. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "230867",
"date": "21 Dec 2023",
"name": "Rahadian Zainul",
"expertise": [
"Reviewer Expertise 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\nThe study \"Determination of pharmacological activity of bioactives in Allium sativum using computational analysis\" is scientifically robust, employing computational methods to assess garlic's bioactive compounds. Key aspects include:\nAppropriate Study Design: The computational approach is suitable for initial drug candidate screening. Detailed Methods: Methodology is comprehensively described, facilitating potential replication. Statistical Analysis: Not relevant due to the computational nature of the study. Data Availability: Partially addressed. Clarity on the accessibility of source data for full replication would enhance the paper. Conclusions and Results Alignment: The conclusions are well-backed by the computational analysis results.\nTo improve, the authors should clarify the availability of source data for full replication, reinforcing the study's reproducibility and scientific contribution.\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?\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? Yes",
"responses": []
},
{
"id": "230873",
"date": "20 Feb 2024",
"name": "Sandeep Kumar",
"expertise": [
"Reviewer Expertise Plant bioactives"
],
"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 evaluates the in silico docking and toxicity of bioactive compounds present in garlic. The authors report the binding affinity of the bioactive present in the garlic with potential targets. The binding affinity to targets is relatively less than the standard ligands/drugs. However, the authors propose a synergistic action might be responsible for the pharmacological activity. A few points which need to be addressed are as follows: In the introduction part of the abstract and article, it would be better if the use of Allium sativum for COVID-19 and cancer management was removed. Instead, the potential protective role could be mentioned. The full form of SMILES should be written in the first mention. Similarly, full enzyme names must be written in the first mention, e.g. for cyclooxygenase (COX). In the methods section, I think it will be in PDB format for receptors instead of PDF. The - sign seems to be missing in the manuscript in several places. Also, while discussing the docking score, its basis, i.e., binding energy, can be mentioned. The toxicity profiles for different compounds can be mentioned in one paragraph instead of its discussion in every paragraph. In Figure 1, the full form of FXR needs to be mentioned. Also, if the figure is re-used/reproduced from the source mentioned, a statement for permission from the authors could be added. The beta must be replaced with the appropriate symbol, i.e., β. In the second paragraph, the use of allium is not due to its flavonoid compounds but organosulphur compounds like allicins, which are a major part of the discussion in this manuscript, too. It can be changed appropriately. The sentences towards the end of the discussion section can be rewritten to bring clarity to the manuscript.\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?\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": []
}
] | 1
|
https://f1000research.com/articles/12-151
|
https://f1000research.com/articles/12-150/v1
|
09 Feb 23
|
{
"type": "Research Article",
"title": "Identification of binding sites in nicastrin and binding modes of its inhibitors",
"authors": [
"Ngceboyakwethu P Zinyama",
"Upenyu Guyo",
"Grace Mugumbate",
"Ngceboyakwethu P Zinyama",
"Grace Mugumbate"
],
"abstract": "Background: Nicastrin is a confirmed breast cancer target, but the lack of knowledge about its binding sites and the structural basis of interactions with known small molecules makes the development of small molecules against it challenging. Methods: Molecular docking and molecular dynamics simulations were used in this work to identify binding sites in nicastrin, a gamma-secretase component that has been implicated in breast cancer and a potential drug target in cancer chemotherapy. Results: Docking calculations identified three binding sites, however binding site analysis using druggability assessment identified a region that encompasses the DYIGS motif, the DYIGS site as the most favorable binding site. This site was validated by a 50 ns molecular dynamic simulation with a known inhibitor CID44433923 and free energy of binding was found to be -11.4 kcal/mol and mainly driven by hydrophobic interactions. Per residue decomposition analysis showed that Gln139, Val138 and Arg105 had a relatively high contribution towards the free energy of binding. These results suggest that these residues might be critical in nicastrin inhibition. Binding mode analysis by docking previously reported nicastrin inhibitors identified residues Gln139, Val138 and Asp143 as key in the interactions. Conclusions: This work affords an insight into the binding mechanism of small molecules and might direct drug design efforts towards nicastrin.",
"keywords": [
"nicastrin",
"docking",
"molecular dynamic simulations",
"binding site",
"free energy of binding",
"druggability",
"breast cancer"
],
"content": "Introduction\n\nBreast cancer's devastating effects are revealed by high incidence and mortality rates worldwide. Breast cancer is the most commonly diagnosed cancer, accounting for 11.6% of all cases and being the leading cause of cancer deaths in women, according to GLOBOCAN estimates from 2018.1–3 Because the estrogen receptor alpha (ER) stimulates more than 75% of breast cancer cases, most standard breast cancer therapies inhibit the function of ERα.4,5 However, the success is obscured by 40 to 50% resistance due to alternative signaling pathways that fuel the growth of breast cancer cells6,7 and overexpression of nicastrin, a member of a four-contained gamma-secretase complex implicated in the resistance mechanism.6,8,9 The resistance mechanism relies on breast cancer stem cells, a subpopulation of cancer cells that drive breast cancer progression and recurrence, and these cancer stem cells thrive on signaling pathways critical to normal stem cell survival, for example, the notch signaling pathway. The notch signaling pathway is processed by the gamma-secretase complex, which results in the formation of the notch intracellular domain (NICD), which when released into the nucleus initiates a variety of cellular processes such as stem cell maintenance, cell differentiation, and cell death.6 The notch-signaling pathway must be modulated for standard breast cancer drugs to be effective. As shown in Figure 1, the gamma-secretase complex is composed of presenilin, presenilin enhancer-2 (pen-2), anterior pharynx defective-1 (aph-1), and nicastrin.\n\nThe four subunits are shown as presenilin, pen-2, aph-1, and nicastrin.\n\nPresenilin bears the catalytic site of the complex and pen-2 directly binds to presenilin and contributes to the maturity and catalytic mechanism of the complex.10 Aph-1 and nicastrin function to stabilize the complex11 and nicastrin are also involved in substrate recognition and recruitment.12,13 The modulation of the notch can be done by targeting the gamma-secretase complex that mediates its proteolysis, however, inhibition of the gamma-secretase complex by targeting the catalytic site has confounding effects due to its functional link to critical signaling processes. Various studies have looked at modulation of the gamma-secretase complex rather than its inhibition to avoid these confounding effects on normal cell processes. Since nicastrin is involved in substrate recognition and recruitment and not in the catalytic events of the complex, targeting nicastrin could modulate the functions of the complex without completely inhibiting it.14\n\nNicastrin is a single-pass transmembrane protein with a heavily glycosylated ectodomain. Functional domains have been identified in nicastrin and are a possible location of binding sites that can be used in designing small molecules that target nicastrin. The ectodomain shares structural similarity with aminopeptidases, especially with the bacterial aminopeptidase (BAP) both having a large and small lobe in the ectodomain. The active site in BAP is located in the large lobe and bears two zinc ions which are essential for protease activity, whilst a similar region in nicastrin is covered by a loop that acts as a lid extending from the small lobe to the large lobe.13 The area covered by the lid in nicastrin does not have the zinc ions for protease activity but bears the conserved hydrophilic DYIGS motif corresponding to residues Asp336, Tyr337, Ile338, Gly339, and Ser340, that are thought to be essential in modulating gamma-secretase activity, and in substrate recognition and recruitment.15,16 The tetratricopeptide repeat-like domain is another functional domain that has been identified in nicastrin. The tetratricopeptide repeat-like region is homologous to the tetratricopeptide repeat domain that is usually involved in peptide recognition. A study by Zhang et al. (2012) revealed that binding an antibody to a conformational epitope in the tetratricopeptide repeat-like domain resulted in the loss of enzymatic activity by the gamma-secretase complex.17 Efforts in targeting nicastrin have seen the development of monoclonal antibodies to modulate the substrate binding and these monoclonal antibodies managed to reduce the production of the NICD.14,18 Recently, it was reported that a notch inhibitor cowanin was found to reduce levels of nicastrin without affecting the expression of other gamma-secretase subunits.19 A search through bioassay data in PubChem20 provides more than 500 small molecules that target nicastrin and other components of the gamma-secretase complex though binding data does not show small molecules that are specific to nicastrin only. Insight into the binding modes and structural basis of interactions of small molecules in nicastrin and the preferred binding sites of these compounds in nicastrin are still to be published.\n\nIn silico approaches such as molecular docking can be used to identify binding sites and determine binding modes of small molecules in protein structures. Molecular dynamics can be used to validate the binding site and interactions. An assessment can also be done to ascertain if drug-like molecules can bind to the binding sites. These drug-like molecules possess properties such as solubility predicted by the octanol-water partition coefficient less than 5; molecular weight between 200 and 500 Daltons; polar surface area and charge described by less than 10 H-bond acceptors and 5 H-bond donors.21 These properties influence in vivo and in vitro activity of orally active compounds.\n\nThe present work aimed to identify possible binding sites in nicastrin and determine modes of binding of a set of previously reported nicastrin inhibitors. Blind docking calculations were used to predict binding sites in nicastrin. The docking calculations were validated by molecular dynamics simulations to establish the stability of the ligand in the binding site. Binding modes of known nicastrin inhibitors are also reported. The results of this study can be used to enhance the structure-based drug design efforts of anticancer drugs targeting nicastrin.\n\n\nMethods\n\nProtein preparation\n\nThe structures of the gamma-secretase complex (PDB ID 6IDF)22 and (PDB ID 5A63)23 were retrieved from the Protein Data Bank and nicastrin (Chain A) was extracted from these structures. Two nicastrin structures were used to select the best conformer during binding mode analysis. Using AutoDock Tools,24 nicastrin structures were prepared for docking calculations by adding Gasteiger charges, merging non-polar hydrogens, as well as assigning the correct AutoDock4 atom types, and adding hydrogen atoms. The prepared Nicastrin structures were saved in pdbqt format.\n\nLigand preparation\n\nA dataset was obtained from the PubChem database,20 which contained 536 human nicastrin inhibitors with their biological activities expressed as IC50 values. Inhibitors labelled Inconclusive and Unspecified impair the ability of derived models to predict bioactivity and, as a result, were removed from the dataset. Because the data was collected from various bioassay types, the bioactivities were normalised by converting them to molar units and then logarithmically transforming them to pIC50 (-logIC50) values. The data set's inhibitory potencies, expressed as pIC50, ranged from 4.3 to 11.7. With a pIC50 of 8.0, the molecules were classified as active. The dataset was clustered using hierarchical clustering in DataWarrior, and 30 compounds (Figure 2) from the clusters were chosen for docking.\n\nUsing AutoDockTools,24,25 the 30 ligands were prepared for docking by carrying out energy minimization for 200 steps using conjugate gradient and MMFF94 force field, adding Gasteiger charges, merging non-polar hydrogen atoms, assigning AutoDock4 atom types, and adding hydrogen atoms. The root, torsion degree of freedom, and the number of rotatable bonds were defined for each of the ligands. The ligand structures were saved in pdbqt format.\n\nBlind docking in Autodock Vina was done to identify potential binding sites in nicastrin. From the docking set of 30 ligands, ligand CID 44433923 ([1-[[(7S)-5-methyl-6-oxo-7H-benzo [d][1]benzazepin-7-yl]amino]-1-oxopropan-2-yl]N-(2,2,3,3,3 pentafluoropropyl)carbamate) with a high nicastrin bioactivity from PubChem was selected for use in the blind docking calculations. The grid box for docking was centered on the protein with a 0.375 Å default spacing and x,y,z dimensions of 70.6636 × 122.1096 × 64.2142 Å and 92.3445 × 67.4301 × 108.9436 Å for 5A63 and 6IDF, respectively.\n\nThe Internal Coordinate Mechanism (ICM) method developed by Molsoft L.L.C26 was used to validate the predicted binding sites of the two protein structures (PDB IDs 6IDF and 5A63). Using receptor preparation tools in ICM, the protein structures were individually prepared by optimizing hydrogen, histidine, proline, glycine, and cysteine residues. Missing hydrogens and heavy atoms were added and the structures were saved as ICM objects. Potential binding pockets on the proteins were identified using ICM PocketFinder27 and their druggability was given by the calculated DLID score.28\n\nTo determine the stability of the docked complex as well as the intermolecular interactions over time, molecular dynamics simulations were performed using GROningen MAchine for Chemical Simulations (GROMACS) 2022.129 software and Chemistry at Harvard Macromolecular Mechanics (CHARMM36)30 as an all atom forcefield. The AnteChamber Python Parser interface (ACPYPE)31 portal was used to generate ligand topology for CID44433923. The complex was solvated in an octahedral TIP3P water-box with a distance of 10 Å between the box's edges and neutralized using K+ and Cl- ions. This was followed by a steepest descent method used to minimize the system and set at 5000 steps. The steepest descents converged at 2368 steps when the maximum force was less than 1000 kJ/mol/nm. The system was equilibrated for 125 ps and all bonds and heavy atoms were restricted by the LINCS (Linear Constraints Solver) algorithm. The temperature and pressure were set to 310 K and 1 atm respectively and finally the system was subjected to a 50 ns production run saving the trajectories every 2 ps.\n\nTo determine the stability of the docked complex as well as determine the intermolecular interactions over time, the root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (RoG) and number of hydrogen bonds (hBond) were obtained from gromacs routines for the analysis.\n\nFree energy of binding was calculated using molecular mechanics with generalized Born surface area solvation (MMPBSA) using gmx-mmpbsa.32 These calculations considered snapshots from 27 to 50 ns of the molecular dynamic simulations. The binding energy calculated considered only the enthalpy of a single trajectory to minimize computing costs. Per residue energy decomposition analysis was also done to identify residues in the binding site contributing to the binding energy.\n\nTo characterize the binding modes and interactions of known nicastrin inhibitors, the 30 prepared ligands were docked into the DYIGS binding site of nicastrin PDBID 6IDF using the Autodock Vina tool. The grid box for docking was centered on the protein at 171.8221, 192.4385, 218.7799 Å with a 0.375 Å and x,y,z dimensions of 42.6757 × 41.9425 × 42.4690 Å.\n\n\nResults and discussion\n\nInitially, blind docking calculations was performed to predict potential binding sites in nicastrin conformers. The blind docking predicted three distinct binding sites which are located in similar locations in both conformers. The identified sites (Table 1) encompass domains or signature regions within nicastrin that are unique to their function (Figure 3A).33 These include a site that contains the DYIGS signature34 (DYIGS site) and the Tetratricopeptide region like site17 including a potential binding site positioned in a central cleft in the hinge region (Hinge region site). The DYIGS site had a higher affinity for compound CID44433923 as compared to the two other sites.\n\nA) The binding sites are situated and hence named according to functional regions in nicastrin. These are shown as B) Tetratricopeptide repeat-like site, C) Hinge site and D) DYIGS site all located in the large lobe of the protein.\n\nA shallow pocket located on the surface of the large lobe was predicted as a binding site and contains the tetratricopeptide repeat-like domain (Figure 3B). The tetratricopeptide repeat-like domain is homologous to TPR domain 2A and 2B helices of the HOP human protein, which binds to the C-terminal peptide of Hsp90. The TPR domains bind to substrates via side chains of α-helix residues.\n\nA hinge region that is conserved in nicastrin homologues facilitates the rotation of the large lobe relative to the small lobe13 during substrate binding.12 The hinge region is composed of phenylalanine residues (Phe286 and Phe287) from the large lobe which interact with side chains of phenylalanine residues from the small lobe through van der Waals interactions. This region forms a central cleft35 that is located at the back of the DYIGS pocket. Blind docking studies identified the central cleft and the residues that surround it as a potential binding site. Figure 3C shows the hinge site.\n\nThe DYIGS site (Figure 3D) houses the DYIGS motif corresponding to residues Asp336, Tyr337, Iso338, Gly339, and Ser340 are situated in the large lobe.12,16,36 These hydrophilic DYIGS residues are proposed to bind to hydrophilic N-termini of substrates.13 The hydrophilic DYIGS residues are buried under a hydrophobic loop or lid that extends from the small lobe.37 The orientation of the hydrophobic loop residues exposes just the side chains of Asp336 oriented towards the surface for interactions. During docking, ligands interact with the lid residues that line the hydrophilic pocket rather than interacting with the conserved residues. The hydrophobic environment conferred by the lid encourages ligand binding via hydrogen and hydrophobic bonds and ion pair interactions. The presence of aromatic residues such as phenylalanine (Phe145, Phe335, and Phe448), histidine (His58, His158, and His444), tryptophan (Trp648), and tyrosine (Tyr173, Tyr337, and Tyr453) is known to influence the function as well as molecular recognition in proteins and their presence in nicastrin might influence substrate recognition and recruitment.38 Glycans in the binding site also control the accessibility of the binding site.39\n\nThe geometry and physicochemical properties of the binding site are important in establishing the ability of the binding site to bind drug-like molecules. Descriptors that characterize geometry include volume, surface area as well as buriedness of the binding site. These descriptors correspond to the shape and size of small molecule binders of that site.27,40,41 Physicochemical properties of the site compliment the drug-like nature of the drug.27 ICM PocketFinder27 was used to assess the geometry and physicochemical properties as well as the druggability of binding sites identified by blind docking studies.\n\nThe three distinct sites identified through blind docking studies and a summary of their druggability assessment are provided in Table 2. Two of these sites (DYIGS site and Hinge site) had DLID scores favorable for binding drug-like molecules. The differences in the geometric features of these sites in the conformers might be explained by ligand-induced changes in nicastrin that were observed by Bolduc et al. (2016).12 When notch binds to the transmembrane domain of the gamma-secretase complex, rotation of the hinge region (residue Phe287) in nicastrin is induced which affects the hydrogen bond network and flexibility of the ectodomain,12 resulting in increased volume of the binding sites. The increased volume in PDB ID 6IDF can positively impact the free energy of binding ligands within the binding site.\n\nThe Hinge site in both conformers has the same hydrophobicity and approximately the same buriedness, however, the 6IDF conformer has higher aromaticity and volume and hence a higher DLID score. The volume of the 6IDF conformer is approximately 200 Å3 (Table 2) and volumes of most ligands in the dataset average 250 Å3. Considering that the volume of the ligand is known to be correlated to that of the binding site, with the ligand rarely occupying the entire binding site, binding modes of ligands were not assessed in the hinge site due to the small volume of the binding site relative to the volume if the ligands in the data set.\n\nThe tetratricopeptide repeat-like site, though having the second-largest volume had negative DLID scores in both conformers due to its low hydrophobic and aromatic character. The negative DLID score shows preferential binding to highly polar molecules that are not drug-like.\n\nAn assessment of the druggability landscape of nicastrin (PDB ID 6IDF) was done since it was the most druggable conformer (Table 2). The assessment was done by comparing attributes that define a druggable binding site using a druggability landscape. The attributes include volume, hydrophobicity, and buriedness. In the druggability landscape (Figure 4), volume was plotted against hydrophobicity and coloured according to buriedness, with larger dots indicating a druggable site. The druggability landscape shows the twenty pockets identified in ICM PocketFinder, which include the DYIGS, tetratricopeptide repeat-like, and hinge sites predicted through blind docking. ICM PocketFinder provides a DLID score which is a druggability assessment to ascertain the potential of the binding sites to interact with drug-like compounds. A positive DLID score close to 1 assumes a site to be targeted by drug-like molecules.28 Out of the twenty binding sites that were identified, just two (DYIGS site and hinge site) were predicted to be druggable by drug-like molecules.\n\nPredicted binding sites are represented by dots coloured according to their DLID scores with a positive high DLID score (purple) denoting a very druggable site and a negative DLID (red) score describing a site that is very difficult to target using drug-like molecules.\n\nThe landscape shows that the druggability of binding sites in nicastrin increases with hydrophobicity. This is understandable as hydrophobicity dominates free energy binding in protein-ligand interactions.42 Considering the characteristics of the DYIGS site which is covered by a hydrophobic lid and the hinge site which is surrounded by hydrophobic residues like Phe103, Leu171, Phe176, and Ile180, this greatly contributes to their hydrophobicity.13\n\nTo determine the stability of the docked complex and understand intermolecular interactions over time, molecular dynamics simulations were carried out. To achieve this, the root mean square deviation (RMSD), root mean square fluctuation (RMSF) and radius of gyration (RoG) was obtained from gromacs routines for the analysis.\n\nThe RMSD describes the overall conformational stability of the protein-ligand system by calculating the changes in the protein's carbon alpha (Calpha) and primary conformation, as well as that of the ligand's, during the simulation timescale. The results show that there were no major conformational changes in nicastrin as indicated by the RMSD of the complex (Figure 5). This suggested that within the 50 ns simulation the ligand was stable within the DYIGS binding site.\n\nThe RMSD for nicastrin was found in the range of 0.11-0.32 nm with an average of 0.23 nm and from 0.07-0.34 nm with an average of 0.22 nm for the ligand. The complex of nicastrin bound to CID44433923 had an RMSD in the range 0.27-0.72 nm with an average of 0.48 nm.\n\nTo account for the structural integrity of nicastrin when bound to the ligand, the RMSF (Figure 6) was evaluated. The lower the RMSF values per amino acid residue, the more stable, rigid and compact the receptor. A low RMSF value of binding site residues of not more than 0.54 nm shows that the ligand was stable within the binding site. The compactness and stability of nicastrin is also shown by its radius of gyration in Figure 7. The complex is compact as shown by the range of radius of gyration of 2.65-2.67 nm with an average of 2.66 nm.\n\nThe red dots indicate binding site residues identified.\n\nThe Gibbs free energy of -11.40 kcal/mol for ligand binding to nicastrin was calculated using MM/GBSA, as indicated in the Table 3. The van der Waals energy contribution was -21.24 kcal/mol and since this was the lowest energy term it shows that binding free energy is mainly driven by hydrophobic interactions. On the other hand, the electrostatic energy was -15.15 kcal/mol which shows its importance in the binding of ligands to nicastrin in the DYIGS site. To better understand the interactions that affect the binding's free energy the conformation with the lowest binding energy was examined. This conformation was found at 45.6 ns with a binding energy of -19.34 kcal/mol and is presented in Figure 8. The residues Gln139, Cys140, Gly144, His158, Gly168, Asn169, Gly170, and the glycan Bma805 were involved in van der Waals interactions. Along with Val138, Arg105 had a role in hydrophobic alkyl interactions. Also, the presence of Arg105 and Glu174 encouraged electrostatic interactions, with the positively charged Arg105 creating pi-cation contacts and the negatively charged Glu174 creating pi-anion interactions with the aromatic rings. Asp143 created a strong hydrogen bond of 1.79 Å by donating a hydrogen from the amide hydrogen. Per residue free energy decomposition using MM/GBSA identified residues Gln139, Val138 and Arg105 as contributing to the binding energy the most, which indicates their importance in nicastrin activity. These residues can be used in selecting small molecules during drug design.\n\nTo analyse binding modes of known nicastrin inhibitors, the selected 30 ligands (Figure 2) were docked into the DYIGS site. These compounds in the data set were first grouped according to their common substructures. A total of eight groups were obtained and the common substructures are shown in Figure 9. Groups 1, 2, and 3 contain the sulfonamide group, with groups 2 and 3 having the sulfonamide group linked to a phenyl ring. Groups 4, 5, and 6 are related through the 3-aminopropanamide component within their maximum common substructures. Generally, the analysis shows that these compounds interact with residues Val138 and Gln139 which were identified through per residue free energy decomposition analysis as contributing to the binding energy in the DYIGS site in nicastrin.\n\nCompounds that bear the sulfonamide group are generally known to be effective with good pharmacokinetic properties.43 This is observed in the diverse set used in this study, sulfonamide bearing compounds are more potent (IC50 values ranging between 6.0×10-5 μM and 8.3×10-3 μM) than other compounds without the sulfonamide group. Group 1 consists of a spiro[1,2,5-thiadiazolidene-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide substructure with two compounds; CID 23571085 and CID 15953832 bearing this moiety. These compounds are oriented similarly in the binding site; with the spirocyclic sulfonamide group predicted to interact with Val138 and Gln139 through hydrophobic interactions. Hydrogen bonding was observed between residues Tyr173 and trifluoromethyl and difluorophenyl groups in CID 15953832 and CID 23571085 respectively. Group 2 has eight compounds and contains the 4-chlorobenzene sulfonamide moiety. The sulfonyl component mostly interacts with Val138 and Gln139 through hydrophobic interactions just as with Group 1 compounds, however salt bridges between Asp 143 and Asp336 and the tert-amine group on the sulfonamide are also observed. The orientation of Group 2 compounds differs from that of Group 1 in that the halogenated phenyl part of the substructure is mostly anchored into the binding site via hydrophobic contacts with the glycans.\n\nConsidering Group 3 with four compounds containing the methyl pyrazole conjugated to a substituted benzenesulfonamide group (CIDs 53308121, 73356579, 73345935, and 16045395). Fluoro and chloro substituents in the compounds are suggested to interact with Nag803 and Nag804 through hydrophobic interactions, similar to the orientation of Group 2 4-chlorobenzene. However, the orientation of the sulfonyl part of Group 3 interacts with Cys140. This differs from the interaction of sulfonyls in Groups 1 and 2 which interact with Val138 and Gln139. Hydrogen bonds and hydrophobic contacts with Val138, Asp143, His158, and Bma805 were also common with the pyrazole group.\n\nThe binding mode of compounds that contain the sulfonyl moiety is elaborated by the schematic representation of the orientation of CID 15953832 and its interactions in the DYIGS binding site (Figure 10A and B). CID 15953832 is a potent gamma-secretase inhibitor.22 Hydrophobic interactions with residues Val138, Gln139, Asn142, Asp143, Cys159, Tyr173, Asp336 and Trp648 were observed. Interactions from docking show hydrophobic contacts between the fluorine of the difluorophenyl part of the inhibitor and the Asp336 residue, which is part of the DYIGS motif. A salt bridge between the tertiary amine group of the methylpyrazole with Asp143 was established. Hydrogen bonds are revealed between Gln163 and oxygen on the sulfonyl centre.\n\nA. Glycans in the periphery of the binding site are depicted as green (NAG) and orange (BMA) balls and sticks. B. 2D representation of binding interactions between compound CID 23571085 and DYIGS binding site residues. Green dashed lines represent hydrogen bonds and the red arcs depict hydrophobic contacts. C. Docked pose of compound CID 11306390 (magenta) in the DYIGS binding site. Glycans in the periphery of the binding site are depicted as green (NAG) and orange (BMA) ball and sticks. D. 2D representation of binding interactions between compound CID 11306390 and DYIGS binding site residues. Green dashed lines represent hydrogen bonds and the red arcs depict hydrophobic contacts.\n\nThe 3-aminopropanamide component common in Groups 4, 5, and 6 compounds interacts with residues Val138, Asp143, Nag803 and Nag804 mostly through hydrophobic interactions. The two Group 4 compounds (CIDs: 44435456 and CID44435489) have the 1,3-thiazol-2-yl]amino]-1-oxopentan-2-yl] propanamide group in their structures. The 1,3-thiazole interacts with His158 via hydrophobic contacts and the aminopropanamide with Val138. Asp143 nitrogen forms a hydrogen bond with the oxygen on the dimethylbutanamide in CID 44435456 whilst in CID 44435489, the aspartate oxygen and Gly144 nitrogen form hydrogen bonds with phenylacetylamino oxygens.\n\nCompounds in Group 5 contain the phenylacetyl amino [1-(2-methylpropan-2-yl) imidazol-4-yl] pentanamide maximum common substructure. The phenyl group in the substructure is halogenated and electrostatic interactions between the fluorines and nitrogen of Nag804 are observed. The phenylacetyl amino [1-(2-methylpropan-2-yl) imidazol-4-yl] pentanamide substructure interacts with Asp143, Cys140, Bma807, His158, Bma805 and Bma806 via hydrophobic interactions in both compounds. These compounds also interact with Asp336. The nitrogen on the trifluoromethylamino group forms hydrogen bonds with the aspartate 336 oxygen, whilst the fluorines form hydrogen bonds with Tyr173 and Asn142.\n\nThe 3,5-difluorophenyl-acetylamino propanamide substructure is common to the gamma-secretase inhibitor Compound E (CID 11306390) and CID 23656215 making up Group 6. Group 6 compounds are anchored into the binding site by electrostatic interactions between glycans Nag803 and Nag804 and propanamide oxygens. The diazepine group in both compounds interacts with Val138 and whilst residues Asp143, Tyr173, Nag803 and Bma805 form hydrophobic contacts in both compounds.\n\nThe binding mode of Groups that contain the 3-aminopropanamide moiety has been illustrated by the schematic representation of the orientation of CID 11306390 in the binding site (Figure 10C and D). This is a potent L-alanine derivative that was developed for the treatment of Alzheimer's disease.44 Halogen bond between His158 and the difluoro substituent was identified. Nag803 and Nag804 form hydrogen bonds with acetylamino propenamide oxygen and oxygen on the diazepine respectively. Aps336 forms a salt bridge with the nitrogen on the acetylamino propenamide. Asp143 forms a pi-anion interaction with the phenyl group. Hydrophobic interactions between the phenyl-2,3-dihydro-1H-benzodiazepine and Val138, Cys140, Trp648, Tyr173, Gly170 and Gly144 and Phe145 residues were also shown.\n\nGroup 7 contains two compounds that have the 3-methoxyphenyl-2-methyl-1, 2, 4-triazol-3-amine. CID67606672 contains two methoxyphenyl groups and are positioned such that one methoxyphenyl oxygen interacts with Asn142 via hydrogen bonding whilst the other methoxyphenyl forms hydrophobic contacts with His158, Bma805 and Bma807. The amino group that bridges the methoxyphenyl group and the triazole group is stabilized by hydrogen bonds with Nag803 and Asp336 via hydrophobic contacts. In CID118717947, the methoxyphenyl oxygen shares a hydrogen bond with Gln163 nitrogen.\n\nThe eighth group is composed of two compounds, CIDs 89908079 and 68380304 that share the dihydro pyrido[1,2-a]pyrazine-2,3-diol conjugated to a methyl imidazole group. Upon binding a salt bridge is formed between tertiary amines of pyrazine-2, 3-diol in both compounds with Asp143. CID89908079 displays two of these salt bridges with Asp 143 and also with the tertiary amine of the imidazol portion with Asp336. In addition, a T-π stacking exists between the phenyl group in Tyr173 and the pyrido group.\n\n\nConclusion\n\nDocking calculations were used to predict binding sites in this study. Three binding sites in nicastrin were discovered through binding site analyses. The druggability of these binding sites was assessed, and the DYIGS site was found to be the most druggable by drug-like compounds. Molecular dynamics simulations, free energy calculations, and residue decomposition analysis were used to validate the binding site. The analysis reveals that hydrophobic interactions and electrostatic forces dominate binding in nicastrin. Residues Arg105, Gln139 and Val138 were identified as the residues contributing the most to the binding energy. Known nicastrin compounds were docked in the DYIGS site and the interactions reveal that they interact with the residues Arg105, Gln139 and Val138. These findings lay the groundwork for developing small molecules targeting nicastrin for anticancer drug discovery.",
"appendix": "Data availability\n\nDryad: Nicastrin binding sites, https://doi.org/10.5061/dryad.sj3tx968f. 45\n\nThis project contains the following underlying data:\n\n- BINDING_AFFINITIES.csv\n\n- final_decomp.dat\n\n- hbonds.dat\n\n- RESIDUES_PER_FRAME_-_RESIDUES_PER_FRAME.csv\n\n- (Decomp_normal)_System-1_GB_DELTA_BDC.csv\n\n- (Normal)_System-1_GB_DELTA_TOTAL.csv\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nProtein Data Bank: Cryo-EM structure of gamma secretase in complex with a Notch fragment. Accession number: 6IDF, https://identifiers.org/pdb/6IDF. 22\n\nProtein Data Bank: Cryo-EM structure of the human gamma-secretase complex at 3.4 angstrom resolution. Accession number: 5A63, https://identifiers.org/pdb/5A63. 23\n\n\nAcknowledgements\n\nThis work was supported by the Department of Chemical Sciences at the Midlands State University through the Research and Innovation Division.\n\n\nReferences\n\nFerlay J, et al.: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer. 2010; 127: 2893–2917. PubMed Abstract | Publisher Full Text\n\nHeer E, et al.: Global burden and trends in premenopausal and postmenopausal breast cancer: a population-based study. Lancet Glob. Health. 2020; 8: e1027–e1037. PubMed Abstract | Publisher Full Text\n\nTorre LA, et al.: Global cancer statistics, 2012. CA Cancer J. Clin. 2015; 65: 87–108. PubMed Abstract | Publisher Full Text\n\nChen J, Russo J: Estrogen receptor alpha-negative and triple negative breast cancer: molecular features and potential therapeutic approaches. Biochim. Biophys. Acta. 2010; 1796: 162–175.\n\nShiau AK, et al.: The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen. Cell. 1998; 95: 927–937. PubMed Abstract | Publisher Full Text\n\nLombardo Y, et al.: Nicastrin and Notch4 drive endocrine therapy resistance and epithelial to mesenchymal transition in MCF7 breast cancer cells. Breast Cancer Res. 2014; 16: R62. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKatzenellenbogen JA, Mayne CG, Katzenellenbogen BS, et al.: endocrine therapy resistance. Nat. Rev. Cancer. 2018; 18: 377–388. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFaronato M, Lombardo Y, Coombes RC: Endocrine therapy resistance and epithelial to mesenchymal transition are driven by Nicastrin and Notch4 cooperation in MCF7 breast cancer cells. Can Cell Microenviron. 2014; 4–6. Publisher Full Text\n\nLombardo Y, Filipovi A: Nicastrin regulates breast cancer stem cell properties and tumor growth in vitro and in vivo. PNAS. 2012; 109: 16558–16563. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBammens L, Tolia A, Zwijsen A, et al.: Functional and Topological Analysis of Pen-2, the Fourth Subunit of the γ-Secretase Complex. J. Biol. Chem. 2011; 286: 12271–12282. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee S, et al.: A Conserved GXXXG Motif in APH-1 Is Critical for Assembly and Activity of the γ-Secretase Complex. J. Biol. Chem. 2004; 279: 4144–4152. PubMed Abstract | Publisher Full Text\n\nBolduc DM, Montagna DR, Gu Y, et al.: Nicastrin functions to sterically hinder γ-secretase – substrate interactions driven by substrate transmembrane domain. Proc. Natl. Acad. Sci. U. S. A. 2016; 113: 509–518.\n\nXie T, et al.: Crystal structure of the γ-secretase component nicastrin. Proc. Natl. Acad. Sci. 2014; 111: 13349–13354. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang X, et al.: A synthetic antibody fragment targeting nicastrin affects assembly and trafficking of γ-secretase. J. Biol. Chem. 2014; 289: 34851–34861. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYu G, et al.: Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature. 2000; 407: 48–54. PubMed Abstract | Publisher Full Text\n\nShah S, et al.: Nicastrin Functions as a γ-Secretase-Substrate Receptor. Cell. 2005; 122: 435–447. PubMed Abstract | Publisher Full Text\n\nZhang X, et al.: Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of γ-secretase using synthetic antibodies. PNAS. 2012; 109: 8534–8539. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFilipović A, et al.: Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells. Breast Cancer Res. Treat. 2014; 148: 455–462. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArai MA, Akamine R, Tsuchiya A, et al.: The Notch inhibitor cowanin accelerates nicastrin degradation. Nat. Sci. Rep. 2018; 8: 1–8.\n\nKim S, et al.: PubChem 2019 update: improved access to chemical data.2019; 47: 1102–1109.\n\nLipinski CA, Lombardo F, Dominy BW, et al.: experimental and computational approaches to estimate solubilty and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 1997; 23: 3–25. Publisher Full Text\n\nYang G, et al.: Structural basis of Notch recognition by human γ-secretase. Nature. 2019; 565: 192–197. PubMed Abstract | Publisher Full Text\n\nBai X, Scheres SHW: The atomic structure of human γ - - secretase.2015; 10.\n\nMorris GM, et al.: AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. J. Comput. Chem. 2010; 30: 2785–2791.\n\nRizvi SMD, Shakil S, Haneef M: A simple click by click protocol to perform docking: Autodock 4.2 made easy for non-bioinformaticians. EXCLI J. 2013; 12: 830–857.\n\nAbagyan R, Totrov M, Kuznetsov D: A New Method for Protein Modeling and Design: Applications to Docking and Structure Prediction from the Distorted Native Conformation. J. Comput. Chem. 1994; 15: 488–506. Publisher Full Text\n\nAn J, Totrov M, Abagyan R: Pocketome via Comprehensive Identification and Classification of Ligand Binding Envelopes. Mol. Cell. Proteomics. 2005; 4: 752–761. PubMed Abstract | Publisher Full Text\n\nSheridan RP, Maiorov VN, Holloway MK, et al.: Drug-like Density: A Method of Quantifying the “Bindability” of a Protein Target Based on a Very Large Set of Pockets and Drug-like Ligands from the Protein Data Bank. J. Chem. Inf. Model. 2010; 50: 2029–2040. PubMed Abstract | Publisher Full Text\n\nAbraham MJ, et al.: Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015; 1–2: 19–25.\n\nBrooks BR, et al.: CHARMM: The biomolecular simulation program. J. Comput. Chem. 2009; 30: 1545–1614. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSousa Da Silva AW, Vranken WF: ACPYPE - AnteChamber PYthon Parser interfacE. BMC. Res. Notes. 2012; 5: 1–8.\n\nValdés-Tresanco MS, Valdés-Tresanco ME, Valiente PA, et al.: gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS. J. Chem. Theory Comput. 2021; 17: 6281–6291. PubMed Abstract | Publisher Full Text\n\nEsler WP, et al.: Transition-state analogue inhibitors of γ -secretase bind directly to presenilin-1. Nat. Cell Biol. 2000; 2: 428–434. PubMed Abstract | Publisher Full Text\n\nBolduc DM, Wolfe MS: Structure of nicastrin unveils secrets of -secretase. Proc. Natl. Acad. Sci. 2014; 111: 14643–14644. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee JY, Feng Z, Xie X, et al.: Allosteric Modulation of Intact g -Secretase Structural Dynamics. Biophysj. 2017; 113: 2634–2649. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHu Y, Ye Y, Fortini ME: Nicastrin is required for γ-secretase cleavage of the Drosophila Notch receptor. Dev. Cell. 2002; 2: 69–78. PubMed Abstract | Publisher Full Text\n\nBai X, et al.: An atomic structure of human gamma secretase. Nature. 2015; 525: 212–217. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMakwana KM, Mahalakshmi R: Implications of aromatic – aromatic interactions: From protein structures to peptide models. Protein Sci. 2015; 24: 1920–1933. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGao Y, Luan X, Melamed J, et al.: Role of Glycans on Key Cell Surface Receptors That Regulate Cell Proliferation and Cell Death. Cells. 2021; 10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMacari G, Toti D, Polticelli F: Computational methods and tools for binding site recognition between proteins and small molecules: from classical geometrical approaches to modern machine learning strategies. J. Comput. Aided Mol. Des. 2019; 33: 887–903. PubMed Abstract | Publisher Full Text\n\nBroomhead NK, Soliman ME: Can We Rely on Computational Predictions To Correctly Identify Ligand Binding Sites on Novel Protein Drug Targets ? Assessment of Binding Site Prediction Methods and a Protocol for Validation of Predicted Binding Sites. Cell Biochem. Biophys. 2016; 75: 15–23. Publisher Full Text\n\nSnyder PW, et al.: Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase. Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 17889–17894. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKeown LE, et al.: Novel Orally Bioavailable gamma secretase Inhibitors with Excellent in vivo Activity. J. Med. Chem. 2009; 52: 3441–3444. PubMed Abstract | Publisher Full Text\n\nShelton CC, et al.: Modulation of gamma secretase specificity using small molecule allosteric inhibitors. PNAS. 2009; 106: 20228–20233. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZinyama NP, Guyo U, Mugumbate G:Nicastrin binding sites. [Dataset]. Dryad. Publisher Full Text"
}
|
[
{
"id": "171137",
"date": "24 May 2023",
"name": "Guanghui Yang",
"expertise": [
"Reviewer Expertise Gamma-secretase",
"structural 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 authors try to identify binding pockets for the inhibitors that target Nicastrin through computational methods. They identified three potential sites and proposed that the DYIGS site was the most druggable pocket. Well, such efforts are indeed important for the drug development, however, further experimental and biochemical characterizations are needed to support the conclusions of this study.\nThere are some major concerns about the predicted results.\nFirst, none of the identified inhibitors or modulators that target gamma-secretase has been found to bind DYIGS region. Validation of the predicted sites is needed biochemically or computationally.\nSecond, several compounds listed in the manuscript are similar with E2012, a well-known gamma-secretase modulator found to be inserted into the cavity formed by Nicastrin and Presenilin (Yang et al, Cell, 2021). Is there any possibility that some of the drugs can bind to the similar site of E2012?\nThird, this study focused on the drug binding site in Nicastrin, however, the role of the other subunits in gamma-secretase should not be negligible. Nonetheless, I partially recognize that the biochemical trials might not be completed at the current stage, however, lack of the assay-based data would reduce the novelty and weaken the conclusion of the predicted drug binding sites.\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? Partly",
"responses": []
},
{
"id": "226979",
"date": "10 Jan 2024",
"name": "Peter Mbugua Njogu",
"expertise": [
"Reviewer Expertise Synthetic Medicinal Chemistry"
],
"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\nIntroduction The present study is a computer-aided drug discovery initiative based on the Notch signaling pathway that is processed in Metazoans by the gamma-secretase complex1. The multiprotein g-secretase complex comprises four integrated functional domains namely, presenilin, presenilin enhancer-2, anterior pharynx-defective 1, and nicastrin. The proteolytic complex performs the intramembrane cleavage of more than 60 type-I transmembrane proteins2. Although best known for its role in the pathophysiology of Alzheimer's disease3, several research studies have revealed that g-secretase complex is involved in several other pathologies, particularly degenerative syndromes and carcinogenesis4. Pointedly, there already are drug repositioning efforts of g-secretase inhibitors towards chemotherapy of Notch-dependent cancers.5,6 Relevant to this study is the fact that nicastrin is overexpressed in certain types of breast cancer and has been implicated in drug resistance mechanisms.\nThe authors hypothesized that the modulation of nicastrin could be exploited therapeutically in breast cancer. The attractiveness of nicastrin as a drug target is supported by the observation that while it is not involved in the catalytic functions of the g-secretase complex, it is central in substrate recognition and recruitment. Its modulation could therefore avoid the confounding system biology compensatory mechanisms that characterize inhibition of catalytic sites such as presenilin.\n\nMethods To test and confirm the study hypothesis, the authors conducted an intensive in silico screening of a set of previously described nicastrin inhibitors for their affinity and binding poses on potential nicastrin binding sites using molecular docking tools including AutoDock4 and AutoDock Vina, as well as molecular dynamics simulation software, Gromacs®. They also investigated binding modes and probable chemical bonding involved in the interactions between the ligands and the nicastrin binding sites.\nThirty small-molecule compounds, clustered into eight chemical classes, were selected for the study based on their reported nicastrin bioactivity reported in the PubChem. The initial blind docking calculations were carried out using one of the most active nicastrin inhibitors, CID44433930.\nResults Three binding pockets for nicastrin inhibitors were described: DYIGS site, Hinge site, and Tetratricopeptide site. All are located on the larger lobe of nicastrin. The DYIGS site was adjudged as the most druggable, and the major interactive mechanisms with the inhibitors were hydrophobic and electrostatic forces. Other mechanisms of interactions included van der Waals forces, hydrogen bonding, π-π stacking, and salt bridges.\nConclusion Using relevant software and compounds with known in vitro bioactivity on nicastrin, the authors attempted to validate DYIGS site as a potential druggable target for breast cancer. The work is a meaningful application of CADD to drug discovery and development. Nevertheless, there is a need to carry out subsequent in vitro screening assays to validate the usability of the predicted DYIGS site for cancer therapy.\nConcerns\nThe ligand used in the blind docking calculations is recorded in the body text as CID 44433923. However, this code is not identified with any of the 30 known nicastrin inhibitors shown in Figure 2. The IUPAC name given to this compound matches CID 44433930. The authors refer to chemical classes given as Group 1, 2 and 3 as sulfonamides. While this is true for Groups 1 and 2, this does not hold true for all the Group 2 ligands some of which do not have a nitrogen atom connected to the sulfone group (e.g., CID 60150510). The authors should make exception to this categorization. The terms π-π stacking and pyridinyl group (not pyrido) should be properly written. The same applies to the amino acid Asp336 (erroneously spelled as Aps336).\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/12-150
|
https://f1000research.com/articles/11-524/v1
|
16 May 22
|
{
"type": "Research Article",
"title": "Development and feasibility testing of action observation training videos in acute stroke survivors",
"authors": [
"Arunima Biswas",
"Manikandan Natarajan",
"Sandeep K Subramanian",
"John M. Solomon",
"Arunima Biswas",
"Sandeep K Subramanian",
"John M. Solomon"
],
"abstract": "Background: Action observation training (AOT) is used for lower limb (LL) stroke rehabilitation in subacute and chronic stages, but concise information regarding the types of activities to be used and the feasibility of administration in the acute stroke population is unknown. The aim of this study was to develop and validate videos of appropriate activities for LL AOT and test administrative feasibility in acute stroke.\n\nMethod: A video inventory of LL activities was created after a literature survey and expert scrutiny. Five stroke rehabilitation experts validated the videos per domains of relevance, comprehension, clarity, camera position and brightness. LL AOT was then tested on ten individuals with acute stroke for uncovering barriers for clinical use in a feasibility study. Participants watched the activities and attempted imitation of the same. Determination of administrative feasibility was undertaken via participant interviews.\n\nResults: Suitable LL activities for stroke rehabilitation were identified. Content validation of videos led to improvements in selected activities and video quality. Expert scrutiny led to further video processing to include different perspectives of view and speeds of projected movements. Barriers identified included inability to imitate actions shown in videos and increased distractibility for some participants.\n\nConclusion: A video catalogue of LL activities was developed and validated. AOT was deemed safe and feasible for acute stroke rehabilitation and may be used in future research and clinical practice.",
"keywords": [
"action observation",
"feasibility",
"lower extremity",
"video"
],
"content": "Introduction\n\nStroke is the second largest cause of physical disability in adults worldwide.1 The ability to walk independently is a significant goal for stroke patients; however, post-stroke motor deficits like loss of muscle strength, range of motion and tonal abnormalities significantly limit the stroke survivors’ walking capacity.2,3 Over the years, various rehabilitation techniques have emerged for improvement of lower limb (LL) function. A focus shift has been observed towards therapies that influence neuroplasticity in the acute stage of stroke like motor imagery.4,5\n\nAction observation training (AOT) works on the neurophysiological notion that the same neural areas are activated during observation of an action performed by another individual and execution of the same action by self.6,7 LL rehabilitation has resulted in improvements in ability to walk greater distances, gait velocity and activities of daily living (ADL) in subacute to chronic stages of stroke.8 It is known that the potential for recovery of motor function is maximal in the acute stage of stroke. This is brought about by a combination of spontaneous recovery post stroke and subsequent neuroplastic changes.9 Priming techniques like AOT add to this restorative process through motor learning.7 Transcranial Magnetic Stimulation (TMS) studies on AOT have reported its influence on enhancing cortical excitability and promoting adaptive plasticity, if the movement practiced is specific for the desired task to be learned.7 This makes AOT an intervention suitable for conditions with severe physical limitations like the acute stroke.8\n\nAOT requires active participation from its recipients; and for adequate motor learning to occur, the videos of activities used for training must be suited to their level of deficit. Given that the available research revolves around subacute to chronic stroke, it is imperative to test if AOT is fit for administration in the acute stroke population. Moreover, currently, there are no activity sets designated for LL AOT in acute stroke. Therefore, there is a need to compile a collection of pertinent LL activities that can be used from the acute stage of stroke and amended as the patients improve. Hence, this study aimed to develop and validate AOT videos for LL rehabilitation and test its feasibility on acute stroke survivors.\n\n\nMethods\n\nThis is a methodological study focusing on the development of AOT videos for post-stroke LL rehabilitation. This study was approved by the Institutional Ethics Committee of Kasturba Hospital, Manipal, India (IEC 437-2019) and registered under the Clinical trials Registry of India (CTRI/2019/08/020598). The process of video development and validation was carried out as follows:\n\nLiterature survey\n\nThe existing literature on LL AOT for stroke rehabilitation was searched to understand the extent of information available on the video content used for training. Rayyan Systems Inc. software10 was used to screen AOT studies on LL stroke rehabilitation obtained from the electronic databases (See Underlying data).11 The authors extracted information on types of LL activities from the included studies using the ‘descriptive-analytical’ approach and created a preliminary list of activities.\n\nExpert scrutiny and final inventory\n\nThe list of activities obtained from the literature was scrutinized by two experts working in the field of stroke rehabilitation (both physiotherapists with clinical experience of five and 15 years). Addition of routine exercises and modifications based on Indian contexts (mainly regarding community ambulation) were made to the inventory by the experts based on their experience and expertise. Any conflict arising after revision of the list was resolved through consultation with another expert who has over 15 years of experience. The items agreed upon by all experts were finalized for the video catalogue.\n\nVideo recording and processing\n\nA Nikon D3400 camera mounted on a tripod stand was used for recording the activities. The videos depicted men and women aged between 40 to 60 years of age, having no history of neurological illness, who willingly participated in the study. Various locations (hospital wards, home environment and community spaces) were selected for video recording, and care was taken to ensure proper brightness and the least amount of background distraction. In addition, the camera was placed at different angles to get a first-person or egocentric perspective and a third-person or allocentric perspective of the movement to encourage a clear understanding of the activities under study. The videos obtained were then grouped into six domains, namely gait prerequisites, gait initiation, walking within the hospital, walking inside home, walking out of home, and walking in the community.\n\nSample videos (random selection of one video from each domain) were subjected to content validation by a team of five stroke rehabilitation experts (two physiotherapists, two occupational therapists and an optometrist) having clinical experience ranging from four to 20 years. The study was explained to the experts, and they were asked to scrutinize the videos based on clarity, movement comprehensibility, relevance of activity, camera angle, background distraction, brightness, and video quality. A five-point Likert scale ranging from strongly disagree to strongly agree was used for scoring each item.12 The experts were also requested to provide additional comments regarding the videos wherever appropriate.\n\nThe scores for each item and comments were analyzed. Since our panel consisted of five experts, the components having 100% agreement were accepted, while the rest were modified according to their suggestions.13 The modified videos were reviewed, and the finalized video catalogue was used for feasibility testing.\n\nStudy setting and participants\n\nA feasibility study was carried out in the neurological unit of a tertiary care hospital in Karnataka, India. Through purposive sampling, ten individuals with stroke, as confirmed by a CT or MRI, were obtained. Individuals of either gender with stroke duration less than seven days, haemodynamically stable, who had functional vision and cognition (Montreal Cognitive Assessment score ≥ 26) were included in the study. Individuals having neglect, communication disorders, or those having previous or coexisting neurological, cardiovascular, or musculoskeletal disorders were excluded from the study. The participants were given a detailed description of the study, and written informed consent was obtained.\n\nProcedure\n\nDemographic characteristics and stroke-specific clinical parameters like LL voluntary control (VC) according to Brunnstrom grading14 and Fugl Meyer Assessment for LL (FMA-LE) scores15 of all participants were recorded. The AOT videos were viewed on a laptop with a 15.5-inch screen. The participants were positioned comfortably in semi fowler’s position so that the monitor was visible clearly (Figure 1). Proper lighting and noise-free environment were ensured at all times. Participants observed side appropriate videos (corresponding to their more-affected side) on bed mobility and in-bed transitions (gait prerequisite domain).\n\nTen videos of 30 seconds each were used during the intervention (See Underlying data).11 Comprehension of observed activities was tested by asking them to identify the limb moving in the videos and explain the movement observed (either verbally or through demonstration of activity on the less-affected side.\n\nAfter observing each video, participants were encouraged to imitate the movements viewed for the next 30 seconds. Participants having VC greater than two attempted five repetitions of the observed activities, while those with VC less than two performed mental practice of the movements alone. A rest period of one minute was given between observations of consecutive videos to prevent fatigue, bringing the total duration of the intervention to 20 minutes.\n\nPost intervention, the participants were interviewed to understand their perception of the intervention using an interview guide (See Underlying data).11 The feedback obtained from the interviews were compiled and analyzed. Feasibility test was done based on the following metrics: process, resource, management and scientific metrics16,17 (See Underlying data).11\n\n\nResults\n\nInventory of LL activities\n\nIn this study, 269 unique records were obtained from the electronic search after the removal of duplicate entries. In total, 32 full-text records were screened, and nine eligible articles were included for data extraction.18–26 From the included studies, 14 types of activities were identified (Table 1).\n\nActivities were added after expert scrutiny, mainly pertaining to in-bed mobility, balance and stepping activities that are more relevant for the acute stage of stroke before attaining walking capacity. Context-specific walking activities suited to the Indian environment were also added. Table 2 enumerates the 34 activities divided into the domains mentioned above, selected for the video catalogue.\n\nCreation and validation of AOT videos\n\nA total of 130 videos, each 10 to 30 seconds long, were created based on the activities from the inventory. As mentioned above, similar videos were clubbed together in a single domain (total six domains). One video was randomly selected from each domain for content validation by experts. The level of agreement reached by the validation experts for the different scrutiny components of AOT videos is described in Table 3, along with their comments for the required modifications.\n\nAccording to experts, 100% consensus was reached regarding the relevance of activities for stroke rehabilitation except for walking in community domain. The activity deemed inappropriate (e.g., walking on the beach) was excluded from the inventory. Movement comprehension and camera position components also attained complete agreement. Domains with disagreements (clarity, background distraction, video quality and brightness) were modified according to the received suggestions. The final catalogue contained the videos processed in accordance with the expert recommendations.\n\nIn this study, 10 respondents approached for feasibility testing of AOT participated. Table 4 describes the demographic characteristics of the participants as well as the feasibility metrics. The participant interviews carried out after the intervention revealed barriers to AOT administration in the acute stroke population including imitation inability (4/10 participants) and distractibility affecting the adherence to intervention (2/10 participants).\n\nThe hospital setting was found suitable for AOT due to the ease of video dissemination and movement practice at the bedside. All participants reported ease of comprehension of activities observed in the videos, and no adverse events were reported during the administration of the intervention.\n\n\nDiscussion\n\nIn the current study, a video catalogue of various LL activities was created, and content validation was performed. This set of videos included activities at a functional task difficulty level well suited for post-stroke rehabilitation beginning at the acute stage.\n\nThe existing literature on LL AOT mainly uses videos of walking in different contexts. This could be because the participants in said studies were individuals in the subacute to chronic stage of stroke with some available walking capacity.19–22,24–26 Since acute stroke patients have more significant motor deficits, using mere videos of gait training may be beyond their capacity for imitation. Hence, as per suggestions from stroke rehabilitation experts, mat activities and gait prerequisite exercises were added to our inventory of LL activities to make the videos relevant for AOT through different stages of stroke.\n\nAlthough the video inventory obtained was sizeable, activities in a given domain were similar to each other, and the same parameters were used for video recording. Hence, only one video was selected from each domain randomly for content validation, as the suggested modifications were applicable to all activities of the domain. This process not only helped hasten the content validation process, but also made it less tedious for the experts.\n\nThe suggestion of the experts to use a plain white background for mat activities, keeping minimal distractors in the frame, and blurring faces of the models, is in accordance with previous studies. Simple backgrounds and removing extra objects from the frame reduce distractions and help enable better attention of the main subject. Hence, these are critical features of good quality videos.27 Regarding the anonymity of models in the videos, facial blurring achieves the necessary balance between maintaining the anonymity of models and preserving the details of the activity of interest.28 Specific instructions included the use of male models for activities like hip knee flexion and bridging so that proximal joints could be clearly visualized. Community ambulation videos like walking on sand were best avoided as it is not a routinely required activity in the acute stage and necessitates high-level balance function, which might not be a reality for all participants.\n\nFurthermore, the emphasis on playing the movements at slow speed in addition to normal speed was to facilitate easier recognition of elements of complex movements and a better understanding of activities observed.29 Lastly, previous studies have shown that egocentric perspective activates the hemisphere contralateral to the side of movement, while allocentric perspective activates the ipsilateral hemisphere.30 Although this study did not explicitly test for this, it can be postulated that the use of egocentric and allocentric perspectives of the same movements probably facilitated the activation of the lesioned hemisphere in the form of either anatomical imitation or mirroring of activities observed.\n\nThe results of this study suggest that the AOT can be safely administered in acute stroke and that such individuals have the capacity to understand and follow the intervention with minimal difficulty.\n\nProcess and resource metrics\n\nAll individuals approached for the study expressed interest in the intervention. This could be due to the use of videos as a motivating feature31 or the ease of participation despite lacking significant motor function. The time required for administration of the intervention, inclusive of the observation and imitation phases, was 20 minutes. The barrier faced by four participants was inability to imitate movements. Although post-stroke impairment of imitation is mainly attributed to apraxia,32,33 our participants could perform the movements with their ipsilesional leg, ruling out apraxia. Given that our participants had poor FMA scores and LL voluntary control, the difficulty faced by some participants to imitate movements might well be attributed to the same.\n\nManagement and scientific metrics\n\nNo falls, or other adverse events occurred during the intervention, making AOT safe for administration in acute stroke survivors in a hospital setting. Adherence to the intervention was found to be good except for distractibility in two participants. It is known that hospitalised patients in the acute stage of stroke display decreased selective attention and distractibility.34 Barker-Collo et al. found that acute stroke patients tested poorly on various forms of attention compared to their normal counterparts. This could be the case in our participants who displayed low attention and could not adhere to the complete intervention.\n\nTo the best of our knowledge, this is one of the first studies to develop a comprehensive inventory for LL AOT and test the same on an acute stroke population. However, some limitations of this study include the lack of expert scrutiny of every video during content validation and a small sample of participants for feasibility testing. Limited generalizability of the videos having been shot in an Indian context. In addition, almost all included studies seem to be an Asian Perspective, with almost no European perspective. This, in itself, could be a limitation.\n\n\nConclusion\n\nIn this study, an exhaustive video catalogue for post-stroke LL rehabilitation for different stages of stroke was created, validated, and tested for administrative feasibility in acute stroke. This system of AOT video construction may enable clinicians to formulate streamlined interventions for routine therapy. AOT was found to be safe and easy to administer in individuals with acute stroke having good cognitive capacity. Future research could focus on large scale studies testing the effect of LL AOT in acute stroke, focussing more on the recipients’ preference towards the videos used in therapy.\n\n\nData availability\n\nFigshare: Development and feasibility testing of action observation training videos in acute stroke survivors, https://doi.org/10.6084/m9.figshare.19625271.\n\nThis project contains the following underlying data:\n\nData file 1. (Literature search)\n\nData file 2. (Interview guide)\n\nData file 3. (Definition of feasibility metrics)\n\nData file 4: (Intervention videos)\n\nData are available under the CC0 1.0 Universal (CC0 1.0) Public Domain Dedication.\n\n\nAuthor contributions\n\nAB: study design and conceptualization, data collection, data analysis, manuscript writing; MN: conceptualization and study design, data analysis, manuscript writing; SKS: data analysis, manuscript writing; JMS: conceptualization and study design, data analysis and manuscript editing. All authors have read and approved the final manuscript.",
"appendix": "Acknowledgements\n\nThe authors would like to thank Dr. Abraham Samuel Babu for critiquing this manuscript.\n\n\nReferences\n\nToell T, Boehme C, Mayer L, et al.: Pragmatic trial of multifaceted intervention (STROKE-CARD care) to reduce cardiovascular risk and improve quality-of-life after ischaemic stroke and transient ischaemic attack–study protocol. BMC Neurol. 2018; 18(1): 1–10. Publisher Full Text\n\nVerstraeten S, Mark R, Sitskoorn M: Motor and cognitive impairment after stroke: a common bond or a simultaneous deficit. Stroke Research & Therapy. 2016; 1(1): 1.\n\nHatem SM, Saussez G, Della Faille M, et al.: Rehabilitation of motor function after stroke: a multiple systematic review focused on techniques to stimulate upper extremity recovery. Front. Hum. Neurosci. 2016; 10: 442.\n\nBelda-Lois JM, Mena-del Horno S, Bermejo-Bosch I, et al.: Rehabilitation of gait after stroke: a review towards a top-down approach. J. Neuroeng. Rehabil. 2011; 8(1): 1–20.\n\nMonteiro KB, dos Santos CM , da Costa Cabral VR , et al.: Effects of Motor Imagery as a Complementary Resource on the Rehabilitation of Stroke Patients: A Meta-Analysis of Randomized Trials. J. Stroke Cerebrovasc. Dis. 2021; 30(8): 105876. PubMed Abstract | Publisher Full Text\n\nBuccino G: Action observation treatment: a novel tool in neurorehabilitation. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 2014; 369(1644): 20130185. Publisher Full Text\n\nStoykov ME, Madhavan S: Motor priming in neurorehabilitation. J. Neurol. Phys. Ther. 2015; 39(1): 33–42. PubMed Abstract | Publisher Full Text\n\nPeng TH, Zhu JD, Chen CC, et al.: Action observation therapy for improving arm function, walking ability, and daily activity performance after stroke: a systematic review and meta-analysis. Clin. Rehabil. 2019; 33(8): 1277–1285. PubMed Abstract | Publisher Full Text\n\nFelling RJ, Song H: Epigenetic mechanisms of neuroplasticity and the implications for stroke recovery. Exp. Neurol. 2015; 268: 37–45. PubMed Abstract | Publisher Full Text\n\nOuzzani M, Hammady H, Fedorowicz Z, et al.: Rayyan—a web and mobile app for systematic reviews. Syst. Rev. 2016; 5(1): 1–10.\n\nBiswas A, Biswas A: Underlying additional data. figshare. Dataset. 2022 [cited 2022 Apr 26]. Reference Source\n\nJebb AT, Ng V, Tay L: A Review of Key Likert Scale Development Advances: 1995–2019. Front. Psychol. 2021 [cited 2022 Apr 20]; 12. PubMed Abstract | Publisher Full Text\n\nPolit DF, Beck CT: The content validity index: are you sure you know what’s being reported? Critique and recommendations. Res. Nurs. Health. 2006; 29(5): 489–497. PubMed Abstract | Publisher Full Text\n\nShah SK, Harasymiw SJ, Stahl PL: Stroke Rehabilitation: Outcome Based on Brunnstrom Recovery Stages. The Occupational Therapy Journal of Research. 1986 Nov; 6(6): 365–376. Publisher Full Text\n\nHernández ED, Forero SM, Galeano CP, et al.: Intra- and inter-rater reliability of Fugl-Meyer Assessment of Lower Extremity early after stroke. Braz. J. Phys. Ther. 2021 Nov 1; 25(6): 709–718. PubMed Abstract | Publisher Full Text\n\nBowen DJ, Kreuter M, Spring B, et al.: How we design feasibility studies. Am. J. Prev. Med. 2009; 36(5): 452–457. PubMed Abstract | Publisher Full Text\n\nLearmonth YC, Motl RW: Important considerations for feasibility studies in physical activity research involving persons with multiple sclerosis: a scoping systematic review and case study. Pilot Feasibility Stud. 2018; 4(1): 1–11. PubMed Abstract | Publisher Full Text\n\nBae S, Kim KY: Dual-afferent sensory input training for voluntary movement after stroke: a pilot randomized controlled study. NeuroRehabilitation. 2017; 40(3): 293–300. PubMed Abstract | Publisher Full Text\n\nKim JH, Lee BH: Action observation training for functional activities after stroke: a pilot randomized controlled trial. NeuroRehabilitation. 2013; 33(4): 565–574. PubMed Abstract | Publisher Full Text\n\nPark HJ, Oh DW, Choi JD, et al.: Action observation training of community ambulation for improving walking ability of patients with post-stroke hemiparesis: a randomized controlled pilot trial. Clin. Rehabil. 2017; 31(8): 1078–1086. PubMed Abstract | Publisher Full Text\n\nPark HR, Kim JM, Lee MK, et al.: Clinical feasibility of action observation training for walking function of patients with post-stroke hemiparesis: a randomized controlled trial. Clin. Rehabil. 2014; 28(8): 794–803. PubMed Abstract | Publisher Full Text\n\nPark EC, Hwangbo G: The effects of action observation gait training on the static balance and walking ability of stroke patients. J. Phys. Ther. Sci. 2015; 27(2): 341–344. PubMed Abstract | Publisher Full Text\n\nLee HJ, Kim YM, Lee DK: The effects of action observation training and mirror therapy on gait and balance in stroke patients. J. Phys. Ther. Sci. 2017; 29(3): 523–526. PubMed Abstract | Publisher Full Text\n\nBang DH, Shin WS, Kim SY, et al.: The effects of action observational training on walking ability in chronic stroke patients: a double-blind randomized controlled trial. Clin. Rehabil. 2013; 27(12): 1118–1125. PubMed Abstract | Publisher Full Text\n\nOh SJ, Lee JH, Kim DH: The effects of functional action-observation training on gait function in patients with post-stroke hemiparesis: A randomized controlled trial. Technol. Health Care. 2019; 27(2): 159–165. PubMed Abstract | Publisher Full Text\n\nKleynen M, Jie LJ, Theunissen K, et al.: The immediate influence of implicit motor learning strategies on spatiotemporal gait parameters in stroke patients: a randomized within-subjects design. Clin. Rehabil. 2019; 33(4): 619–630. PubMed Abstract | Publisher Full Text\n\nLuo Y, Tang X: Photo and video quality evaluation: Focusing on the subject. European Conference on Computer Vision. Springer; 2008; p. 386–399.\n\nSilas MR, Grassia P, Langerman A: Video recording of the operating room—is anonymity possible?. J. Surg. Res. 2015; 197(2): 272–276. Publisher Full Text\n\nMoriuchi T, Iso N, Sagari A, et al.: Excitability of the primary motor cortex increases more strongly with slow-than with normal-speed presentation of actions. PLoS One. 2014; 9(12): e114355. PubMed Abstract | Publisher Full Text\n\nVingerhoets G, Stevens L, Meesdom M, et al.: Influence of perspective on the neural correlates of motor resonance during natural action observation. Neuropsychol. Rehabil. 2012; 22(5): 752–767. PubMed Abstract | Publisher Full Text\n\nCicek A, Ozdincler AR, Tarakci E: Interactive video game-based approaches improve mobility and mood in older adults: A nonrandomized, controlled trial. J. Bodyw. Mov. Ther. 2020; 24(3): 252–259. PubMed Abstract | Publisher Full Text\n\nHoeren M, Kümmerer D, Bormann T, et al.: Neural bases of imitation and pantomime in acute stroke patients: distinct streams for praxis. Brain. 2014; 137(10): 2796–2810. PubMed Abstract | Publisher Full Text\n\nRumiati RI, Weiss PH, Tessari A, et al.: Common and differential neural mechanisms supporting imitation of meaningful and meaningless actions. J. Cogn. Neurosci. 2005; 17(9): 1420–1431. PubMed Abstract | Publisher Full Text\n\nBarker-Collo SL, Feigin VL, Lawes CM, et al.: Attention deficits after incident stroke in the acute period: frequency across types of attention and relationships to patient characteristics and functional outcomes. Top. Stroke Rehabil. 2010; 17(6): 463–476. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "148949",
"date": "01 Sep 2022",
"name": "Adrià Arboix",
"expertise": [
"Reviewer Expertise Acute stroke",
"cerebrovascular diseases",
"lacunar stroke",
"vascular cognitive impairment."
],
"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 clinical study aimed at developing and validating Action Observation Training (AOT) videos for lower limb (LL) rehabilitation and testing their feasibility in acute stroke survivors. Ten patients participated in this study. A video catalog of various LL activities was created and content validation was performed. The results of this study suggest that AOT can be safely administered in acute stroke and that these individuals have the ability to understand and follow the intervention with minimal difficulty.\nThis novel information is interesting from a clinical point of view. However, some amendments are suggested to improve the quality of the manuscript:\nDue to the small sample size of the study the title should clearly mention “preliminary findings”.\n\nIt would be helpful to mention in the Introduction that post-stroke \"cognitive impairment\" is another clinical manifestation of patients with acute ischemic and hemorrhagic stroke (see and add this reference: Grau-Olivare et al. 20101).\n\nIt would be interesting to know if the authors found differences in the results obtained in patients with LL weakness secondary to pure motor hemiparesis, the most common lacunar syndrome usually due to a small subcortical infarct versus LL weakness secondary to extensive non-lacunar cerebral infarction or cerebral hemorrhage. Lacunar infarcts usually have a better spontaneous functional prognosis than other strokes (see and add this recent reference: Rudilosso et al. 20222).\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": "9172",
"date": "09 Feb 2023",
"name": "Manikandan Natarajan",
"role": "Author Response",
"response": "Dear reviewer, Thank you for taking the time to review our article and give your comments to improve the paper. The modifications done to the manuscript according to your comments are mentioned below: Comment 1: Due to the small sample size of the study the title should clearly mention “preliminary findings”. Response: Thank you very much for the suggestion. We have added “preliminary findings” to our study title. Comment 2: It would be helpful to mention in the Introduction that post-stroke \"cognitive impairment\" is another clinical manifestation of patients with acute ischemic and hemorrhagic stroke (see and add this reference: Grau-Olivare et al. 2010). Response: Thank you for the comment. Modification in text and addition of the required reference has been done in the manuscript. Comment 3: It would be interesting to know if the authors found differences in the results obtained in patients with LL weakness secondary to pure motor hemiparesis, the most common lacunar syndrome usually due to a small subcortical infarct versus LL weakness secondary to extensive non-lacunar cerebral infarction or cerebral hemorrhage. Lacunar infarcts usually have a better spontaneous functional prognosis than other strokes (see and add this recent reference: Rudilosso et al. 2022). Response: Thank you for the comment. The aim of our study was to simply determine the feasibility of administering action observation training for lower extremity rehabilitation in the acute stage of stroke. Since our objective was not to find out the effect of AOT on the functional recovery, it is beyond the scope of this paper. However, we have clarified this detail in the limitations section of the manuscript for better clarity. Regards & thanks, Dr. Manikandan Natarajan"
}
]
},
{
"id": "154357",
"date": "12 Dec 2022",
"name": "Sivakumar Balasubramanian",
"expertise": [
"Reviewer Expertise Neurorehabilitation engineering",
"Movement 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 article describes a study on the feasibility of action observation in lower-limb rehabilitation is acute stroke. The study is well-written with a simple, clean design.\nIs there some evidence for AOT in the subacute and chronic phases?\n\"It is known that the potential for recovery of motor function is maximal in the acute stage of stroke.\" Could you provide a reference for this?\nWhat videos were the participants shown? Were these only the gait prerequisite videos? If not, were the patients asked to walk if they were shown videos of people walking? More details are required for the intervention. Was the intervention done under the supervision of a therapist? Did the therapists provide any comments or inputs while patients watched the video?\nWhen showing egocentric videos of gait, what is being shown to the participant? The view of the environment in front of them or their legs? Both of them have problems. Showing the environment might not allow them to connect it to gait. If the legs are shown, then it's unnatural. We do not look at our legs while walking. The egocentric view might make more sense for upper limb activities, but not for the lower limb.\nI have a basic question about the AOT modality. Many stroke participants who can benefit from AOT would see people walk around and do actions with their upper limbs for most of their waking hours. Why do we believe that a dedicated session of watching custom-made videos would be beneficial? This question is motivated by the reviewer's lack of a deep understanding of the AOT literature. But addressing this issue would allow other such readers to fully appreciate the rationale for the work.\nOverall, this is a good study. It can be accepted for publication after the aforementioned issues are addressed.\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?\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? Yes",
"responses": [
{
"c_id": "9173",
"date": "09 Feb 2023",
"name": "Manikandan Natarajan",
"role": "Author Response",
"response": "Dear reviewer, Thank you for taking the time to review our article and give your comments to improve the paper. The modifications done to the manuscript according to your comments are mentioned below: Comment 1: Is there some evidence for AOT in the subacute and chronic phases? Response: There already exists evidence for the efficacy of AOT in subacute and chronic stroke. The reviewer may peruse through the works of Tzu-Hsuan Peng et al (Action observation therapy for improving arm function, walking ability, and daily activity performance after stroke: a systematic review and meta-analysis), and Deirdre Ryan et al (Effect of Action Observation Therapy in the Rehabilitation of Neurologic and Musculoskeletal Conditions: A Systematic Review) for further clarification on the subject. Comment 2: \"It is known that the potential for recovery of motor function is maximal in the acute stage of stroke.\" Could you provide a reference for this? Response: Thank you for point out this. The required reference in the introduction has been updated. Comment 3: What videos were the participants shown? Were these only the gait prerequisite videos? If not, were the patients asked to walk if they were shown videos of people walking? More details are required for the intervention. Was the intervention done under the supervision of a therapist? Did the therapists provide any comments or inputs while patients watched the video? Response: Thank you for the comment. The participants were shown only gait prerequisite videos (lower limb movements in sitting and lying position). The intervention was undertaken under the supervision of the treating physiotherapist and comments regarding the movements watched were also given during the therapy. The details have been added in the methods section of the article. Comment 4: When showing egocentric videos of gait, what is being shown to the participant? The view of the environment in front of them or their legs? Both of them have problems. Showing the environment might not allow them to connect it to gait. If the legs are shown, then it's unnatural. We do not look at our legs while walking. The egocentric view might make more sense for upper limb activities, but not for the lower limb. Response: Thank you very much for the comment and we totally agree for the same. Regarding the use of egocentric perspective of view, the participants were shown videos lower limb movements to be performed in lying or sitting positions only (as they had not yet achieved ambulation capacity). Hence the egocentric videos showed only the legs/ lower body of the model such that the participant visualizes performing the movement himself. We agree that egocentric view is more beneficial for upper limb training, but in this instance, we believed that getting an anatomically congruent view of the movement to be performed would be beneficial for the participants, as opposed to just the mirror image. Comment 5: I have a basic question about the AOT modality. Many stroke participants who can benefit from AOT would see people walk around and do actions with their upper limbs for most of their waking hours. Why do we believe that a dedicated session of watching custom-made videos would be beneficial? This question is motivated by the reviewer's lack of a deep understanding of the AOT literature. But addressing this issue would allow other such readers to fully appreciate the rationale for the work. Response: The success of AOT relies on the activation of mirror neuron system and mental practice by the participant. We agree that as the patients see biological movements occurring in their environment, the MNS must get activated on its own, to certain extent. However, unless dedicated observation and mental practice of the desired activities is performed (as is true with learning any new skill), the patients will not attain the required level of functioning. Regards & thanks, Dr. Manikandan Natarajan"
}
]
}
] | 1
|
https://f1000research.com/articles/11-524
|
https://f1000research.com/articles/10-1157/v1
|
15 Nov 21
|
{
"type": "Research Article",
"title": "Teaching-learning behavior in medicine according to students’ perspective: what most influences academic achievement?",
"authors": [
"Mia Kusmiati",
"Susanti Dharmmika",
"Asri Maharani Dewi",
"Susanti Dharmmika",
"Asri Maharani Dewi"
],
"abstract": "Background: The medical student is a part of education that has a pivotal role in contributing to the teaching-learning process. Assessing the learning process by student perception can give valuable input to predict academic achievement. This study aims to identify the student’s perspective regarding teaching-learning behaviour and which factor most influences academic achievement. Methods: A total of 443 medical students of the preclinical phase were selected to participate in this study. Design of the study comprised three single-groups time sequences with the observational approach. This study is divided into three phases: item construction by conducting exploratory factor analysis (EFA), validation through confirmatory factor analysis (CFA), and true surveys. Sample size calculation employed formulation of subject to item ratio for EFA and CFA; true survey utilized the estimate proportion population. Using regression linear, we determine the most influential factor to academic performance. Results: Results were summarized following two factors that influencing academic performance, namely learning experience (p value=0.013, r=0.041) and exam effectiveness (p value=0.041, r=0.028). Our work highlights the lecturer capacity and integrated module have contributed the academic success (79.46% and 77.80%). Conclusions: Our finding has novelty in which contribute the knowledge regarding exam significance on medicine. Meanwhile, related to the learning experience domain is increasingly proving an essential factor to achieve academic performance. The major strength of this study is the systematic manner in which it was conducted.",
"keywords": [
"Learning behaviour",
"student’s perspective",
"academic achievement",
"exploratory methods"
],
"content": "Introduction\n\nIdentifying the academic achievements of students and learning behavior is one of the essential factors in evaluating the success of curriculum delivery (Klug et al., 2013). The medical student is a part of education that has a pivotal role in contributing to the teaching-learning process. This is due to medical students are internal stakeholders who are directly involved with the teaching provided by lecturers. They feel for themselves how the learning process is performed. Therefore, assessing the learning process by student perception can give valuable input to diagnose academic achievement.\n\nFocusing on students’ learning behaviour seems a promising approach for identifying the academic performance in addition to teacher’s competence (Klug et al., 2013)‚ precise curriculum, and learning environment (Struyven et al., 2005). Thus, we wanted to look at a students’ perspective regarding teaching-learning behaviour which will be further explained in the methods section. A theoretical basis was needed to develop the new measurement method.\n\nA study conducted by Yeo and Chang in Daegu, Korea, showed that the achievement level of the students was approximately 60% to 70% (Yeo & Chang, 2019). This is related to the content curriculum, while the students’ self-evaluation reliability can predict academic achievement. Besides, by observing teaching-learning behavior, we can assess their perception of the teaching process. Perception is a person's response to what is seen or felt to affect thought patterns. If a person's perception of an object is good, there will be a sense of pleasure and interest in that object. Likewise, in the learning process, if it is following their abilities and expectations, students will feel content and give a good perception of it. Learning behaviour was defined as observable behavioural patterns that students demonstrate as they approach and undertake learning tasks. Such learning behaviours include noticeable problem-solving strategies, flexibility, attention, and responses to learning situations (competition, novelty, error, etc.) in classroom settings and facing the exam. Several studies showed the relationship between students’ learning behaviour and their academic performance observed by the teacher (Klug et al., 2013; Lin et al., 2019). The new focus set a need for measuring teaching-learning behaviour from students’ perspective was not done yet. Learning behaviour are learned actions that enable students to access learning and interact with others productively in the community. Teaching behaviour was defined as action, interaction and communication of teacher with the students in the instructional process. Teaching behavior that is instructionally supportive in terms of providing opportunities for students to respond, to choose, or to receive positive feedback, promotes academic achievement (Trickey et al., 2015).\n\nThus, in this study, we first identified item construction regarding teaching-learning behaviour from students’ perspective by conducting psychometric properties; validating a tool consisting of seven domains using confirmatory factor analysis. Second and most importantly, this study aims to investigate the student’s perception regarding teaching-learning behaviour and which factor that most influences academic achievement.\n\n\nMethods\n\nA total of 443 medical students of the preclinical phase were recruited to participate in this study. The study was divided into three stages: item construction, validation and reliability, and assessing students’ perspectives on teaching-learning behaviour. Item construction was conducted by exploratory factor analysis to 105 medical students from different cohorts during November-December 2018. A total of 182 medical students were involved in conducting validation and reliability stages using confirmatory factor analysis. This took three months from January to March 2019. Taking the survey involved 156 medical students to assess students’ perspectives regarding teaching-learning behavior during four months in 2020.\n\nItem construction phase\n\nThis section described the psychometric properties that have been previously identified to develop an assessment instrument of the teaching-learning behaviour from the student’s perspective. Exploratory factor analysis (EFA) was conducted on 105 medical students from two batches, namely year three and year four, with ages ranging between 19–23 years old used random sampling strategies. There were 46 items of questionnaire from the qualitative study that preceded item development. This phase used 105 medical students as participants, representing a subject-to-item ratio of 2-3:1 (Worthington & Whittaker, 2006) with a purposive sampling strategy.\n\nBefore conducting factor analysis, Kaiser-Myer-Olkin (KMO) and Bartlett’s test of sphericity were performed to obtain sampling adequacy (Worthington & Whittaker, 2006). Sampling adequacy was achieved if it has Kaiser-Myer-Olkin (KMO) value of great than 0.5. After the sample was adequate, the extraction method and rotation in the oblique or orthogonal manner using SPSS version 21 were carried out. Confirmation of the data extraction that can be loaded in the same factor or scale was done using the maximum likelihood.\n\nInclusion criteria of the item construction phase were as follows: fresh year medical student, active status and registered in the university database.\n\nValidation and reliability\n\nThe instrument validation phase was carried out through confirmatory factor analysis (CFA). Validity determines whether an instrument truly measures what it is intended to measure. At the same time, reliability assesses the consistency of the result or outcome so that the research can be replicated (Lynch et al., 2004). This study used construct validity to assess the instrument. In terms of confirmatory factor analysis, conducting factor analysis can examine construct behaviour (Agung et al., 2017; Anthoine et al., 2014).\n\nReliability is the test used to assess the compatibility of the result of measurement (Stalmeijer et al., 2008), and it is identified by a coefficient ranging from very low coherence < 0.2 to very high coherence > 0.9 (Shirali et al., 2018). Reliability (r11) is the proportion of observed variance that is due to errors of measurement (Aiken, 1996). In other words, reliability refers to the degree to which a questionnaire measures the concepts of interest consistently (e.g., are the items enough? are the scores reproducible?) (Van Der Vleuten & Schuwirth, 2005).\n\nThis part describes the stage of the validation and reliability of an instrument that exists previously in initial testing based on the EFA result. Using structural equation modelling, we applied confirmatory factor analysis (CFA) toward 182 medical students. A total of 182 students were selected by simple random.\n\nThe inclusion criteria to participate in this phase are as follows: the 2nd level medical students and above level who have conducted learning activity of generic phase, this is due to assess the teaching-learning behavior, students must have a comprehension regarding the foundational concept of good learning.\n\nTrue survey to assess students’ perspective\n\nThe 156 students from batches 2017, 2018, and 2019 were selected and invited to participate in this survey with a random sampling strategy. The sample size was determined based on an estimated proportion population as formulated:\n\nInclusion criteria of medical students are as follows: the active students on the academic year run, have followed academic activity > 1 year. The inclusion criteria were established to anticipate the occurrence of dropout research and ensure the consistency of the data. Students who are still at 1st-year votes in the-adaptation of teaching-learning and attendance rates are still fluctuating. Therefore, only the students in 2nd-year and above are involved in this research.\n\nThe 33-items questionnaire was distributed to 156 medical students of UNISBA for four months from September to December 2020. Upon receiving written consent, the participants were asked to fill out the instrument for 15–25 minutes. The participants were asked to score their agreement for each item in the questionnaire on a 5-point Likert scale ranging from 1 (disagree) to 5 (strongly agree).\n\nThis study has some potential of bias as follows: filling out questionnaires may cause dishonesty for fear of affecting performance assessments by lecturers. Medical students possibly feel uncomfortable expressing their thoughts. In anticipation of potential bias, the researcher ensured that involvement in the study was voluntary and there was no implication toward their assessment.\n\nIn summary, the phases passed in this study, the sample size, and the method approach taken can be seen in Figure 1.\n\nItems construction\n\nUsing SPSS version 21, the extraction method of maximum likelihood (ML) was implemented to extract the data. The Varimax rotation method was applied with Kaiser Normalization to simplify and describe the data structure. A factor analysis conducted on the 105 completed questionnaires indicated an adequate sample size had been achieved, as evidenced by a KMO value of 0.705 (> 0.5) and Bartlett’s test of sphericity of p < 0.001 (X2 = 2584.12).\n\nThe detailed analysis identified seven factors based on the initial Eigenvalue of more than one (Figure 2). These seven factors were retained in the study and accounted for 73.42% of the total variance after nine iterations (Table 1). The instrument items were grouped into the same component based on the factor loading value of more than 0.4.\n\nThirty-three items were retained as an indicator variable (loading value of > 0.4). Thirteen subjects were removed from 46 items because they had a loading value of less than 0.4. The items excluded were q2, q3, q5, q6, q7, q8, q22, q30, q31, q34, q35, q39, and q40. The Cronbach’s alpha values for all 33 items were 0.913, indicating very high consistency (Guilford, 1978; Van Der Vleuten & Schuwirth, 2005).\n\nValidation through confirmatory factor analysis\n\nAfter the sample achieves fitness, conducting confirmatory factor analysis to determine the t loading factor as an indicator validity and error measurement as indicator reliability of each item. It was performed using the LISREL 8.8 program. Counting t loading factor is deemed valid if it has a value of more than 1.96 (95% degree of confidence) and shows a significance representing its latent variable. Then, the lambda and delta value to structural equation modelling was determined. The distribution frequency from each sample group was represented with a table and graph.\n\nTrue survey\n\nA pre-tested performance captures the demographic data, admission test, the value of GPA (grade point average), and perception of teaching-learning behaviour among the undergraduate medical students of UNISBA. The data collected were tabulated and analyzed using the Statistical Package for Social Sciences (SPSS) version 24.0. The presenting of results in terms of numbers and proportions. The linear regression test was conducted to identify the influence of perception variable on academic achievement with its 95% Confidence interval (CI) and then proceeded with Dunnett’s posthoc multiple comparison test for comparison purposes. In this study, p-value <0.05 was considered as statistically significant, it does deem variable perception influence the academic achievement in terms of grade point average (GPA).\n\nThe variables of this study were identified based on the definition variable following. Gender was defined as generally conceived as a set of characteristics or traits that are associated with specific biological sex (male or female). The age is when someone has been alive or something has existed (<20 years old and >20 years old). Student's perception was recognition and interpretation of students regarding sensory information and how they respond to the data. Academic achievement resulted from students’ academic performance in terms of GPA and was categorized as low-moderate if GPA < 2.75, called high if GPA 2.75-3.50, and excellent if GPA > 3.50.\n\nEthical considerations\n\nThe study protocol complied with the Helsinki Declaration, and the Joint Committee approved it of Research and Ethics of the medical faculty of Universitas Islam Bandung, Indonesia. This research has received ethical approval from the medical faculty of Bandung Islamic university research ethics committee no. 005/Ethic committee FK/VI/2017.\n\nParticipant consent\n\nAll the participants involved in this study have gave written consent and agreed to participate, also permitted the data to be analyzed and published in a scientific journal.\n\n\nResults and discussion\n\nTable 1 indicated that the items were grouped into the same component based on the factor loading value of more than 0.4. For example, learning material and body of knowledge (Factor 1) consist of items q13, q14, q15, q16, q17, q18, q19, q20, q23, and q24 as the loading values were above 0.40. The other items were also classified in the same manner. As seen in Table 1, the matrix pattern of the Varimax rotation method with Kaiser Normalization showed the grouping of the items based on a loading value of more than 0.4 (Kusmiati, Dharmmika & Dewi, 2021).\n\nThirty-three items were retained as an indicator variable (loading value of > 0.4). Thirteen subjects were removed because they had a loading value of less than 0.4. The items excluded were q2, q3, q5, q6, q7, q8, q22, q30, q31, q34, q35, q39, and q40. The Cronbach’s alpha values for all 33 items were 0.913, indicating very high consistency (Guilford, 1978; Van Der Vleuten & Schuwirth, 2005).\n\nItems retained of the instrument were 33 items and represented all indicators to assess the teaching-learning behaviour starting from the body of knowledge to the assessment method. The factor of the lecturer’s capacity had the most items among the factors (10 things). In contrast, elements such as the difficulty level of the exam and linking material within the learning module were factors that had the fewest questions (two items).\n\nThe results of the t-loading values and β-reliability of 183 medical students can be seen in Figures 3 and 4.\n\nFigures 3 and 4 showed that the loading factor of each item against a factor is 1 to 7. The value of the t loading element of all things was higher than the critical point 1.96, so the observed variable (indicator variable) describes the latent variable (7 factors) and shows a significant influence of the latent variables on its indicator variables.\n\nThirty-three questions represent seven analysis groups as latent variables (Figures 3 and 4). The connection between latent variables with 33 items as indicator variables is analyzed using confirmatory factor analysis (CFA). All 33 questions described a significant relationship to their respective factor groups, with a range of t-loading values from 7.55 to 16.47. Each factor group (factors 1–7) is represented by the questions in its respective factor group.\n\nTable 2 indicates the amount of item/subscales for each factor based on EFA result.\n\nFigure 4 showed that the latent variable of exam effectiveness (f4) has four indicator variables, with the strongest indicator being question no. 25 (t value = 14.91). Questions no. 26–29 represented the latent variable for the suitability of learning (f5). Question no. 27 was the strongest indicator for the latent variable of learning suitability with a test (t value = 13.97). Meanwhile, the latent variables of the difficulty level of the exam (f6) and learning module variables (f7) are represented most strongly by a question no. 31 and no. 33 (t value = 3.76; 10.93). These latent variables each have two items as their indicator variable.\n\nAfter data cleaning, a total of 152 samples were remaining because four data were incomplete in terms of there is no data of gender. Table 3 shows the socio-demographic information of the students (n = 152). Many of the students are females (69.08%), with the age group was dominated by the age of greater than 20 years old. The Year 2 students (19.74%) were those who had sat for their end of the second-semester summative examination, while the Year 3 students (44.08%) were those who had taken their fourth summative examination. The students of Year 4 (36.18%) are those who had taken a review for a whole core module of medicine. The number of students who had taken regular admission tests was more than those who took specific interest and ability test with the ratio of 6:1 (or 131:21 student) due to allocation for specific interest test was limited of 20% from all new students accepted.\n\nThis study also depicted that academic achievement in terms of GPA value was dominated by the group of high achievement (77.33 %). This result showed that the academic performance of medical students in our faculty had obtained good achievement.\n\nThe output of the perception of teaching-learning behaviour to the academic achievement (GPA) was stated significant if p-value less than 0.05 with confidence interval amount of 95%.\n\nBased on Table 4, it was found that perception of learning experience and exam effectiveness were two factors influencing academic achievement from the students’ perspective. It was understood that learning experience is the most important aspect in influencing academic achievement. This is due to how a student thinks about learning and studying determines how he/she accomplish assignments and evaluation tasks. Conversely, the learner’s experience with evaluation and assessment processes determines how the student approaches learning (Struyven et al., 2005). Besides, a positive learning experience furnishes students with chunks of time that intentionally prompt them in achieving their learning goals (Schmidt et al., 2019). Undeniably, the learning experience of students changes over time and is dependent on the interventions, peer interactions, and changing circumstances (Fredricks et al., 2016). Its impact on faculty can help them to improve the contemporary design of teaching and learning. This is due to having the ability to assess students' experience which indicates utilizing good self-monitoring, self-assessment, and metacognitive reflection (Giannakos et al., 2020).\n\nThe academic achievement depicted success in curriculum delivery. This finding rhymes with the statement of Dent and Harden that curriculum has six aspects: content, educational strategies; learning experiences; assessment process; learning outcomes; and the slight contrast point, learning environment (Dent et al., 2018). Two things under this study are in terms of learning experience and assessment method (exam significance). In this context, students perceived that the assessment addressed more on conformity with learning materials and the effectiveness of grade score achievement that includes the level of difficulty. In this regard, students are learning more about practice aspects and their goals in the undertaken examination.\n\nExperience is an episode, a chunk of time to remember; it is feelings and thoughts, motives and activities, all closely knitted together. Learning is an experience (Schmidt et al., 2019) that portrays students’ feelings and thoughts, motives, and actions when they interact with the teaching and learning environment. Other variables of perception that slightly influence though not significant, namely perception regarding lecturer capacity and integrated module (79.46% and 77.80%). An interesting finding from this study is about the ability of lecturers, students assume there are 10 items that must be owned by a lecturer. The ten items are grouped into 4 abilities including: teaching kills, expertise in teaching materials, personality styles, and interaction with students. According to the students, the lecturer’s competency or capacity was an essential factor in encouraging success in achieving academic performance. This is in line with the Indonesian directorate general of higher education that a lecturer ought to have four competencies, as follows pedagogical competency, knowledge or subject competency, personal competency, and social competency. Pedagogical competency relates to the teacher’s ability in managing the teaching-learning process. They comprise five aspects, namely learning climate, modelling, coaching, exploration, and articulation (Boerboom et al., 2011).\n\nThe result of confirmatory factor analysis (Figure 3) found that the essential aspect of lecturer capacity was about lecturer ability in mastering the material taught (C18) and in managing the teaching process (C17) because both items have the highest of t- loading values (16.47 and 15.85). It was understood that pedagogical competence consists of the ability to deal with the understanding of students, designing, implementing, and evaluating learning outcomes as a representing the academic achievement, as well as developing students to embody their various potential (Mulyasa, 2012). To summarize, if the teacher can deliver the lessons in line with the student’s expectations, it makes the teaching-learning process run effectively and efficiently. Student’s perceptions regarding the pedagogical competence of lecturers influence positive student motivation; therefore it could affect the performance of academics indirectly (Lumbantobing, 2020).\n\nMeanwhile, statement item about learning experience was the most represented by experiencing when learn of clinical skill practice (C10). Variable indicator in exam effectiveness (Figure 3) was most indicated by the results of an oral exam and objective structured clinical examination (OSCE) (C25). Academic success in medical education is more emphasized to the clinical skill learning, ability in diagnostic reasoning, and clinical reasoning. In contrast, related aspects to them reflect learning experiences about clinical practice and clinical diagnosis.\n\nThe integrated module is a crucial factor in learning medicine. This is due to the teaching method in problem based-learning was incorporating multidisciplinary-system-based courses rather than discipline-specific ones (Atta & AlQahtani, 2015). One of the approaches in problem based-learning is the integrated module. This is related to greater knowledge acquisition and more excellent improvement in clinical skills than the lecture-based approach. The finding in this study showed that integrated module/material also affects academic achievement. Similar to McParland's study that the performance of the students holding PBL was better in both multiple-choice questions and the final exam (Atta & AlQahtani, 2015).\n\nThis study can be generalized to medical students of other medical faculty that have similar characteristics to our faculty. This is due to each institution have different characteristics.\n\n\nConclusions\n\nOverall, our work demonstrates that student perception of learning experience and exam effectiveness affect academic performance. Other factors that contribute to achieving academic success are lecturer capacity and the integrated modules. We provide evidence that lecturer capacity and integrated modules can enhance academic success in the educational process indirectly.\n\nThe original 46-item and 33-item questionnaires were distributed to the medical student in the Indonesian language. There could also be a misinterpretation of meaning when the factors extracted from the literature were translated from English to Indonesian language for the questionnaire and when it was translated again into English for publication. To generalize the results of research at other medical faculty in Indonesia given the limited number of samples, more research is needed with a larger sample which involves other samples of medical faculty.\n\n\nData availability\n\nFigshare: Raw data of the research-Teaching learning behavior in medicine according to students’ perspective, https://doi.org/10.6084/m9.figshare.16456983 (Kusmiati et al., 2021b).\n\nThis project contains the following underlying data:\n\n- Raw data of research-Teaching Learning Behaviour in Medicine.csv\n\nFigshare: Table 3 characteristic of demographic data of students, https://doi.org/10.6084/m9.figshare.16934977 (Kusmiati et al., 2021a).\n\n- This project contains characteristic of demographic of students' participant on teaching learning behaviour in medicine.\n\nFigshare: List of questions and description of the questionnaire-Teaching learning behavior in medicine according to students' perspective, https://doi.org/10.6084/m9.figshare.16457001.\n\nThis project contains the following extended data:\n\n- List of questions and description of the questionnaire-Teaching learning behavior in medicine according to students' perspective.csv\n\nFigshare: Figure 1 steps summary of participant involving in the study, https://doi.org/10.6084/m9.figshare.16935064.\n\n- This project contains figure of steps summary of participants involving in the study of teaching learning behaviour.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nAgung R, Mahatmaharti K, Ardhana W, et al.: Construct Validity in Research Development Instruments: The Analysis of Self-Discipline Factors. Int. J. Humanit. Soc. Sci. 2017; 22(6): 33–40. Publisher Full Text\n\nAiken LR: Rating scales & checklists: evaluating behavior, personality, and attitude. John Wiley & Sons; 1996.\n\nAnthoine E, Moret L, Regnault A, et al.: Sample size used to validate a scale: A review of publications on newly-developed patient reported outcomes measures. Health Qual. Life Outcomes. 2014; 12(1): 1–10. Publisher Full Text\n\nAtta I, AlQahtani F: Hybrid PBL Radiology Module in An Integrated Medical Curriculum Al-Baha Faculty of Medicine Experience. J. Contemp. Med. Sci. 2015; 3(1): 46. Publisher Full Text\n\nBoerboom TBB, Dolmans DHJM, Jaarsma ADC, et al.: Exploring the validity and reliability of a questionnaire for evaluating veterinary clinical teachers’ supervisory skills during clinical rotations. Med. Teach. 2011; 33(2): e84–e91. Publisher Full Text\n\nDent J, Harden RM, Hunt D: A Practical Guide for Medical Teachers. Elsevier; (sixth edit) ed: 2018.\n\nGiannakos MN, Sharma K, Papavlasopoulou S, et al.: Fitbit for learning: Towards capturing the learning experience using wearable sensing. Int. J. Hum. Comput. Stud. 2020; 136(November 2019): 102384–102314. Publisher Full Text\n\nGuilford JP: Fundamental statistics in psychology and education. McGraw-Hill; (6th ed). ed: 1978.\n\nKlug J, Bruder S, Kelava A, et al.: Diagnostic competence of teachers: A process model that accounts for diagnosing learning behavior tested by means of a case scenario. Teach. Teach. Educ. 2013; 30(1): 38–46. Publisher Full Text\n\nKusmiati M, Dharmmika S, Dewi AM: Characteristic of demographic data of students.csv. Figshare. 2021a. Publisher Full Text\n\nKusmiati M, Dharmmika S, Dewi AM: Raw data of research-Teaching Learning Behaviour in Medicine.csv. Figshare. 2021b. Publisher Full Text\n\nLin YK, Lin BY, Chen D: Do teaching strategies matter ? Relationships between various teaching strategies and medical students’ wellbeing during clinical workplace training. Med. Teach. 2019; 42(0): 39–45. Publisher Full Text\n\nLumbantobing PA: The Contribution of Lecturer Pedagogical Competence, Intellectual Intelligence and Self-Efficacy of Student Learning Motivation. Budapest International Research and Critics in Linguistics and Education (BirLE) Journal. 2020; 3(1): 564–573. Publisher Full Text\n\nLynch DC, Surdyk PM, Eiser AR: Assessing professionalism: A review of the literature. Med. Teach. 2004; 26(4): 366–373. PubMed Abstract | Publisher Full Text\n\nMulyasa E: Competency Standards and Teacher Certification. PT Remaja Rosdakarya; 2012.\n\nShirali G, Shekari M, Angali KA: Assessing Reliability and Validity of an Instrument for Measuring Resilience Safety Culture in Sociotechnical Systems. Saf. Health Work. 2018; 9(3): 296–307. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStalmeijer RE, Dolmans DHJM, Wolfhagen IHAP, et al.: The development of an instrument for evaluating clinical teachers: Involving stakeholders to determine content validity. Med. Teach. 2008; 30(8): e272–e277. PubMed Abstract | Publisher Full Text\n\nStruyven K, Dochy F, Janssens S: Students’ perceptions about evaluation and assessment in higher education. Assess. Eval. High. Educ. 2005; 30(4): 325–341. Publisher Full Text\n\nTrickey S, Topping KJ, Trickey S, et al.: Teaching Behavior and Well-Being in Students: Development and Concurrent Validity of an Instrument to Measure Student-Reported Teaching Behavior. J. Res. Adolesc. 2015; 44(2): 70–88. Reference Source\n\nVan Der Vleuten CPM, Schuwirth LWT: Assessing professional competence: From methods to programmes. Med. Educ. 2005; 39(3): 309–317. PubMed Abstract | Publisher Full Text\n\nWorthington RL, Whittaker TA: Scale Development Research: A Content Analysis and Recommendations for Best Practices. Couns. Psychol. 2006; 34(6): 806–838. Publisher Full Text\n\nYeo S, Chang BH: Students’ self-assessment of achievement of terminal competency and 4-year trend of student evaluation on outcome-based education. Korean J. Med. Educ. 2019; 31(1): 39–50. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "100282",
"date": "30 Nov 2021",
"name": "Umatul Khoiriyah",
"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\nThe manuscript describes the scale development of teaching-learning behaviour from the student perspective. It also explains the factors from this behaviour that influence student achievement. The authors had written the manuscript clearly; however, some remarks are identified to improve the quality of the papers.\nThe main topic explained in this paper is scale development, which needs a validity framework. It is recommended to use the current validity framework, viewing the validity as the extent to which the evidence and theories supporting the interpretation of assessment results align with the tool's underlying construct (AERA, APA, 1999). In this current framework, validity evidence consists of content evidence, response process, internal structure, correlation to other variables, and consequence. For detail, please refer to one of these references:\nCook, D. A., & Beckman, T. J. (2006). Current concepts in validity and reliability for psychometric instruments: Theory and application. The American Journal of Medicine, 119(2), 166.e167-166.e116.\n\nDowning, S. M. (2003). Validity: on the meaningful interpretation of assessment data. Medical Education, 37(9), 830-837.\n\nIt is suggested that the aim of this study is to collect validity evidence of the tool measuring student perspectives of teaching and learning behaviour. Based on the current description in this paper, I think that the validity evidence in this tool includes content, response process, and correlation to another variable.\nThe authors have explained the EFA and CFA in detail, which is part of internal structure evidence. Moreover, the authors have correlated the tool with student achievement. This analysis is part of the evidence of \"correlation to other variables\". However, the explanation about the content evidence is not clear. The step in developing the items such as blueprint development, review expert (if it is available) should be informed to the reader. The author should state the domain number underlying the construct of the tool so the reader can understand easily why the EFA was extracted in 7 domains. The response process evidence by tying the items to some students also should be stated clearly. The response process is usually conducted before collecting data for EFA analysis.\n\nSo, it is suggested to revise the manuscript (abstract and main text) based on the current validity framework. Furthermore, since the aim would be revised, the method, results, discussion, and conclusion should also be revised to answer the research aim.\nIn terms of data analysis, I note that the authors extracted the data into seven domains in the EFA part even though the scree plot (figure 2) shows that three domains are better for this data. Please clarify the reason in the method section.\nThe EFA results also show that factors 5 (the difficulty level of the exam) and 7 (integrated and material) only consist of 2 items. The CFA also show similar results. Why did they not merge this domain with another domain? The literature said that a good subscale consists of at least three items.\nIn this study, the analysis of CFA was divided into two parts (figure 3 and figure 4). Please clarify why the seven factors were not analyzed together in one model since they derive from one construct. Furthermore, I also notice that the model in figure 3 is not quite fit since it does not fulfil the fit indexes (RMSEA < 0.1 and chi-square/df < 3) The authors calculated the Cronbach alpha of the total item. Please also analyse the Cronbach alpha of each subscale.\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": "9235",
"date": "23 Jan 2023",
"name": "Mia Kusmiati",
"role": "Author Response",
"response": "1. As suggested by reviewer 1, I have added the current validity framework that the known source of validity in terms of content validity, internal structure, response process and correlation to other variables. (change manuscript will be sent to editorial F1000R). 2. As Reviewer suggested, I have added that the aim of this study is to collect validation evidence of the tool measuring student perspectives of teaching and learning behaviour besides investigating the student’s perception regarding teaching-learning behaviour and which factor most influences academic achievement. 3. In terms of data analysis, the scree plot (figure 2) shows that seven domains are results based on the initial Eigen Value >1 (I have remarked in the figure, there 7 domains with each eigenvalue). Regard to Why we do not merge domains 5 and 7 with another domain because items of these domains have the objective alone to measure a differ what the researcher targeted. 4. Relates to an explanation of Figures 3 and 4, as well as The Cronbach alfa has given some explanation including the Cronbach alfa for each domain. Thank you for Reviewer and regards. Author"
}
]
}
] | 1
|
https://f1000research.com/articles/10-1157
|
https://f1000research.com/articles/10-23/v1
|
14 Jan 21
|
{
"type": "Opinion Article",
"title": "The ideal repository for hosting data from clinical trials: blueprint using business process management",
"authors": [
"Mirko Gabelica",
"Damir Sapunar",
"Matko Marušić",
"Livia Puljak",
"Damir Sapunar",
"Matko Marušić",
"Livia Puljak"
],
"abstract": "In this article, we suggest a blueprint for an ideal open-access repository for clinical trial data with a description of a model of such a repository using a business process analysis approach. Firstly, we suggested which features an ideal repository should have. Secondly, we used business process management software to describe the whole process, from the decision to share clinical trial data to either publication of data in a repository or discarding data. The research community, legislators and society at large should be interested in a transparent open-access repository that will host clinical trial data. We hope this work can inspire relevant stakeholders to engage in discussion about the necessity of creating such repository, and that we will witness the creation of such a repository in the near future.",
"keywords": [
"repository",
"business process management",
"clinical trials",
"data sharing",
"raw data",
"individual patient data"
],
"content": "Introduction\n\nConsiderable interest has been shown recently in increasing transparency of clinical trials. National Institutes of Health (NIH) defined clinical trials as research studies that explore whether a medical strategy, treatment or device is safe and effective for humans, and, if conducted well, they produce the highest level of evidence available for healthcare decision making among primary studies1. However, very often raw data from clinical trials are hidden from scientific community2,3. Sharing individual patient data (IPD) from clinical trials in a central openly available repository was suggested as a solution4.\n\nAlthough ideas about open data sharing come mostly from researchers, it has recently been shown that clinical trial participants support this idea too. A recent survey of individuals who participated in a diverse group of clinical trials showed that the overwhelming majority would support sharing of their data and that their willingness to share data would not be much different depending on the purpose of the data use5.\n\nIn computer sciences, a repository is defined as a central location in which data are stored and managed6. Currently, there are no repositories that host exclusively open-access data from clinical trials. Our recent study (Gabelica et al.; unpublished data) indicated that there are 13 open-access repositories on the Internet, which host clinical trial data together with data from other types of studies. However, those repositories were highly heterogeneous, are not devoted to clinical trials exclusively and most allow data providers to restrict data access for the “shared” data. For this reason, there is a need for a universally adopted open-access repository devoted specifically and exclusively to data from clinical trials.\n\nThe US National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM), has indicated that it would be beneficial to have one single centralized data store, “to collect all clinical trial data worldwide into one central database”. Such a model would benefit from economies of scale, and individuals or groups interested in data would need to search in one database only7. It is recognized that there are challenges associated with such an approach, but if we start addressing the challenges, and considering how such a repository would look like, we could make it a reality one day.\n\nThis manuscript aimed to propose how an ideal open-access repository for clinical trial data should look like and to develop a model of such repository using business process analysis approach.\n\n\nOur approach\n\nFirstly, we suggested which features an ideal repository should have. Some of the features were informed by the earlier study that searched for repositories hosting raw data from clinical trials and analyzing their characteristics. Insufficiencies of existing repositories were taken into account and several additional characteristics were suggested, as we continued envisioning an ideal repository8.\n\nSecondly, we used business process management BPA software, ARIS Express (Software AG, Darmstadt, Germany) to describe the flow of the entire process from decision to deposit data to either data being published or discarded. ARIS was selected as an adequate tool for this task, as it contains a visual representation of vital elements needed for the task. Documents, software, people at hand, etc. are placed in a 2D setting, connections are plain and unambiguous, the expected outcome is clear and perspective is not tainted with complex models. Business process management software allows precise problem identification, and reference model towards solving weak points, continuous quality control and monitoring9.\n\n\nFeatures of an ideal repository\n\nThe ideal clinical trial data repository should be the first place on the internet for searching clinical trial data from published and unpublished clinical trials. The ideal open-access repository for hosting raw data from clinical trials would be a public Internet-based resource.\n\nGeneral features:\n\n1. Exclusivity. Repository accepts exclusively data from clinical trials, including raw data, analyzed data and meta-data. The user interface will be exactly tailored to fit the deposition of clinical trial data.\n\n2. Mandatory use. In line with the requirements of the International Committee of Medical Journal Editors (ICMJE) for mandatory trial registration, relevant stakeholders such as employers, funders and journal editors could agree that clinical trial data need to be deposited in a clinical trial repository.\n\n3. International governance. An international board of relevant stakeholders from academia, industry and funders is governing the repository. These stakeholders should be internationally renowned, non-profit organizations with stable funding, such as large universities, research funding agencies, European Medicines Agency (EMA), or similar.\n\n4. The repository is self-sustainable. An ideal repository needs to develop a sustainable collaborative funding model that will ensure the maintenance and continuing development of the repository, providing new tools and storing new datasets, while ensuring that the repository is free to access and reliable10. Such a collaborative model could, for example, include financial support of governments, as part of their investment in research.\n\nCost of data deposit is free or minimal. Data deposit is free for data depositors, or partially funded from grants, or institutions or government if such funds exist. Lack of funds should not prevent data deposition. Since funders now regularly cover the cost of publications in open-access journals, principal investigators applying for grants can also include the cost of data deposition in an open-access repository. Principal investigators without funds can apply for a fee waiver. The cost of data deposition, if there is any cost at all, should not be prohibitively high, and in line with the cost of manuscript publication.\n\nFeatures related to user experience:\n\n5. English is the main language of the repository framework, with the option to create sibling web sites in other languages. The uploaded files can be in any language, and language of files is indicated, with the preference for uploading files in the English language to achieve maximum visibility.\n\n6. Simple user interface and searching. The user interface is a friendly and self-explanatory environment, which enables step by step upload. All the content in the repository is searchable.\n\n7. Updates and corrections are archived. The repository enables subsequent updates and corrections to a deposited dataset, where each change is explained and recorded, and each version of the dataset is archived and accessible.\n\n8. Mandatory inclusion of metadata with clinical trial data. Metadata include a comprehensive separate data set that should answer all potential answers about the clinical trial and data from a trial. Such metadata enables managing clinical data portfolio, enable assessment of the conduct and analysis of those trials, and reanalysis11–13\n\n9. Instructions for preparing and depositing data and metadata. Extensive instructions on data preparation for deposition are available on-site, with clear statements on mandatory data and metadata deposition13. da Silva et al. concluded that most researchers store their data in various formats and the main reason for data loss is lack of appropriate annotation14.\n\n10. The maximum upload file size is 2 GB, while the maximum project upload size is unlimited so that researchers can upload all the files that are associated with a clinical trial. Image compression in an ideal repository should be lossless. Currently, there is a problem with deposition and archiving of medical images from MR, CT scans and similar devices that generate large file sizes. Mezrich and Siegel addressed the need for universal and technological appropriate guidelines regarding storing digital medical images, with the help of the information technology community. Image compression has been suggested as an approach but no guidelines have yet been made and adopted15. Although Koff’s study found no difference in diagnosis based on low level compressed and uncompressed images, evaluating the standards for irreversible compression in digital diagnostic imaging has been proposed by the Canadian association of radiologists16.\n\n11. Persistent identifier is assigned to each dataset. A digital object identifier (DOI) is an important international standard for identification of online material. A DOI is therefore provided to each dataset (complete data and metadata for one study). It is vital for digital objects (articles, datasheets, images) to receive a DOI, as it helps to avoid several issues with citations, such as broken links (marked with a warning: error 404), copy-paste errors in citation text and copyright violation. Also, a DOI enhances verifiability, because it always leads to the correct web source17. According to Klump and Huber, a DOI is used in 75% of repositories as the most common persistent identifier, making it most successful persistent identification system currently in use18. Price of DOI is 1$ in the most expensive scenario for an article and 0.06$ for data set; the price varies according to DOI issuing agency19.\n\n12. Mandatory manual curatorship of datasets. After deposition, data are verified by at least two experts independently, such as a biocurator and a statistician20,21. The UK’s Digital Curation Centre suggests outlines of their approach to digital curation procedure, with several steps, of which the following are relevant for ideal repository: i) conceptualization: considering which digital material will be stored, which data capture methods will be used and available storage options; ii) creation: production of relevant metadata because it enhances accessibility; iii) access and use: determining whether data are publicly accessible, whereas for ideal clinical trial open data repository limited accessibility is an option to consider, as well as embargo options before the publication of results; iv) appraisal and selection: determining what digital data is relevant, in respect to legal guidelines if they exist; v) disposal: discarding irrelevant data; vi) ingesting: placing digital objects to predetermined storage locations; vii) preservation: taking actions that will ensure long-term data protection and retention of the nature of digital material; viii) reappraisal: reevaluate material to ensure that is still relevant and is true to its original form; ix) storage: keeping the data secured; and x) access and reuse: routinely check that material is still accessible22,23.\n\n13. A limited embargo period is allowed. Investigators can deposit the data after obtaining results, before the manuscript is submitted, but with an embargo that will be in effect until manuscript publication. The maximum embargo period that investigators can request is 1 year24.\n\n14. Data and metadata are reusable. Curators need to confirm that data is reusable and analyzable by performing minimal reanalysis according to the internally-agreed uniformed data reanalysis protocol, to confirm at least one result from the published manuscript.\n\n15. Access to data is open after the registration. Users have open access to data after registration on the site, accredited via affiliation.\n\n16. Data can be reused. Datasets are published under a Creative Commons Attribution 4.0 International License, which allows maximum dissemination and data reuse. Users will be free to share and remix the dataset, under the condition that they attribute the source of the dataset to the original author25,26.\n\n17. Enabled interconnectivity. Clinical trial data repository should be connected with protocol registries, such as ClinicalTrials.gov, ISRCTN and EudraCT, and with published journal article by using a DOI. Links to protocol registrations and journal articles are to be found on the repository website.\n\n18. Researcher identification should be managed with an ORCID ID, a nonproprietary alphanumeric code whose purpose is to provide a unique persistent identifier to academic authors. An ORCID ID is thus similar to DOI. Even though the ORCID organization warns that they are not an identity verification system, many universities and publishers, along with commercial companies, promote and use ORCID27.\n\n19. Management of IPD is crucial and the most demanding process related to the design of the ideal repository. It has to be defined according to the EU General Protection Regulation (GDPR) which is designed to harmonize data privacy laws across Europe and to protect all EU citizen data privacy and redefine the way organizations across the EU approach data privacy. The enforcement date for GDPR was May 25, 2018, and since that date organizations in non-compliance will face heavy fines. Deposited data should be prepared and deposited in such a way that the data subject is no longer identifiable. For example, IPD should contain a code instead of participant real name, address, email, photo, phone number or social security number should not be in the table. It is not likely that someone could be identified via sex, age and arterial pressure, blood glucose and TNM stage. All other questions regarding GDPR compliance should be managed by the clinical trial principal investigator or dedicated officer28.\n\n20. The repository should qualify for CoreTrustSeal, which guarantees that the repository has been created according to 16 guidelines for a sustainable and trustworthy repository29.\n\n21. Organization of metadata should be following the Dublin Core Metadata Initiative, specifically DCMI metadata terms30. DCMI maintains authoritative specification of metadata terms, and those terms are published as IETF RFC 5013 [RFC5013], ANSI/NISO Standard Z39.85-2007 [NISOZ3985], and ISO Standard 15836:2009 [ISO15836]. Description of every single metadata repository element is beyond the scope of this article\n\nFor the uploader: The repository would be safe archival space where one can store an unlimited amount of data. These data may serve to others, but also as a backup for the uploader, in terms of data protection and preservation.\n\nFor other researchers: It would be a user-friendly interface and smart search engine that would provide easy access to clinical trial results, and dataset acquisition in just a few seconds. These data can then be reused and reanalyzed.\n\nFor stakeholders concerned with research integrity: It would help stakeholders check whether clinical research data have been fabricated or falsified. Preventing statistical analysis results unfavourable to the researcher (including the funding agency) from being concealed, and preventing fraud in a clinical trial results publishing2,31.\n\nFor legislators: The repository would combine ethical science and reporting of results with good clinical practice. If problems emerge, all data from the beginning to the end of the study is available on site.\n\nFor science, at large: Implementation of the repository would lead to a reduction of waste in research. Currently, many RCTs do not report all data collected within the study. Other researchers or healthcare workers may benefit from knowing that certain data were collected and analyzed, and accessible in a repository32. Such a mandatory repository would mark an era of truly open science and data sharing in clinical trials.\n\nThe focus of this project was a development of IPD and clinical trial data deposition and curation scheme, or to put it simply, what happens to data when a researcher deposits them to the repository. BPM was used to identify all necessary steps required for successful data management from deposition, checking whether data were adequately prepared via human curation and DOI assignment, and finally data publishing on the repository website. Figure 1 shows the entire process that we are proposing. The main goal was to ensure that there are no loose ends in the data management lifecycle; once the data is deposited in the repository, the project must end as published or discarded data.\n\nThe process in the middle of the model has left arm which describes the necessary documents and tools. The right arm defines the person responsible for performing a task that leads to another process until the process is finished as discarded data or published data. Every process begins with a decision whether or not one will enter the process. When researchers decide to share their data, clinical trial data manager puts an effort to generate RCT data sheet (block) they want to share. The next step is preparing data according to repository policy so data could be successfully ingested and manipulated until publication, e.g. images, sheets, videos, written data, should be submitted in acceptable formats. After preparation, data is submitted via an online form and the clinical trial data manager’s job is now finished (Figure 1).\n\nThe repository should have curator(s) and statistician(s) proficient in the area of clinical trials. After data submission, curators will now verify whether deposited data has been prepared according to relevant policy; therefore, we see a branching process if data is not prepared accordingly (Figure 1). In that case, clinical trial data manager will be contacted to explain provide an explanation for not following policy instructions. If an explanation is provided, the process begins again from the top; if an explanation is not provided, the process will terminate, and the data will be discarded (Figure 1).\n\nIf data are prepared properly, they are placed in repository archive but are not visible to others. Requesting a DOI for an archived dataset is the next process, which also branches in two arms, depending on registration agency criteria for DOI assignment. This means that the registration agency can decline DOI assignment. If that happens, the process is to be repeated until criteria are met to acquire DOI. Next step is publishing dataset with DOI on the repository website, making it fully visible online (Figure 1).\n\nOther processes that precede data deposition, and processes after data publication are not addressed in this article. Ohman et al. advised 10 principles and 50 recommendations that should be taken into consideration for successful clinical trial data sharing in general. They described steps to be taken from data preparation to data sharing monitoring33. Ohman et al. focused on ideal data sharing prerequisites, while we focus on technical aspects regarding ideal repository features, data validation and publication of such data.\n\n\nDiscussion\n\nThis manuscript describes features of an ideal repository for hosting open-access data from clinical trials, and ideal schema for its creation, using a business management approach. Such a central, mandatory repository for clinical trials is necessary because we are witnessing numerous calls for action, statements, articles, open letters, organizations, projects, and initiatives regarding “open data” movement34,35.\n\nHowever, an ideal repository needs to be backed up by a legislative framework to be usable and sustainable. Without it, all efforts for creating sustainable clinical trials repository will be futile and dispersed36. The legislation behind ClinicalTrials.gov is a relevant example. The first milestone towards open clinical trial science was achieved in 2008, with legislation that backed up mandatory basic results reporting at ClinicalTrials.gov through Section 801 of the Food and Drug Administration Amendments Act (FDAAA 801), and again in January 2017 with the Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11), the law generally includes interventional studies (with one or more arms) of FDA regulated drugs, biological products, or devices that meet one of the following conditions: the trial has one or more sites in the United States, or it is conducted under an FDA investigation and finally if the trial involves a drug, biologic, or device that is manufactured in the United States or its territories and is exported for research37,38.\n\nNow is the time for the next milestone in open clinical trial science, which will include the creation of one exclusive, domain-specific repository that will host raw data from clinical trials, with the strong support of the legislation, and publishing community.\n\nCurrently, the two most promising existing initiatives considering data sharing are ClinicalStudyDataRequest (CSDR)39 and Vivli40. Both initiatives provide data on request, the request is processed, and a decision is made whether or not one is eligible to view the data. If the access to data is granted, one must sign a Data Use Agreement, which differs depending on the company holding the data; the agreement in some way restricts the use of data and publication of finding. Both initiatives are funded by pharmaceutical companies. The good thing regarding these initiatives is relative access to some individual participant data.\n\nStrom et al. have described their experience with CSDR. As members of independent review panel deciding about requests for use of those data, Strom et al. reported on the first 2 years of applications for access to data from 3049 trials that were available through the website. Of the 177 research proposals that were submitted, the majority was granted, and of those only four reports were published by October 2016. Strom et al. suggest that this could indicate inefficiency of the approval process behind CSDR39.\n\nIn our previous research (Gabelica et al.; unpublished data), we screened 1700 (re3data) repositories and found that individual participant data can be found in public repositories such as Dryad, Zenodo, OSF, B2share, Edinburgh data share, Easy/DANS, ICPSR, LSHTM Data Compass, SND, DRUM and University of Bath Research Data Archive. The only repository that was specifically created for hosting raw data from clinical trials was University Hospital Medical Information (UMIN)31 Center’s Individual Case Data Repository (ICDR) within the University of Tokyo Hospital; however, the UMIN repository was not open access; it is open only to researchers from Japan who previously registered their trials in it.\n\nIn 2016., Goldacre and Gray published a manuscript in which they described the creation of an open database for hosting all data and documents threaded together by an individual trial41. Their OpenTrials database has been created online and is available at the URL https://opentrials.net/. However, the way they envisaged their database has multiple serious issues that will not make it sustainable.\n\nFirstly, there is an issue of funding. According to the information on the database web site, they secured funding for the first phase of the project, which allowed them to create a “practical data schema”42. Secondly, OpenTrials proposes web scraping as a method for populating the database. Web scraping, by definition, is the extraction of large amounts of data from websites. For the Open Trials database, web scraping will be done automatically with the help of software. However, certain web sites have barriers that will disable such work. Alternatively, manual web scraping is an option, but that is a very tedious work, which requires additional knowledge on what to scrape41,43.\n\nThe third issue of the OpenTrials database is an expectation about crowdsourced curation. This sourcing model relies on a large network of internet users to participate in data curation, specifically clinical trial data. It is hard to believe that a significant number of people will be available for curating data from such a broad and complicated area of science44.\n\nIt is also unclear how OpenTrials would match the data about the same trial from various sources. Goldacre and Grey wrote in their manuscript that they will “record linkage”41, and on the OpenTrials web site, they write that this is “area of ongoing work and research”45. Thus, it is unclear how they planned to record linkage. Presumably, the idea is to connect deposited data with registered protocols and published manuscripts with results, but this is not clearly indicated, nor are methods to achieve so. Simple linking of records would have to be done manually, and it could not be automated, which would be a major disadvantage of such an approach.\n\nMost importantly Goldacre and Grey propose against hosting IPD to protect patient privacy. However, the anonymity of data is a technical issue that is simple to solve. Planning of the ideal repository must consider full anonymization of the IPD’s data under EU GDPR act28. Without the availability of IPD, there is no open science, and there will be a limited possibility for reuse and reanalysis of clinical trial data. Strom et al. state that meta-analysis of firewalled patient-level data from multiple sources is a grievous endeavour. Open access to data on a dedicated repository is obvious solution46.\n\nWithout proper legislation, manual curation, automation of selected processes, regulation and sustainable funding, it is possible that OpenTrials may not fulfil expectations. Multiple such attempts were made before. One example is OneRepo, which aimed to solve the problem of institutional repositories fragmentation, and open access to scholarly articles47. OneRepo was described as a project whose aim is to “unify the world’s green and gold open-access works” by providing a single access point for searching all of the world’s institutional repositories48. However, it does not look like the research community is taking any notice. As of November 2017, there is no single scholarly article available in major indexing databases about OneRepo. In November 2017, personal communication with the OpenRepo’s founder Mike Taylor indicated that development of OneRepo has been halted due to funding issues.\n\nAn ideal central repository for hosting data from clinical trials should be modelled as a governmental database, such as DNA banks for convicted criminal offenders, fingerprint databases, bank account information, civil registration systems, land and property records, judicial records or vehicle information records49. In the case of an ideal repository, this would be a transgovernmental organization, such as INTERPOL50. The reason for this is that raw information from clinical trial data is too important to be insecurely funded or improperly curated.\n\nWe hope that relevant stakeholders will strive to create a repository which we idealistically propose. While such repository may not be perfect initially, it can be perfected over time, for the reasons that Strom et al. elaborated: “Making trial data broadly available is ethically imperative and scientifically justified and has the potential to increase public understanding of and support for clinical research. But it seems critical to find ways to improve the use and output of data-sharing projects before the clinical research community invests the substantial effort and resources required to broaden the effort to include academic and other non-commercial investigators”46.\n\nWith this manuscript, we hope to foster further activities to reach a consensus of a wider research community about the suggested features of an ideal repository. We have suggested features that we consider important, but the wider community could likely suggest other features that would be important, and that some of the features we suggested could be trimmed. We are not suggesting a crude approach where everyone will simply have to deposit their full data, but a creation of an ideal repository, which will also address concerns regarding the possible re-identification of patients.\n\nThe novel part of our ideal repository is strictly defined technical aspect of deposited data validation, and data curation, while implementing all aspects of FAIR data principles, which include findability, accessibility, interoperability and reusability51.\n\nIn conclusion, we described our idea of an ideal open-access repository for clinical trial data and developed a model of such a repository using a business process analysis approach. We hope this work can inspire relevant stakeholders to engage in discussion about the necessity of creating such repository, and that we will witness the creation of such repository in near future.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "References\n\nNational Heart Lung and Blood Institute: What Are Clinical Trials? National Institutes of Health; U.S. Department of Health and Human Services. Reference Source\n\nEmpty rhetoric over data sharing slows science. Nature. 2017; 546(7658): 327. PubMed Abstract | Publisher Full Text\n\nSchmucker C, Schell LK, Portalupi S, et al.: Extent of non-publication in cohorts of studies approved by research ethics committees or included in trial registries. PLoS One. 2014; 9(12): e114023. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSmith CT, Dwan K, Altman DG, et al.: Sharing individual participant data from clinical trials: an opinion survey regarding the establishment of a central repository. PLoS One. 2014; 9(5): e97886. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMello MM, Lieou V, Goodman SN: Clinical Trial Participants' Views of the Risks and Benefits of Data Sharing. N Engl J Med. 2018; 378(23): 2202–2211. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRepository | Definition of repository in English by Oxford Dictionaries. Oxford University Press. 2018. Reference Source\n\nInstitute of Medicine: Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk. Washington, DC: The National Academies Press. 2015; 304. Reference Source\n\nBanzi R, Canham S, Kuchinke W, et al.: Evaluation of repositories for sharing individual-participant data from clinical studies. Trials. 2019; 20(1): 169. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSapunar D, Grković I, Lukšić D, et al.: The business process management software for successful quality management and organization: A case study from the University of Split School of Medicine. Acta Med Acad. 2016; 45(1): 26–33. PubMed Abstract | Publisher Full Text\n\nKitchin R, Collins S, Frost D: Funding models for Open Access digital data repositories. Online Inform Rev. 2015; 39(5): 664–681. Publisher Full Text\n\nCanham S, Ohmann C: A metadata schema for data objects in clinical research. Trials. 2016; 17(1): 557. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRaftery J, Young A, Stanton L, et al.: Clinical trial metadata: defining and extracting metadata on the design, conduct, results and costs of 125 randomised clinical trials funded by the National Institute for Health Research Health Technology Assessment programme. Health Technol Assess. 2015; 19(11): 1–138. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFORCE11: Guiding principles for findable, accessible, interoperable and re-usable data publishing version B1.0. FORCE11. 2017. Reference Source\n\nSilva JRD, Ribeiro C, Lopes JC, editors: UPData: a data curation experiment at U. Porto using DSpace. Proceedings of the 8th International Conference on Preservation of Digital Objects. 2011. Reference Source\n\nMezrich JL, Siegel E: Storing Medical Images in the Digital Age: The Need for Universal and Technologically Appropriate Guidelines. J Am Coll Radiol. 2017; 14(6): 752–754. PubMed Abstract | Publisher Full Text\n\nKoff D, Bak P, Matos A, et al.: Evaluation of irreversible compression ratios for medical images thin slice CT and update of Canadian Association of Radiologists (CAR) guidelines. J Digit Imaging. 2013; 26(3): 440–6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWikipedia contributors: Digital object identifier. Wikipedia, The Free encyclopedia. 2004 [updated 1 August 2018 03:51 UTC. Reference Source\n\nKlump J, Huber R: 20 Years of Persistent Identifiers – Which Systems are Here to Stay? Data Sci J. 2017; 16: 9. Publisher Full Text\n\nCrossref: Content registration fees. 2017. Reference Source\n\nBuneman P, Cheney J, Tan WC, et al.: Curated databases. Proceedings of the twenty-seventh ACM SIGMOD-SIGACT-SIGART symposium on Principles of database systems; Vancouver, Canada. 1376918: ACM. 2008; 1–12. Publisher Full Text\n\nBourne PE, McIntyre J: Biocurators: Contributors to the World of Science. PLoS Comput Biol. 2006; 2(10): e142. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWikipedia contributors: Digital curation. Wikipedia, The Free encyclopedia. 2008 [updated 9 July 2018 22:59 UTC. Reference Source\n\nJISC: Digital Curation Centre. 2005. Reference Source\n\nSuber P: The evidence fails to justify publishers’ demand for longer embargo periods on publicly-funded research. The London School of economics and Political Science. 2014. Reference Source\n\nNATURE: Scientific data. 2017.\n\nForschungsdaten.info: Laws governing database and repository usage.\n\nORCID: Does an ORCID iD assure my identity? 2018. Reference Source\n\nRegulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation). Official Journal of the European Union. 2016; L119: 1–88. Reference Source\n\nData Seal of Approval, ICSU World Data System: CoreTrustSeal Certification Launched. 2017. Reference Source\n\nDCMI: DCMI Metadata Terms. 2018. Reference Source\n\nUMIN-ICDR: Individual Case Data Repository. UMIN Center, the University of Tokyo Hospital 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan: University of Tokyo Hospital, University hospital Medical Information Network (UMIN) Center. 2013. Reference Source\n\nDwan K, Altman DG, Clarke M, et al.: Evidence for the selective reporting of analyses and discrepancies in clinical trials: a systematic review of cohort studies of clinical trials. PLoS Med. 2014; 11(6): e1001666. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOhmann C, Canham S, Banzi R, et al.: Classification of processes involved in sharing individual participant data from clinical trials [version 2; peer review: 3 approved]. F1000Res. 2018; 7: 138. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEuropean Commission Directorate General for Research and Innovation: EOSC Declaration Action List. 2017. Reference Source\n\nMorey RD, Chambers CD, Etchells PJ, et al.: The Peer Reviewers' Openness Initiative: incentivizing open research practices through peer review. R Soc Open Sci. 2016; 3(1): 150547. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuharoy V: Clinicaltrials.gov: Is the Glass Half Full? Hosp Pharm. 2014; 49(10): 893–5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTse T, Williams RJ, Zarin DA: Reporting \"basic results\" in ClinicalTrials.gov. Chest. 2009; 136(1): 295–303. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDepartment of Health and Human Services U: Clinical Trials Registration and Results Submission. Document Citation 81 FR 64981,CFR 42 CFR 11 Docket number: NIH-20110003. 2017; 0925-AA55: 64981–5157. Reference Source\n\nUnknown: Clinical study data request: ideaPoint. Inc. Reference Source\n\nCenter M: Vivli: The Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard. 2018. Reference Source\n\nGoldacre B, Gray J: OpenTrials: towards a collaborative open database of all available information on all clinical trials. Trials. 2016; 17: 164. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGoldacre B, Gray J: OpenTrials. 2016. Reference Source\n\nWikipedia contributors: Web scraping: Wikipedia, The Free Encyclopedia. 2005. Reference Source\n\nWikipedia contributors: Crowdsourcing: Wikipedia, The Free Encyclopedia. 2006. Reference Source\n\nGoldacre B: Opentrials.net/FAQ/What is your record linkage strategy. 2017. Reference Source\n\nStrom BL, Buyse ME, Hughes J, et al.: Data Sharing - Is the Juice Worth the Squeeze? N Engl J Med. 2016; 375(17): 1608–1609. PubMed Abstract | Publisher Full Text\n\nHammer S: One repo project description: Indexdata.com. 2015. Reference Source\n\nTaylor M: OneRepo. 2015. Reference Source\n\nWikipedia contributors: Government database: Wikipedia, The Free Encyclopedia. 2007; updated 24 July 2018 22:12 UTC. Reference Source\n\nRunjic L: Transgovernmental Organisations - a new kind of international organisms. Zbornik radova Veleucilista u Sibeniku. 2014; 1-2/2014: 91-108. Reference Source\n\ncontributors W: FAIR data: Wikipedia. Reference Source"
}
|
[
{
"id": "80412",
"date": "12 Mar 2021",
"name": "Paul Grefen",
"expertise": [
"Reviewer Expertise Information Systems"
],
"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 opinion article proposes the establishment of a global, true open access repository for clinical trial data, which the authors label as an 'ideal repository'. The proposed repository is further described by a set of requirements to this repository and its supporting software and by a business process for depositing data in the repository.\nAs a researcher, I am very sympathetic to the idea of the proposal. Open data repositories are important to the advancement of any science that includes empirical data analysis - and medical sciences are among the important of these. On the other hand, however, I find the proposal in the paper not very realistic, and from that point of view, not very strong. It is easy to propose an ideal repository and to wave away most practical problems by the remark that 'they should be solved'. Hence, the contribution of the paper in its current form can be questioned. Why not focus more on a structured strategy to address the problems?\nThe set of requirements to the repository is long, but appears rather arbitrary for two reasons. Firstly, there is no clear indication how this set of requirements was established. In other words, many of the listed requirements do not have a proper foundation and therefore appear no more than the (arbitrary) opinion of the authors. A typical example is Feature 10 about the maximum upload size (which, by the way, is not a feature but a constraint). I suggest to explicitly map the requirements/features to the challenges that are mentioned on Page 3.\nSecondly, there is no proper structure in the requirements. They are rather arbitrarily split into 'general features' and 'features related to user experience'. This lack of structure makes it impossible to judge whether this is a complete requirements specification, or in the terminology of the paper, a complete feature set. I suggest that the authors adopt a proper requirements specification structure - there are many textbooks on requirements analysis available that cater for this in the information systems domain.\nIt is unclear to me why the process design for the data uploading process is included in this opinion paper. In my opinion, it is far too operational for an opinion paper. The process that the authors (try to) describe is rather trivial given the purpose of the repository, so does not add much to the 'opinion value' of the paper.\nApart from the (non-)usefulness of the process model in this paper, the process model is flawed for a number of reasons:\nThe model does not have a proper starting point. Please add a proper entry point to the process.\n\nThe model has one 'dangling' end point: it is not specified what happens with a submitted data set if the 'REG Agency criteria are NOT met'. Please complete this branch of the process.\n\nThe concepts event and activity are used inconsistently and incorrectly at multiple points. For example, 'Resolving Unprepared Data' looks like an activity, not an event. Please consult the ARIS manual for proper use.\n\nEven though version management of data sets is (very rightfully) part of the listed requirements, even though not labeled as such (Feature 7), it is not included in the process model at all. Neither is the deletion of data sets on owner's request.\n\nIt is not clear what the difference is between 'IT Manager' and 'IT System Manager'.\n\nIn the model, it is not clear to which organizations the roles belong; the use of swim lanes can solve this problem.\n\nWhy does a 'Dataset with DOI' require a DOI as a resource in the next step?\n\nWhy is 'email' a resource but not 'data transfer mechanism'?\nApart from this, one might ask why the use of data sets is not included in the process model. Instead of all details of the uploading process, I would rather have liked to see a high-level life cycle model that includes all phases of the data life cycle, including the use of the data.\nFinally, it is not clear why the use of ARIS is stressed, as there are many tools that can be used to create high-level process models.\nOn the textual side:\nPlease clarify all acronyms, like IPD and RCT.\n\nPlease check your use of articles (quite some are missing).\n\nSpell names consistently ('Gray' vs. 'Grey')\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? Partly\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Partly",
"responses": [
{
"c_id": "9384",
"date": "01 Mar 2023",
"name": "Mirko Gabelica",
"role": "Author Response",
"response": "This opinion article proposes the establishment of a global, true open access repository for clinical trial data, which the authors label as an 'ideal repository'. The proposed repository is further described by a set of requirements to this repository and its supporting software and by a business process for depositing data in the repository. As a researcher, I am very sympathetic to the idea of the proposal. Open data repositories are important to the advancement of any science that includes empirical data analysis - and medical sciences are among the important of these. On the other hand, however, I find the proposal in the paper not very realistic, and from that point of view, not very strong. It is easy to propose an ideal repository and to wave away most practical problems by the remark that 'they should be solved'. Hence, the contribution of the paper in its current form can be questioned. Why not focus more on a structured strategy to address the problems? 1) The set of requirements to the repository is long, but appears rather arbitrary for two reasons. Firstly, there is no clear indication how this set of requirements was established. In other words, many of the listed requirements do not have a proper foundation and therefore appear no more than the (arbitrary) opinion of the authors. Response to comment 1: We thank Prof. Grefen for his insight, and comment. We are sorry for not clarifying indications on proposing the ideal repository requirements. Earlier, we performed an analysis of repositories listed on re3data website to identify those containing randomised clinical trial (RCT) data. We found 14 of those repositories, and after careful analysis, we identified what was missing in our opinion. Afterwards, we proposed repository features in this paper that we consider to be relevant. We would like to stress that all authors are physicians and medical scientists, and in writing this paper no information scientist was contacted to review the repository features. We now acknowledge that this could be considered a limitation of the study. However, our set of requirements can be considered as the result of an expert opinion. 2) A typical example is Feature 10 about the maximum upload size (which, by the way, is not a feature but a constraint). Response to comment 2: We suggested this feature based on the analyses of existing repositories. In RCTs we do not deal with huge datasets. Limitations in the size of the dataset impose more discipline in data preparation and organization which can be beneficial for the future users of the deposited data. This is now emphasized in the manuscript. 3) I suggest to explicitly map the requirements/features to the challenges that are mentioned on Page 3. Response to comment 3: The comment was not sufficiently specific, so we were unable to revise the manuscript in line with this comment. 4) Secondly, there is no proper structure in the requirements. They are rather arbitrarily split into 'general features' and 'features related to user experience'. This lack of structure makes it impossible to judge whether this is a complete requirements specification, or in the terminology of the paper, a complete feature set. I suggest that the authors adopt a proper requirements specification structure - there are many textbooks on requirements analysis available that cater for this in the information systems domain. Response to comment 4: We have explored the “requirements specification” proposal. From what we can gather in the literature, “requirements specification” refers to software engineering. We would like to highlight that we are not software engineers, and the intention of our manuscript was not to delve into that direction – this is simply not our field. Also, we have highlighted in our manuscript that this is our vision, from our perspective, of characteristics of an ideal repository. We fully acknowledge what Prof. Grefen wrote – that this proposal may not be (entirely) realistic. For this reason, we titled it – the ideal repository. As we did not approach this topic from the software engineering aspect, we did not include any “requirements specification”. 5) It is unclear to me why the process design for the data uploading process is included in this opinion paper. In my opinion, it is far too operational for an opinion paper. The process that the authors (try to) describe is rather trivial given the purpose of the repository, so does not add much to the 'opinion value' of the paper. Response to comment 5: Regardless of the apparent simplicity of the proposed procedure, its description is valuable for IT experts that are not familiar with the concepts of depositing data in repositories. The proposed description of the business processes can serve as a blueprint for developing application software that can be part of the infrastructure for future repositories. Also, the proposed business process design for data uploading can be helpful for young scientists not familiar with the necessary procedures. We believe that transparency is an important issue in this case so, in the same manner as we have instructions for authors in scientific journals, we need a similar description of the data processing procedures. 6) Apart from the (non-)usefulness of the process model in this paper, the process model is flawed for a number of reasons: The model does not have a proper starting point. Please add a proper entry point to the process. Response to comment 6: The starting point is \"Data preparation according to the policy\". This is now marked in Figure 1 legend. Also, the starting point is now emphasized in Figure 1 by making it bold. 7) The model has one 'dangling' end point: it is not specified what happens with a submitted data set if the 'REG Agency criteria are NOT met'. Please complete this branch of the process. Response to comment 7: The reviewer is right, we rectified this weak point in the proposed business process. If the criteria are not met, the dataset will be returned to the authors to determine their willingness to correct the dataset and to share it. This was revised in the flow chart. 8) The concepts event and activity are used inconsistently and incorrectly at multiple points. For example, 'Resolving Unprepared Data' looks like an activity, not an event. Please consult the ARIS manual for proper use. Response to comment 8: We checked the whole manuscript for inconsistent usage of concepts \"event\" and \"activity\". We also corrected the flowchart. 9) Even though version management of data sets is (very rightfully) part of the listed requirements, even though not labeled as such (Feature 7), it is not included in the process model at all. Neither is the deletion of data sets on owner's request. Response to comment 9: We included updates, and corrections are now made in the flowchart to include Feature 7 (\"7. Updates and corrections are archived. The repository enables subsequent updates and corrections to a deposited dataset, where each change is explained and recorded, and each version of the dataset is archived and accessible.\") in the flow chart as well. Option for deletion of data on owners’ request is challenged; in our opinion, that is similar to a request to delete your vehicle or fingerprints from the governmental database. 10) It is not clear what the difference is between 'IT Manager' and 'IT System Manager'. Response to comment 10: We clarified this in the new version of the manuscript. Namely, this was revised in the flow chart. 11) In the model, it is not clear to which organizations the roles belong; the use of swim lanes can solve this problem. Response to comment 11: Our initial model was prepared with the swim lanes however that substantially reduced the clarity of the flow chart. That is why we opted for excluding the stakeholders’ roles. 12) Why does a 'Dataset with DOI' require a DOI as a resource in the next step? Response to comment 12: We corrected the flowchart and removed a DOI as a resource. 13) Why is 'email' a resource but not 'data transfer mechanism'? Response to comment 13: This is now amended in the flow chart. 14) Apart from this, one might ask why the use of data sets is not included in the process model. Instead of all details of the uploading process, I would rather have liked to see a high-level life cycle model that includes all phases of the data life cycle, including the use of the data. Response to comment 14: The proposed idea is interesting but out of the scope of our manuscript since it deals with the Open science paradigm. We tried to limit the focus of our manuscript exclusively to the features of the repositories. 15) Finally, it is not clear why the use of ARIS is stressed, as there are many tools that can be used to create high-level process models. Response to comment 15: We are aware of numerous tools that can be used for this specific purpose. The reason for the usage of the ARIS platform is the fact that some of the authors are certified for the work with it. We have now indicated this in the manuscript. On the textual side: 16) Please clarify all acronyms, like IPD and RCT. Response to comment 16: This was corrected in the manuscript. 17) Please check your use of articles (quite some are missing). Response to comment 17: We have now conducted language editing. 18) Spell names consistently ('Gray' vs. 'Grey') Response to comment 18: This was corrected in the manuscript."
}
]
},
{
"id": "86953",
"date": "30 Jun 2021",
"name": "Ida Sim",
"expertise": [
"Reviewer Expertise Data-sharing"
],
"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 publication proposes an ideal repository for hosting data from clinical trials. The criteria for such a repository was derived and modeled using a business analysis approach. It is not clear why a business analysis approach was utilized for this endeavor which appeared to conduct a landscape scan of current repositories. Data sharing is conducted within legal and cultural contexts that require additional considerations beyond business process management.\nIntroduction - The researchers indicate that the ideal repository is an “open-access” concept and not a managed access or controlled access system. A thorough discussion of the many valid reasons for sharing clinical trial data under managed access rather than open access is needed to support the claim that open access is \"ideal.\" The IOM report laid out the reasons why a fully open access approach is theoretically ideal but not realistic.\nThe authors refer to the existence of 13 such open access “heterogeneous” repositories that provide access to clinical trial data alongside other types of data. However, the authors do not consider these “ideal” repositories due to their heterogeneous nature. The authors do not provide adequate justification for their criteria nor are the 13 open access repositories named.\nOther criteria also appear rather subjective and to conflict with the sustainability criteria if one were to put them into practice. For example, requiring the repository to be sustainable without charging fees to contributors nor requestors but rather placing the burden onto governments of countries who do not have a line-item budget for this type of effort (which countries should support this? and what is their incentive to do so?) is unrealistic. Additionally, many of the requirements are exceedingly expensive and would require highly skilled statistical staff such as requiring two data curators per dataset and that the curators perform re-analysis and reproduce one result from the manuscript. These requirements which on the surface appear to be reasonable QA would require extraordinary resources.\nOther criteria appear arbitrary without justification such as the recommendation for the Dublin core metadata initiative (DCMI).\nThe paper also does not review Vivli's approach, even though the authors state that \"Currently, the two most promising existing initiatives considering data sharing are ClinicalStudyDataRequest (CSDR)39 and Vivli40. \" Vivli demonstrates a working and sustainable model of data sharing that isn't a centralized repository. Readers would be enlightened if the authors could explain how a centralized model would better meet their own criteria.\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? No\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? No",
"responses": [
{
"c_id": "8583",
"date": "08 Feb 2023",
"name": "Mirko Gabelica",
"role": "Author Response",
"response": "Response from authors to reviewers Comment 1. This publication proposes an ideal repository for hosting data from clinical trials. The criteria for such a repository was derived and modeled using a business analysis approach. It is not clear why a business analysis approach was utilized for this endeavor which appeared to conduct a landscape scan of current repositories. Author response: The aim of this article was not to conduct a landscape scan of current repositories. We have mentioned some characteristics of existing repositories to provide context for our ideas. The business analysis approach is utilized to present our way or the ideal way of clinical data processing, curation, storage and publication. Business process management gives unambiguous insight into the process, and we believe it is clear and informative, as the diagram shows. We have now added this to the manuscript. Comment 2. Data sharing is conducted within legal and cultural contexts that require additional considerations beyond business process management. Author response: We acknowledge there are legal and cultural contexts that may be used as a reason, or an excuse, for the lack of data sharing. However, the aim of this article was not to address or solve legal or cultural issues that may prevent data sharing. This was now highlighted in the manuscript. Comment 3. Introduction - The researchers indicate that the ideal repository is an “open-access” concept and not a managed access or controlled access system. A thorough discussion of the many valid reasons for sharing clinical trial data under managed access rather than open access is needed to support the claim that open access is \"ideal.\" The IOM report laid out the reasons why a fully open access approach is theoretically ideal but not realistic. Author response: In this article we proposed features of an ideal repository, with the emphasis on the – ideal. We are fully aware of IOM recommendations. We are also aware of the position that there could be valid reasons for managed access. We would like to emphasise that we have previously written in the manuscript: “It is recognized that there are challenges associated with such an approach, but if we start addressing the challenges, and considering how such a repository would look like, we could make it a reality one day.“ While acknowledging that there might be different opinions, we do not think that managed access or controlled access system is the best solution because it contains a discretional right to withhold data from the requestor. IOM Recommendation (page 12) states: “The committee believes that open access (to the public with no controls) is appropriate and desirable for clinical trial results, and, in some cases, no or few controls on sharing other types of clinical trial data may be the preferred approach when all stakeholders involved in a trial (i.e., sponsors, investigators, and participants) are comfortable with this approach and believe the benefits outweigh the risks. In many cases, however, sponsors, investigators, and/or participants may have concerns about an open access model for certain clinical trial data.” We have already previously included the mention of the IOM recommendations in the manuscript, and we have expanded it now. We firmly support the idea of uncontrolled access to all raw data from clinical trials, but, of course, in a way that will protect the participants’ privacy. The following text was added to the manuscript, at the end of the Introduction: It is acknowledged that there are opinions that valid reasons may exist for sharing clinical trial data under managed access. The IOM recommendation states [quote]: “The committee believes that open access (to the public with no controls) is appropriate and desirable for clinical trial results, and, in some cases, no or few controls on sharing other types of clinical trial data may be the preferred approach when all stakeholders involved in a trial (i.e., sponsors, investigators, and participants) are comfortable with this approach and believe the benefits outweigh the risks. In many cases, however, sponsors, investigators, and/or participants may have concerns about an open access model for certain clinical trial data.” We firmly support the idea of uncontrolled access to all raw data from clinical trials, but, of course, in a way that will protect the participants’ privacy. While acknowledging that there might be different opinions, we do not think that managed access or controlled access system is the best solution because it contains a discretional right to withhold data from the requestor. Comment 4. The authors refer to the existence of 13 such open access “heterogeneous” repositories that provide access to clinical trial data alongside other types of data. However, the authors do not consider these “ideal” repositories due to their heterogeneous nature. The authors do not provide adequate justification for their criteria nor are the 13 open access repositories named. Author response: We have previously analyzed repositories that hosted clinical trial data, but these are unpublished data. We conducted the environmental scan and the date of the last search was in December 2016. In that analysis, we found the following 14 repositories: B2Share, DRUM, Dryad, Easy/ DANS, Edinburgh Datashare, Figshare, ICPSR, OSF, Research Data Australia, SND, Zenodo, University of Bath, LSHM, Harvard Dataverse. Thus, we also need to correct the erroneous information from the manuscript that there were 13 repositories that we have found. We have now updated the manuscript with this list of repositories and with the dates when this search was conducted, and the more elaborate information about that study. The following revision was made to the manuscript: Previously, we had a sentence: “Our recent study (Gabelica et al.; unpublished data) indicated that there are 13 open-access repositories on the Internet, which host clinical trial data together with data from other types of studies.“ Now, this was revised into: “In our earlier study (Gabelica et al.; unpublished data) we found 14 open-access repositories on the Internet, which host clinical trial data together with data from other types of studies. This study was an environmental scan, with the last search date in December 2016. The 14 repositories hosting clinical trial data at that time were: B2Share, Data Repository for the University of Minnesota (DRUM), Dryad, Easy/ DANS, Edinburgh Datashare, Figshare, Interuniversity Consortium for Political and Social Research (ICPSR), Open Science Framework (OSF), Research Data Australia, Swedish National Data Service (SND), Zenodo, University of Bath, London School of Hygiene and Tropical Medicine (LSHTM) Data Compass, Harvard Dataverse.” In this manuscript, we tried to address what should be characteristics of the ideal clinical trial repository. We certainly do not think that we are proposing the ultimate ideal that nobody will contest – we are simply trying to provide our point of view and to foster a discussion on this subject. Hopefully, other researchers will build on our idea and a consensus about the characteristics of the ideal clinical trial repository will be reached in the future. When we wrote that the clinical trial data repositories that we identified in December 2016 were heterogeneous, we did not intend to use the term “heterogeneity” in the pejorative sense – we simply wanted to indicate that they were very different in terms of their characteristics. Instead of having a variety of different repositories, it would be ideal to have one with the desired characteristics. This is now further emphasized in the manuscript. Comment 5. Other criteria also appear rather subjective and to conflict with the sustainability criteria if one were to put them into practice. For example, requiring the repository to be sustainable without charging fees to contributors nor requestors but rather placing the burden onto governments of countries who do not have a line-item budget for this type of effort (which countries should support this? and what is their incentive to do so?) is unrealistic. Author response: We acknowledge that the criteria we have proposed are subjective, as they are proposed by us, a small group of authors. As indicated earlier, we do not think that these characteristics cannot be expanded or improved upon – we would simply like to foster the discussion with our ideas. Regarding funding, we agree that sustainability may be threatened if there is no sustainable funding. However, there are many jointly-funded initiatives in the world, supported by governments that see merit in those initiatives. We consider that clinical trial data are one such initiative that deserves consideration of stable governmental funding. While we acknowledge that such reasoning can be idealistic – we would also like to remind the reviewers that we have proposed our vision of an ideal repository. This response has now been incorporated in the manuscript. Comment 6. Additionally, many of the requirements are exceedingly expensive and would require highly skilled statistical staff such as requiring two data curators per dataset and that the curators perform re-analysis and reproduce one result from the manuscript. These requirements which on the surface appear to be reasonable QA would require extraordinary resources. Author response: The reviewers are indeed correct that these costs will likely be large. However, the reviewers did not write that this is a bad idea; the reviewers are concerned about the cost. In respect to data that directly leads to medical treatment options we strongly advocate the idea of minimal reproducibility. Yes, our idea involves skilled statistical staff, because without them data validity proof is not plausible. This would be expensive. But, again, we would like to remind the reviewers that we are proposing an ideal repository, and not a budget-friendly repository. This is now indicated in the manuscript. Comment 7. Other criteria appear arbitrary without justification such as the recommendation for the Dublin core metadata initiative (DCMI). Author response: We consider that there should be uniform requirements used in an ideal repository that would ensure consistent labelling of the data. The reviewers did not suggest an alternative idea to ensure consistent use of metadata. Comment 8. The paper also does not review Vivli's approach, even though the authors state that \"Currently, the two most promising existing initiatives considering data sharing are ClinicalStudyDataRequest (CSDR)39 and Vivli40. \" Vivli demonstrates a working and sustainable model of data sharing that isn't a centralized repository. Readers would be enlightened if the authors could explain how a centralized model would better meet their own criteria. Author response: We are grateful we can clarify the meaning of “centralized repository”, and we are sorry we have not been unequivocally clear in the manuscript. Also, we agree that more information about Vivli and CSDR would be beneficial. We added the following further information about the Vivli: Vivli has numerous features of a centralised repository; it follows a vision as a mediator between data providers and users, charging a fee to data requestor to remain sustainable, and with a privilege to decline the request. We do not consider that charging a fee to a data requestor and having an option to decline the request is a feature of an ideal repository that aims to foster data sharing and re-use. We added the following further information about the CSDR: CSDR defines itself as consortium of clinical study sponsors. It is acknowledged that CSDR defines a \"Sponsor“ as follows: \"The Sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organisation, or other organization“. However, it appears that the uptake of the CSDR among industrial and academic sponsors is limited. There is not much information on the CDSR website about all the sponsors that have deposited data in the CSDR – on the page titled „Data sponsors“, only 13 logos were present on July 29, 2022. On the page titled \"News“, sub-page \"Academic-Led Clinical Trials Data Shared on CSDR“, there is a news item from November 2019 indicating that the CSDR includes data from 18 academic-led trials. Thus, according to the publicly available information, it appears that the global uptake of CSDR by industrial and non-industrial sponsors is extremely limited. CSDR acknowledges that the part of the approval process for obtaining data is sponsor’s check of a predefined list of criteria. However, we feel that such procedure greatly limits the scientific process. Furthermore, CSDR indicates that the time from data access proposal to approval could be 90 days if no further information is needed. We consider that this process is unnecessarily lengthy, and potentially prone to failure, which could discourage researchers from further attempts to obtain and re-examine data. We added the following further information about our idea of a “centralized repository”: In this manuscript we are advocating for a “centralized repository”, which is unlike any currently existing laboratory. We would like to refer to GISAID initiative (https://www.gisaid.org/) as an example of a centralised repository for rapid sharing of data from all influenza viruses and the coronavirus causing COVID-19. The GISAID Initiative fosters the rapid sharing of data from all influenza viruses and the coronavirus causing COVID-19. This includes genetic sequence and related clinical and epidemiological data associated with human viruses, and geographical as well as species-specific data associated with avian and other animal viruses. The Initiative ensures that open access to data in GISAID is provided free-of-charge to all individuals that agreed to identify themselves and agreed to uphold the GISAID sharing mechanism. Their approach is encouraging, and should inspire similar initiatives in the future related to sharing of clinical trial data. We hope that the revised manuscript will be adequate. Sincerely, The authors"
}
]
}
] | 1
|
https://f1000research.com/articles/10-23
|
https://f1000research.com/articles/12-143/v1
|
07 Feb 23
|
{
"type": "Review",
"title": "Water-energy-food-ecosystem nexus and sustainable development in the Horn of Africa",
"authors": [
"Edwin Kimutai Kanda",
"Willis Awandu",
"Elizabeth Lusweti",
"Micah M. Mukolwe",
"Willis Awandu",
"Elizabeth Lusweti",
"Micah M. Mukolwe"
],
"abstract": "Water, energy and food (WEF) security are key indicators of sustainable development. Realization of sustainable development goals (SDGs) by countries is achieved through a water-energy-food-ecosystem nexus framework. Climate change is a threat to food, energy and water security in the Horn of Africa. The main aim of this review is to assess the status and prospects of WEF nexus as it relates to SDGs in the horn of Africa. The countries considered were Ethiopia, Eritrea, Somalia and Djibouti. The review indicated that the four countries have a challenge in achieving SDGs 2, 6 and 7. Djibouti had the highest (50.9) WEF index in the region followed by Ethiopia and Somalia at 47.5 and 36.8, respectively while Eritrea had the lowest WEF index of 35.8. The energy sub-index was the best performer in the region with an average index of 56 while water and food sub-indices were the worst at 36. Political instability, insecurity, inadequate infrastructure, weak institutional and legal framework are some of the challenges facing WEF and sustainable development in the region. Climate change adaptation measures should be incorporated into the water, energy, food and ecosystem (WEFE) nexus using an integrated approach. Modelling WEFE requires integration of models and should also focus on interactions among the sub-systems.",
"keywords": [
"climate change",
"energy-water-food security",
"renewable energy",
"sustainable development goals",
"water scarcity",
"water-energy-food index"
],
"content": "Introduction\n\nThe provision of water in adequate quality and quantity, affordable and reliable energy services, and food security are key pillars for development of any country. These three sectors (water, energy and food) are interlinked and thus require an holistic approach to maximize and minimize the synergies and trade-offs respectively. A good understanding of the interactive nature among water, energy and food (WEF) resources in their temporal and spatial scale can enhance the resource security and facilitate the inter-sectoral and holistic approaches in decision making that will eventually lead towards the sustainability requirements (Awandu et al., 2022). The demand on the resources required in these sectors are stressed by climate change, population growth, urbanization and industrialization. Therefore, synergies in the nexus need to be addressed through coherent policies and multi-functional systems or models (Liu et al., 2017).\n\nAddressing the WEF nexus requires the knowledge of its strong links with the natural ecosystem and water-energy-food-ecosystem (WEFE) nexus is desirable. Sustainable development goals (SDGs), established by the United Nations General Assembly, on food security, water and sanitation, health, clean and affordable energy, climate action, economic growth, peace and justice, and life in water and life on land implies that an holistic approach to a WEFE system is ideal in achieving them. This is hardly the case in most countries in Africa where the WEF sectors are addressed by sector-specific institutions driven by sector mandates (Nhamo et al., 2018). This silo approach does not achieve desirable outcomes due to the interdependence of these sectors.\n\nSub-Saharan Africa countries have water, energy and food insecurity challenges due to a number of factors such as top-down WEF development approaches, increasing population, low economic growth, natural disasters and unfavourable climatic conditions, overexploitation of WEF resources, conflicts, poorly coordinated market reforms and poor governance in WEF sectors (Nkiaka et al., 2021). The Africa region is off-track in achieving the SDG 7 (access on affordable, reliable, sustainable and modern energy); in 2021, 43% of the population of Africa, around 600 million people, still lacked access to electricity, 590 million of them being in sub-Saharan Africa (IEA, 2022a).\n\nThe Horn of Africa is faced with serious challenges among them water scarcity, which is compounded by climate change. The countries in the Horn of Africa are either arid or arid and semi-arid land (ASAL) with Somalia and Djibouti being 100% arid while Eritrea and Ethiopia are 80% and 51% ASAL respectively (Olet et al., 2020). The countries in the greater Horn of Africa region in general have experienced increased occurrence of drought and flood events (Nicholson, 2014). Besides water insecurity, the region is facing environmental challenges such as deforestation, land degradation, food insecurity and loss of biodiversity (Mohamed, 2014). For example, Ethiopia, home to a rich and diverse flora and fauna, has already been critically affected by the loss of biodiversity (Admassu et al., 2013). The region’s heavy reliance on economic structures in climate-sensitive sectors, such as rain-fed agriculture, pastoralism and fishing, makes them extremely vulnerable to climate induced shocks (IEA, 2022b). A study by Nkiaka et al. (2021) established that none of the countries in the Horn of Africa achieved a WEF index of above 0.5 indicating high insecurity levels with Djibouti ranking the highest at 0.42 followed by Eritrea and Ethiopia with 0.27 and 0.25 respectively.\n\nWater accessibility is a challenge in the Horn of Africa, where most people rely on water delivered by vendors on trucks or donkey carts, which has led to an increase in the cost of water with some areas worst hit by drought increasing by up to 400 per cent (UNICEF, 2022). The water sector in the Horn of Africa countries is characterized by inadequate policy, legal and regulatory frameworks (Olet et al., 2020). Persistent conflicts in the Horn due to political fragility is one of the key drivers of famine and strain on food, water and health systems and forced migrations or displacement (UNICEF, 2022).\n\nThe region is facing food and energy insecurity challenges. Global events such as the Covid-19 pandemic and Russia’s war on Ukraine have increased the region’s vulnerability in terms of food and energy security since most of the countries are net importers of gas and oil, and farm inputs such as fertilizers as well as direct importers of cereals such as wheat and maize from Ukraine and Russia (IEA, 2022b).\n\nThis review aims to understand the WEFE nexus in the Horn of Africa. An evidence search was conducted in the following databases: Web of Science, Scopus, Google Scholar and databases of organizations such as the World Bank, International Energy Agency (IEA), Food and Agriculture Organizations (FAO) and other UN agencies like the World Food Programme (WFP), United Nations Development Programme (UNDP) and United Nations Children Fund (UNICEF). The search strategy utilised the Boolean operators (OR & AND) without emphasis on the publication date in order to get a wider view of the concepts. The search strategy was a trial-and-error process using title, abstract and keywords. Some of the search phrases used include “food security”, “water security”, “energy security” “sustainable development goals” “Horn of Africa”, “Ethiopia”, “Eritrea”, “Somalia”, “Djibouti”, water-energy-food nexus” “climate change impacts and water-energy-food” “water and energy security”, “water and food”, “energy and food” “water management” “droughts”, “floods” and “climate change”.\n\nThe literature on WEFE is wide and it was difficult to conduct an exhaustive search of all articles. Therefore, this review was not meant to be exhaustive but to capture key aspects of the WEF nexus as a way of understanding the status and the prospects of the nexus in achieving sustainable development in the selected countries. This will inform intervention measures for addressing the key challenges in these three critical sectors and their interactive nature with the environment which requires an integrated approach as opposed to silo or sector specific measures.\n\nThe rest of the article is structured as follows: Firstly, the study countries are described and secondly WEFE indicators and sustainable development are discussed. Thirdly, the impact of climate change on the WEF nexus is presented. Fourthly, modelling WEFE nexus is highlighted and finally a conclusion is provided.\n\n\nStudy countries\n\nThe countries considered in the Horn of Africa are Ethiopia, Eritrea, Djibouti and Somalia. This is the traditional definition of the Horn of Africa which distinguishes it with the greater Horn of Africa that includes the additional countries of Kenya, Sudan, South Sudan, Tanzania, Burundi, Rwanda and Uganda.\n\nEthiopia is the second most populous country in Africa (after Nigeria) with a population of 115 million (IEA, 2022b). Agriculture remains the main activity in the Ethiopian economy and contributes, on average, 47 percent of GDP, employing over 85 percent of the population and accounting for about 90 percent of the country’s total export earnings (Admassu et al., 2013). The country is blessed with surface water resources which constitutes approximately 20% of the technically feasible water resources potential in Africa but they are under-exploited (Hailu and Kumsa, 2021).\n\nEritrea has an area of 101,000 km2 and it borders the Red Sea to the northeast and east, Ethiopia to the south and west, Sudan to the west and Djibouti to the southwest (ADB, 2021). The country had a population of 3.5 million in 2020, giving a density of 35.1 people per km2 of land area with an urban population of 63.3% (ADB, 2021). Eritrea has a long coastline (about 1200 km) along the Red Sea with a varying topography and climatic conditions. The climate is hot and arid on the coast of Red Sea, sub-humid in the eastern escarpments and semi-arid in the central highlands (Ghebru et al., 2013). Agriculture contributes 20% of the GDP and employs 50% of the population. Eritrea has varying agricultural systems namely rainfed, commercial and semi-commercial, peri-urban, irrigated, and agro-pastoral (Ghebru et al., 2013).\n\nThe federal republic of Somalia has a total population of 15 million in an area of 637,655 km2 and is bordered by the Indian Ocean (to the east), Kenya (to the west and south), Ethiopia to (the west) and Djibouti (to the north) (Mourad, 2022). The country has one of the lowest GDP in sub-Saharan Africa (Karamba, 2021) and poverty is widespread, with 70% of Somalis living on less than USD 1.90 a day (WFP, 2022). The agriculture sector, especially the livestock sub-sector, still forms the backbone of Somalia’s economy, accounting for about 65 percent of Somalia’s GDP and 93 percent of total exports (Karamba, 2021). The country is in a fragile state and one of the least environmentally sustainable countries due to deforestation occasioned by charcoal being a main source of energy in both rural and urban areas (Aynte et al., 2022).\n\nDjibouti is located to the southern extremity of the Red Sea in the Horn of Africa bordering Eritrea to the north, Ethiopia to the west and south and Somalia to the southeast (Dabar et al., 2022). It has the smallest population in the Horn of Africa with around one million inhabitants (IEA, 2022b). The majority of the population (65%) live in the capital, Djibouti-ville, and 20% live in other urban areas. The hinterland, an extension of the arid lands of Ethiopia, Eritrea and Somalia, is sparsely populated by pastoral and nomadic populations (Mora et al., 2010). Djibouti’s climate varies considerably with hot and dry season occurring from June to September and cooler but erratic rainfall season from October to March (Moussa Omar et al., 2021).\n\n\nWEF indicators and sustainable development\n\nAchievement of water, energy and food inter-sectoral security without jeopardizing the ecosystem health with consideration of the existing and future external pressures such as population growth, increased urbanization and industrialization, and climate change can be summarized as attaining key SDG targets. This requires both national and international co-operation and partnership more so because of the transboundary nature of some of these resources such as water and food supply chains.\n\nThe WEF nexus indicators obtained from Simpson et al. (2022) at https://www.wefnexusindex.org shows that the four countries have varying WEF indices, but the region has a low WEF index (42.7) which implies higher WEF insecurity. The countries are at varying levels of attaining SDG 2, SDG 6 and SDG 7. Djibouti is the only country with a WEF index above 50 (50.9) with Ethiopia, Eritrea and Somalia having indices of 47.5, 35.8 and 36.8 respectively (Figure 1). These results were more or less the same as those found by Nkiaka et al. (2021) where Djibouti ranked the highest with a WEF index of 0.42 followed by Eritrea and Ethiopia with 0.27 and 0.25 respectively with no data for Somalia.\n\nThe energy sub-index was the highest in the region with an average score of 56. Water and food sub-indices were very low with a score of 36 each implying that these two sub-indices contributed to the region’s poor WEF status. Therefore, interventions targeting food and water but under the nexus framework will help in achieving SDGs in the region.\n\nThe energy sub-index was highest in all the countries with Djibouti leading with 60.4 followed by Ethiopia and Somalia with 59.4 and 58.5 respectively. Eritrea has the lowest score of 45.8. Energy data for Somalia and Djibouti is scant (Table 1) and thus the indices obtained in Figure 1 may not be a true representation of the energy situation. Somalia has the lowest electricity access in the region with only 36% of the population being able to access the service (Table 1) but this value is offset by a 0.95 (the highest in the region) ratio of renewable energy consumption to final energy consumption. Djibouti has the highest access to electricity in the region at 61% while Ethiopia and Eritrea have 48% and 50% respectively. Therefore, these countries must work very hard to achieve SDG 7.\n\nThe water sub-index was highest in Djibouti (52.5) while the rest of the countries were below 40 with Ethiopia, Eritrea and Somalia achieving 34.5, 29.3 and 27.3 respectively (Figure 1). Djibouti’s performance is buttressed by a higher number of people having access to basic drinking water and sanitation services, 76% and 67% respectively (Table 1). Ethiopia’s water index is dwarfed by the sanitation component where more than 90% of the population lack access to at least basic sanitation services.\n\nThe food sub-index was poor in the region with all the countries reaching less than 50 in this category, which was driven by the malnutrition component. Ethiopia was the highest with a food index of 48.5 while Somalia was the lowest at 24.5 (Table 1) with the high prevalence of under-nourishment (59.5%) contributing to the latter score. Stunting in children is prevalent in the region affecting an average of 36% of children under five years. This is critical in Eritrea where almost half of the children under five years are stunted.\n\nWater is central to environmental, economic and social development. Water security is defined in the context of water quantity, quality and accessibility. It is the availability of, and access to sufficient and good quality water for human use and ecosystem functioning (Nkiaka et al., 2021). Water quantity and quality affect ecosystem functions. There is variation in water availability regionally and within countries in the Horn of Africa; for example, the Ethiopian highlands are regarded as the water tower of the Horn of Africa and the greater region through its contribution to the Nile basin (Müller-Mahn and Gebreyes, 2019). Though, water may be adequate in quantity and quality, its accessibility is influenced by socio-economic resources. For example, water insecurity in Ethiopia and Somalia is compounded by inadequate infrastructure and institutional capacity to exploit and manage both surface and groundwater resources (Jemmali and Sullivan, 2014). In the Horn of Africa, water is the major contributor to the region’s food crisis as well as its recurrent famine and social instability (Mohamed, 2014).\n\nIncreased surface water stress due to climate change will occur in countries facing politically and environmentally fragile situations like Somalia and Eritrea (Olet et al., 2020). In Somalia, onsite sanitation systems, open defaecation and poor hygiene practices are a threat to groundwater sources (Mourad, 2022). Djibouti has some of the lowest water resources in the world, with no perennial rivers, and thus most of its water sources are from groundwater aquifers which is threatened by over-exploitation leading to high salinity levels (Mouhoumed et al., 2020) and risk of sea water intrusion in case of over-exploitation of coastal aquifers (Razack et al., 2019).\n\nSomalia relies heavily on water from the Juba and Shabelle rivers where 90% of the flows originate from Ethiopia (Arcanjo, 2020). Therefore, any major water abstractions in Ethiopia jeopardize livelihoods in Somalia. Mohamed (2013) argued that the planned dam projects in the Juba and Shabelle rivers will have an economic and ecological impact in Somalia through reduction of water flows in the rivers. This will cause a collapse of existing irrigation schemes and planned irrigation developments and have a negative effect on the wetlands in the Shabelle depression areas and the Juba estuary at the mouth of the river causing seawater intrusions. Climatic events such as droughts and floods also impact the basin affecting both water supplies and crop production in the southern region of Somalia where irrigation is practiced. Groundwater is also an important source of water where boreholes have been sunk to a depth of 400 m in some areas and shallow wells with some less than 20 m deep (Idowu and Lasisi, 2020).\n\nThe solution to addressing water insecurity in the region lies in the management of shared water resources. The countries in the region share a number of surface and groundwater sources. The major shared river basins and water bodies include Nile River basin (Burundi, Congo, Egypt, Ethiopia, Kenya, Rwanda, South Sudan, Sudan, Tanzania, Uganda), Juba River Basin (Ethiopia, Kenya and Somalia), Laag Dheere (Kenya and Somalia), Shabelle River (Ethiopia and Somalia), Omo River Basin (Ethiopia and Kenya), Awash River (Djibouti and Ethiopia), Tekeze or Atbara (Eritrea, Ethiopia and Sudan), Mereb River (Eritrea, Ethiopia and Sudan), Baro-Akobo (Ethiopia, South and Sudan), Sobata River (Ethiopia and Kenya), Lake Turkana (Ethiopia and Kenya), Merti Aquifer (Kenya and Somalia), and Shabelle Aquifer between Ethiopia and Somalia (Mohamed, 2014). However, the countries in the region do not have regional policies on shared water resources and each state pursues unilateral legislations and frameworks (Mohamed, 2014). These unilateral water policies and development plans are not only unsustainable but also a source of conflict in the region. The construction of the Grand Ethiopian Renaissance Dam (GERD) is one example of individual states pursuing their national projects on a shared water course, in this case the Nile basin, without adequate regional consensus on the effect on downstream riparian countries. The Nile basin is the largest project in the region comprising ten riparian countries with Ethiopia contributing a significant proportion of water through the Blue Nile. The shared rivers and water basins in the region instead of being a source of economic and political integration have become sources of tension and conflict due to declining water availability (Mohamed, 2014). Co-operation among riparian states sharing transboundary river basins and aquifer systems is part of integrated water resources management (IWRM) as anchored in SDG 6.5 and therefore necessary for national and regional WEFE security (Stephan et al., 2018). The degree of implementation of IWRM in the region is low with Ethiopia and Somalia at 41% and 22% respectively (Table 1) while there was no data for Eritrea and Djibouti.\n\nEnergy security components are availability, affordability and reliability (Awandu et al., 2022), which consequently affect access to energy options. It is the access to reliable and affordable energy for cooking, heating, lighting, communications and productive use (Nkiaka et al., 2021). Access to affordable, reliable and modern energy services will transform the region’s development agenda by achieving SDG 7. Generally, energy infrastructure in the Horn of Africa has struggled to match the region’s growth and thus electricity grids remain unreliable rendering many countries dependent on costly fuel imports, and energy utilities are in financial stress (IEA, 2022b).\n\nEthiopia suffers from acute electricity shortages due to a faster population growth than development in the energy sector and also due to over-reliance on hydro-electric power. This is affected by several factors such as trade-offs with domestic, industrial and agricultural water needs, droughts, dam siltation due to catchment degradation, and transboundary water conflicts (Guta and Börner, 2017). There are three main sources of energy in Ethiopia: biomass, petroleum, and electricity, with supply accounting for 90%, 8.2% and 1.8% respectively in 2014 (Benti et al., 2021). Electricity in the country is mainly supplied by hydro-power plants. Hydropower potential is 45,000 MW while geothermal sources have a potential of 1,070 MW (Berta and Zerga, 2015). Traditional biomass energy is not sustainable due to environmental and social costs. Women and children spend hours trekking long distances to fetch firewood while urban dwellers spend a substantial amount of income on fuel (Gebremeskel and Tesfaye, 2008). The country does not have a physical energy scarcity as it is endowed with sufficient potential renewable energy sources, but economic energy scarcity is the major challenge (Tesfaye et al., 2021). Adoption of modern energy sources by rural households in Ethiopia is hindered by shortage of capital, lack of access to alternative energy sources, durability problems associated with renewable sources such as solar, and lack of awareness (Tofu et al., 2022). The country aims to develop renewable sources of energy such as solar and wind, but its capability is limited by a lack of investment capital, an underdeveloped solar and wind supply chain, lack of a skilled workforce, unclear policy and strategies and regulatory uncertainties (Gebreslassie, 2021). The recent political unrest in the country, which has triggered war in the northern region of Tigray, has slowed down access to electricity with destruction of electricity infrastructure (IEA, 2022b). The completion of the 5,150 MW GERD hydropower plant (the largest in Africa) in addition to the Koysha (Gibe IV) hydropower plant (1,500 MW) will boost Ethiopia’s universal access to electricity (IEA, 2022b) and consequently achieve the SDG 7 target.\n\nSomalia is rich in renewable energy resources including solar, wind, hydropower, and vast geothermal energy but their exploitation is limited by political, financial, and institutional factors (Warsame et al., 2022). It is worth noting that Somalia does not have state-owned energy utility and a national grid and most of the energy services are from private entities (Aynte et al., 2022; IEA, 2022b). The government has tried to increase electricity access through provision of incentives to the private sector such as subsidies and tax exemptions (IEA, 2022b). Most of the energy use in the country comes from generators running on imported diesel or from burning charcoal and other biomass (Aynte et al., 2022). Despite the long-running civil war and low development, the country has the potential to achieve sustainable development and contribute to the reduction of greenhouse gases (Warsame et al., 2022) through implementation of policies and encouraging investments in renewable and clean energy production such as solar, wind and hydroelectric power, and reduction in biomass energy (charcoal and firewood) use (Warsame and Sarkodie, 2022). Somalia, through its updated nationally determined contribution, has identified the promotion of clean and fuel-efficient cooking as a pathway for reduced GHG emissions through adaptation actions such as increasing the production of non-forest fuel briquettes, including from agricultural residues and waste (IEA, 2022b).\n\nEritrea initiated reforms in the energy sector in 2007, which revolved around four areas: expansion of the national grid to cover rural areas, adoption of renewable energy technologies, promotion of energy efficiency and saving techniques, and liberation of the energy market (Habtetsion and Tsighe, 2007). However, the country has low hydropower potential and still relies on oil and gas imports to meet its energy demand (Chandrasekharam et al., 2018). The grid is supplied only by electricity from fossil fuels (Alam and Islam, 2019).\n\nImproving energy security in the region requires integration through bodies such as the Intergovernmental Authority on Development (IGAD) where its energy sector strategy for 2050 envisages an interconnected system that harnesses the abundant renewable resources within its member states (IEA, 2022b). Already, Ethiopia has an electricity interconnection arrangement with Djibouti which has boosted the latter’s electricity access (Dabar et al., 2022). The regional efforts can be complemented by Africa-wide interventions through the African Union’s (AU) 2063 agenda which seeks expansion of renewable and clean energy sources to ensure energy security and reduction in carbon emissions (IEA, 2022a).\n\nAchievement of the SDG 7 in the region requires countries to expand the national grid and development of mini-grids and stand-alone (off-grid) systems (IEA, 2022b). The Horn of Africa countries have high solar energy potential (EIB, 2018) which can be used to power rural populations not covered by the national grid systems.\n\nCountries in the Horn of Africa are facing serious food security challenges. In this context, food security is parameterized in terms of availability, accessibility and quality (Awandu et al., 2022). Food security is attained when people have physical, social and economic access to enough, safe and nutritious food which meets their dietary needs and food preferences for an active and healthy life (Nkiaka et al., 2021). Clapp et al. (2021) made a case for dimensionality of food security to include six components i.e. availability, access, utilization, stability, sustainability and agency with the last two being new concepts. Agency in this context refers to the sovereignty of individuals and groups in the food sector as a way of addressing widening inequities and power imbalances of actors within food systems (Clapp et al., 2021). Sustainability in this context refers to food practices which adhere to the three elements of sustainable development i.e. social, economic and environmental. We are of the view that the expanded dimensions of food security will help its advancement in this era of climate change and other externalities in the food and agricultural sector.\n\nEcological systems are important in providing the material sources for food production and dietary diversity and thus relevant in ensuring nutritional quality and quantity (Clapp et al., 2021) and therefore should be given special reference for holistic assessment of food sustainability. Therefore, sustainable agricultural practices need to be adopted to address food security challenges.\n\nThe Horn of Africa is considered one of the most food insecure regions in the world, which is exacerbated by persistent conflicts, climate shocks and economic instability (Abebe, 2021). Eritrea is a low-income country with at least 70 percent of the population depending on traditional subsistence agriculture (Ghebru et al., 2013), which is prone to climate change induced shocks. The country is highly food insecure and relies on imports which account for about 46% of food demand (Chandrasekharam et al., 2018).\n\nFood accessibility in Somalia is affected by poor transport infrastructure and distribution networks which limits price arbitrage between regions (Hussein et al., 2021). The poor transport infrastructure and food distribution channels in Somalia can be attributed to a long period of armed conflict. Somalia’s food insecurity is compounded by climate variables such as droughts and floods, which have increased in frequency and intensity (WFP, 2021). The unsustainable consumption pattern of traditional biomass (charcoal and firewood) has affected forest resources in the country, leading to desertification and loss of grazing and arable lands (Warsame et al., 2022).\n\nEthiopia suffers from chronic and acute food insecurity partly due to climate variability and susceptibility to drought and poorly developed water resource infrastructure (Gebreyes et al., 2020). Food security in Ethiopia is vulnerable to climate change and variability due to the fact that 80% of the population rely on rainfed agriculture coupled with low income which decreases their resilience (Alemu and Mengistu, 2019). Use of firewood and charcoal as sources of energy has contributed to deforestation and consequently affected land productivity and ultimately contributed to food insecurity in Ethiopia (Tofu et al., 2022). In the Tana basin, it was established that the continued use of biomass for energy purposes include deforestation and a depletion of soil organic matter and nutrients from agricultural soils and thus this is unsustainable in the long term (Karlberg et al., 2015).\n\n\nImpact of climate change on the WEF nexus\n\nHuman activities have played a pivotal role in enhancing the extreme effects of climate change impact on day-to-day life. Human beings are the perpetrators of the current and projected global warming of earth and are also the victims of the aftermath of the effects of extreme climate change (Ofori et al., 2021). The global mean temperature ascertained in 2017 depicted an increase of 1°C higher than the pre-industrial values with a projected increase of 0.2°C/decade (Bruhwiler et al., 2021). The temperature increase and warming of the continent of Africa is projected to be a higher value than the global average with anticipated temperature of 3–4°C over the 22nd century (Thompson et al., 2010; Zewdie, 2014). As a result, various regions within the African continent already experience unique extreme changes in precipitation patterns as discussed in Ofori et al. (2021).\n\nClimate change, just like other anthropogenic activities such as changes in land use/cover, diversions, withdrawal of water from rivers and lakes etc., impacts freshwater ecosystems and contributes to their degradation. Climate change has led to a shift in precipitation patterns in the Horn of Africa thereby resulting in decreased precipitation and increased evaporation. For example, projections indicate that the Lake Tana Basin in Ethiopia will decrease in surface water discharge and seasonal run-off volumes (Niang et al., 2014). The climate variability and trends in Ethiopia for instance show no consistent changes in the frequency or intensity of extreme events (Tessema and Lamb, 2003; Seleshi and Camberlin, 2006), with extreme tendency towards lower rainfall during crop growing seasons. Historical flood disruption is an unheard of hazard in Ethiopia but recent years have recorded significant socio-economic disruption in Ethiopia due to flooding in 1997 and 2002 (Jury, 2002). Similar trends of extreme droughts followed by extreme flooding that have led to deaths and destruction in the northeast of Kenya and parts of Somalia have been experienced frequently.\n\nThe Horn of Africa region continues to experience high water scarcity risks due to reduced streamflow and intensified water abstraction (Hirpa et al., 2019). Water related conflicts are rampant in the region. The situation has been made worse by the impact of climate change which has exposed the vulnerability of the region through successive droughts, water shortages, floods, and desertification (Burgess, 2008).\n\nHydropower production is heavily relied on by Ethiopia, Eritrea, Somalia and Djibouti. The man-made energy generation dams are susceptible to extreme climate change resultants such as floods, drought and cyclones (ICPAC, 2007). Climate change influences the spatial and temporal rainfall distribution and intensity, which is an essential determinant of catchment hydrology. The increase in temperature coupled with decrease in rainfall are two hydrological processes that have profound influence on hydropower generation potential (Bunyasi, 2012). Reduced river flows significantly affect hydropower generation due to inadequate reservoir levels. Due to extreme low rainfall in the vast Horn of Africa ASAL regions, the low flows have constantly resulted in power outages thus negatively affecting energy security in the region and encouraging overdependence on fossil fuels for running generators to provide power (Awandu et al., 2022).\n\nMitigating the effects of climate change in the region requires adoption of mix of renewable energy options. For example, a study by Oyewo et al. (2021) found that it is least-cost to supply about 66% of electricity demand with solar PV, 14% with wind and 10% with hydropower in Ethiopia as a best policy scenario in 2050. However, Boke et al. (2022), noted that the stochastic nature of solar and wind energy sources threatens the stability of the electricity grid. Use of geothermal energy sources offers baseload power generation making it a great option to complement the intermittent power supply from solar and wind with Ethiopia planning to expand its geothermal power capacity to 10,000 MW by 2030 (IEA, 2022b). Ethiopia has also developed energy policy and biofuels strategy with the aim of supporting energy diversification and development of renewable energy options and biofuel development as an energy security and climate change mitigation measure (Motuma, 2017). Eritrea has huge potential for geothermal energy. Adoption of renewable energy options in Somalia is hindered by weak and fragmented independent electricity service providers facing financial challenges and limited support from federal and regional state governments (Aynte et al., 2022).\n\nClimate change events such as drought and floods have a negative impact on food security in Africa, particularly in the horn of Africa. Drought is a serious environmental problem in the Horn of Africa countries of Ethiopia, Somalia, Eritrea and Djibouti (AghaKouchak, 2015). Agriculture is more affected than any other sector because it is susceptible to climate variability and change such as extreme weather events of droughts and floods, irregular rainfall patterns and increase in temperature. Drought decreases water availability for irrigation thus leading to a decrease in yield, which enhances food insecurity and also increases irrigation water demand. Water is required at various stages of food production and in the Horn of Africa rain-fed agriculture is heavily impacted by climate change.\n\nLow-income countries such as those in the Horn of Africa largely depend on the agriculture sector as it contributes a significant proportion of their GDP. The high dependency on the agriculture sector and lack of climate change adaptation policies make developing countries more vulnerable (Ghebrezgabher and Yang, 2018). Therefore, there is need for the development of policies and institutions for climate change adaptation and resilience building at regional or national levels.\n\nSomalia faced drought in 2017 leading to the monetary loss of USD 71 million for the maize, sorghum, cowpeas and sesame industries; these are the four most important crops for the country (World Bank and FAO, 2018). On the other hand, floods that occurred in 2019 claimed many lives and led to 412,000 individuals being displaced and substantial damage to crops (FAO, 2020). A study on the climate change and crop production nexus in Somalia revealed that climate change is a significant determinant of Somalis’ crop production specifically rain fed crops as Somalia’s agricultural land totals about 3 million hectares (World Bank and FAO, 2018).\n\nEl Nino led to a drought in the Horn of Africa in 2015 where Ethiopia faced severe hunger with 15 million people needing immediate food aid (UNICEF, 2015). In 50 years, it is predicted that Ethiopia will experience erratic weather patterns, higher intensity rainfall and temperature rise (Mcsweeney et al., 2010). This climate change could result in prolonged periods of drought and floods, which might lead to crop yield reduction and resource use conflicts (Simane et al., 2012). However, using agroecology analysis with the Ricardian model, Solomon et al. (2021) established that climate change in Ethiopia will have marginal effects on crop yields as a result of changes in temperature and rainfall\n\nClimate change in Eritrea is associated with environmental problems such as desertification, deforestation, soil erosion and overgrazing (Nyssen et al., 2004). It has been established that climate change and drought are serious long term environmental problems due to the long-term trend in annual precipitation decrease and temperature increase (Ghebrezgabher and Yang, 2018). Global warming is a great threat in Eritrea affecting crop production and increasing crop water requirements (Alam, 2017).\n\nDjibouti has limited arable land (0.1% by area), rainfall and groundwater reserves (Ozer and Mahamoud, 2013). Vulnerability to natural hazards is enhanced by poor water resources management and by environmental degradation and/or contamination (Wilby et al., 2010). In the past decades, Djibouti has experienced increased occurrence of climate change induced shocks especially droughts and floods which have decimated the country’s economic pillars of food security, water supply, public health systems and environment (Yamin et al., 2005). Ozer and Mahamoud (2013) conducted a study which analyzed changes in extreme precipitation between 1980 and 2011 and found a strong decline in total precipitation −17.4% per decade.\n\nThe increasing threat of climate change coupled with urbanization, population and industrialization pressures require interventions aimed at improving water use in agriculture by improving crop water productivity in order to ensure sustainability of resources. Some of the techniques for improving crop water productivity include efficient irrigation systems and agronomic practices such as deficit irrigation and soil water conservation (Kanda et al., 2021). Despite the importance of efficient irrigation systems and prudent agricultural water management, most countries in the Horn of Africa still use traditional methods of irrigation such as furrow and spate irrigation systems. For example, irrigation development in Ethiopia has failed to enhance food security in the country (Kassa and Andualem, 2020) due to a myriad of challenges such as low technology adoption, lack of technical support given to smallholder farmers, lack of awareness of irrigation water management practices such as irrigation scheduling techniques, water saving irrigation technologies, operation and maintenance of irrigation facilities (Haile, 2015).\n\nThe four pathways identified by the African Union (AU) for improving agricultural production is one of the holistic approaches for addressing water and food nexus challenges. These pathways are (1) improved water control and watershed management in rain-fed farming, (2) farmer-led irrigation development (FLID), (3) irrigation scheme development and modernization, and (4) unconventional water use for irrigation (AU, 2020). These pathways are necessary for the Horn of Africa where climate change is a threat to water resources and consequently food production. The unconventional use of water in agriculture (pathway 4) requires consideration of food safety and improvement in sewerage and wastewater treatment infrastructure. This may be a challenge in the Horn of Africa where sanitation systems are poorly developed. According to Alemngus et al. (2017), wastewater is used for irrigation in Asmara, Eritrea though it could not qualify as wastewater re-use since there is no wastewater treatment facility. Use of untreated wastewater for irrigation presents food safety risks which can cause harm to human health.\n\nFood production accounts for 30% of energy use in the world (FAO, 2011). Energy inputs are required throughout the food production chain; from farm, storage, processing, handling, distribution and preparation for consumption (Awandu et al., 2022). Poor access to energy sources is one of the main causes of post-harvest losses in the agricultural sector in Africa and thus a big contributor to chronic food insecurity and malnutrition (Lynd et al., 2015).\n\nBiomass energy is a classic example of a direct link between agriculture (food) and energy production (Tashtoush et al., 2019). Therefore, reliance on biomass energy by households in Africa and specifically in the Horn of Africa exposes them to the risks of climate variability and change. Also, feedstocks used for biofuel production are mainly rainfed with few under irrigation. Therefore, climate change impacts on energy production from agricultural biomass cannot be ignored.\n\nBioenergy production requires land, and is thus inextricably linked with social development, agriculture, and environmental quality and if these links are not managed properly it can lead to undesirable consequences (Lynd et al., 2015).\n\nProduction of biofuel from sugarcane mollases, Jatropha and castor beans in Ethiopia has improved social security by creating employment but increased the risk of food insecurity due to competition for land resources (Gebremeskel and Tesfaye, 2008). Land grabbing for biofuel crop production has diminished the land for food crops. For example, Ethiopia has allocated 700,000 ha and 23 million ha to multinational companies for cultivation of sugarcane and Jatropha for biofuel production respectively (Dobaa et al., 2014). The use of animal dung as bioenergy presents a direct competition from agriculture where it is used as manure and thus contributes to low agricultural productivity.\n\nThe pressure to feed an increasing population requires increasing food production from existing agricultural land or expanding the area under crop production. Since most areas in the Horn of Africa are ether arid or semi-arid, rainfed agriculture is vulnerable to climate change and variability and thus irrigation is necessary. Irrigation requires energy for pumping and distribution of water and thus expanding irrigation areas increases energy demand. For example, in Ethiopia electricity demand from large-scale irrigation schemes is increasing and is projected to reach about 13,000 GWh in 2030 (Yalew, 2022). As discussed in the previous section, hydropower is vulnerable to climate variability and change and consequently irrigated agriculture is affected.\n\nAdoption of climate-smart energy use and management practices can help in climate change adaptation and mitigation as described by Girmay and Gebreegziabher (2019) in the context of Ethiopia (Table 2). These practices can apply to other Horn of Africa countries.\n\n\nModelling the WEFE nexus\n\nModelling the WEF nexus requires integration of models/tools in the energy, water and food spheres. Kaddoura and El Khatib (2017) reviewed tools developed to model the WEF nexus. Some of these tools included Climate, Land-use, Energy, and Water (CLEW), the Water, Energy, Food Tool 2.0 and MARKAL/TIMES (MARKet Allocation). These tools were found to be useful in modelling the synergies in the WEF nexus but the problem was intensive data requirements. Therefore, these models may have limited applications in countries where data are limited.\n\nWater resource (hydrological) models which focus on integrated water resource management are important as water affects both energy and food production. Some of the common hydrological integrated tools include SWAT (Soil and Water Assessment Tool) and WEAP (Water Evaluation and Planning system) models. The water and food sectors can be modelled using water allocation tools such as WEAP while the energy sector can be through the LEAP (Long-Range Energy Alternatives Planning System) model (Karlberg et al., 2015). The advantage of WEAP is its applicability on many scales: municipal and agricultural systems, single catchments or complex transboundary river systems (Droogers et al., 2012). WEAP can also extend to model energy, biomass and climate (Shannak et al., 2018). Agricultural water management models such as the FAO’s AquaCrop helps in improving crop water productivity under rainfed or irrigation conditions thus linking the idea of more yields (food for human and animal use) using less water. However, some of these water resources models do not include the energy component.\n\nA systems dynamic modelling (SDM) approach was applied in understanding the effects of the GERD dam and its implications on the WEF nexus of riparian states. This SDM approach was appropriate because it addresses the interdependent relationships among the WEFE nexus components and the spatio-temporal socio-economic dynamics. This is due to its ability to provide both a qualitative and quantitative modelling framework without the need for additional software modules (Elsayed et al., 2020). The study established that GERD will impact the water, energy and food sectors in the countries considered and downstream Egypt will have reduced hydropower generation, water flows and food production by an average of 6%, 23% and 10% respectively. This will depend on the filling rates with less reductions during operation while boosting hydropower generation of Ethiopia by 360% (Elsayed et al., 2020). Thus, GERD can be a source of co-operation or conflicts among the countries affected depending on how the issue is handled.\n\nIt is difficult to find a model which meets the integrated nature of the WEF nexus and achieves a balance between simplicity, in data requirements and model structure, and accuracy. Shannak et al. (2018) identified four key challenges in modelling the WEF nexus: a) complex interactions and dynamics between WEF resources; b) high temporal and spatial variations of WEF parameters necessitating detailed data; c) difficulty in incorporation of spatial and temporal WEF resource variation in planning; d) factoring external forcing variables into the modelling and planning approaches. The existing WEF nexus models such as CLEW have limitations in terms of spatial representation and inadequate inclusion of WEF sub-system interactions (Soleimanian et al., 2022).\n\n\nConclusions\n\nThis review aimed to understand the WEFE nexus in the Horn of African countries of Ethiopia, Eritrea, Somalia and Djibouti and the status of achieving sustainable development. The review established that the region is highly WEF insecure with an index of 42.7 and performance in the food and water sub-indices poorest compared to the energy sub-index. Djibouti is the only country with a WEF index above 50. Therefore, attaining SDG 2, 6 and 7 is a challenge in the region.\n\nThe WEF nexus is highly impacted by climate change through droughts which has reduced water availability for both water and sanitation, energy production and agricultural use. Lack of a regional framework for managing transboundary water resources is a source of tension and conflict in the region. Other challenges facing the WEF nexus include political, legal and institutional factors and persistent armed conflicts which undermine the efforts to adapt to climate change.\n\nThere is need for improved water governance at country and regional level as well as adoption of efficient irrigation systems, rainwater harvesting, improvements in water supply and energy infrastructure, climate-smart energy technologies, and climate-smart agricultural practices.\n\nModelling the WEF nexus requires use of models which not only simulate the individual components but also their interactions in the system. The model should strike a balance between simplicity and accuracy while considering the spatial and temporal dynamics of the WEF resources.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nAbebe W: Food Insecurity in the Horn of Africa and Its Impact on Peace in the Region. IPSS Policy Brief. 2021; 15: 1–8.\n\nADB: Country Profile- Eritrea. Asmara, Eritrea:African Development Bank;2021.\n\nAdmassu H, Getinet M, Thomas TS, et al.:Ethiopia.Waithaka M, Nelson GC, Thomas TS, et al., editors. East African agriculture and climate change: A comprehensive analysis. Washington, D. C.:International Food Policy Research Institute (IFPRI);2013; pp. 149–182.\n\nAghaKouchak A: A multivariate approach for persistence-based drought prediction: Application to the 2010–2011 East Africa drought. J. Hydrol. 2015; 526: 127–135. Publisher Full Text\n\nAlam MA, Islam Z: The Potential of Sustainable Energy Resources in Eritrea: Solar Energy-An Overview. J. Glob. Econ. 2019; 15: 243–254. Publisher Full Text\n\nAlam ME: Impact of Climate Change on Agro-Economy of Eritrea, Africa. Transactions. 2017; 39: 211–222.\n\nAlemngus A, Amlesom S, Bovas L: An overview of Eritrea’s water resources. Int. J. Eng. Res. Dev. 2017; 13: 74–84.\n\nAlemu T, Mengistu A:Impacts of climate change on food security in Ethiopia: adaptation and mitigation options: a review.Castro P, Azul AM, Filho WL, et al., editors. Climate Change-Resilient Agriculture and Agroforestry. Climate Change Management. Cham, Switzerland:Springer Nature;2019; pp. 397–412.\n\nArcanjo M: Water Security in the Horn of Africa: Climate Change in Somalia, Ethiopia, Eritrea and Djibouti. Washington DC, USA:Climate Institute;2020.\n\nAU: Framework for Irrigation Development and Agricultural Water Management in Africa. African Union Addis Ababa;2020.\n\nAwandu W, Kanda EK, Kimokoti SN: The Water-Energy-Food nexus in Kenya: Climate Change Impacts and Adaptation Strategies- A Review.Behnassi M, Al-Shaikh AA, Gurib-Fakim A, et al., editors. The water, Climate, and Food Nexus-Linkages, challenges and Emerging Solutions. 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Springer, Cham:Switzerland;2021; pp. 53–63.\n\nKaramba W: Improving Access to Jobs for the Poor and Vulnerable in Somalia. Washington DC, USA:World Bank;2021.\n\nKarlberg L, Hoff H, Amsalu T, et al.: Tackling complexity: understanding the food-energy-environment nexus in Ethiopia’s Lake tana sub-basin. Water Altern. 2015; 8: 710–734.\n\nKassa M, Andualem TG: Review of Irrigation Practice in Ethiopia, Lessons from Israel. Irrig. Drain. Syst. Eng. 2020; 9: 1–6.\n\nLiu J, Yang H, Cudennec C, et al.: Challenges in operationalizing the water–energy–food nexus.2017; 62: 1714–1720.\n\nLynd LR, Sow M, Chimphango AF, et al.: Bioenergy and African transformation. Biotechnol. Biofuels. 2015; 8: 1–18. Publisher Full Text\n\nMcsweeney C, New M, Lizcano G, et al.: The UNDP Climate Change Country Profiles: Improving the accessibility of observed and projected climate information for studies of climate change in developing countries. Bull. Am. Meteorol. Soc. 2010; 91: 157–166. Publisher Full Text\n\nMohamed AE: Managing shared basins in the Horn of Africa–Ethiopian projects on the Juba and Shabelle rivers and downstream effects in Somalia. Nat. Resour. Conserv. 2013; 1: 35–49. Publisher Full Text\n\nMohamed AE: Water Scarcity in the Horn of Africa: A Threat to Security or an Incentive to Cooperation for Development.Dahre UJ, editor. Resources, Peace and Conflict in the Horn of Africa: A Report on the 12th Horn of Africa Conference. Lund, Sweden:Media-Tryck;2014; pp. 167–184.\n\nMora S, Jalludin M, Mahdi D, et al.:Modelling and quantifying risk in Djibouti.Williams AL, Pinches GM, Chin CY, et al., editors. 11th IAEG Congress. Auckland, New Zealand:Taylor & Francis Group;2010; pp. 1345–1353.\n\nMotuma FY: A review on policy change for climate change in Ethiopia. Journal of Resources Development and Management. 2017; 28: 1–13.\n\nMouhoumed EI, Abdillahi MM-a, Elmi YM, et al.: Classification of Various Bottled Mineral Waters Marketed in Djibouti. World J. Eng. 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Earth Sci. Clim. Change. 2014; 5: 1–4."
}
|
[
{
"id": "269823",
"date": "02 May 2024",
"name": "Raghavendran Sivasubramanian",
"expertise": [
"Reviewer Expertise Wastewater treatment",
"Aerobic sludge",
"Linear regression statistics",
"Algae biodiesel",
"Advanced reduction process",
"Environmental Sustainability"
],
"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 a review paper on the status of the water-energy-food nexus in four countries: Ethiopia, Eritrea, Somalia, and Djibouti. Comparisons were made on the accessibility and availability of the services, impact of the climate change on the interrelationships of these parameters and how it affects the regions specifically, and the available tools used to predict the dynamic modeling of the nexus. Index rates are compared, and the reasons for challenges in sustainable development are also explored for the 4 countries. Verdict: Accepted- No modifications needed! This is a brilliant paper! It is very well-reviewed and well-written! Only suggestion: It will be nicer if there is also a WEFE nexus diagram/ flowchart that encompasses the food, energy, and water security programs pointing out commonalities among the Horn of African regions.\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/12-143
|
https://f1000research.com/articles/10-244/v1
|
26 Mar 21
|
{
"type": "Case Report",
"title": "Case Report: COVID-19 with cytokine storm in a 16-year-old patient: if heart failures comes think about levosimendan",
"authors": [
"Veronica Rodriguez-Garcia",
"Jose Luis Guerrero Orriach",
"Daniel Ariza Villanueva",
"Jose Manuel Garcia Pinilla",
"Ainhoa Robles Mezcua",
"Manuel Rubio Navarro",
"Jose Cruz Mañas",
"Jose Luis Guerrero Orriach",
"Daniel Ariza Villanueva",
"Jose Manuel Garcia Pinilla",
"Ainhoa Robles Mezcua",
"Manuel Rubio Navarro",
"Jose Cruz Mañas"
],
"abstract": "Introduction: Our case is unique because the differential diagnosis was a challenge. At first, the patient presented with septic shock and multi-organ failure in the context of a suspected lymphoproliferative syndrome. Once the lymphoproliferative process had been ruled out, hemophagocytic syndrome due to COVID-19 infection was suspected, so he is probably one of the few patients with such an exhaustive study that could contribute to our understanding of COVID-19. We followed therapeutic guidelines that differ from the usual, using adrenalin and levosimendan. Corticosteroids helped to modulate the cytokine storm. Case report: A 16-year-old adolescent was admitted to the intensive care unit with fever, diarrhea, multiorgan failure and septic shock. He was IgG positive for COVID-19 and IgM negative. Thoraco-abdominal computed tomography demonstrated multiple para-aortic and peri-pancreatic lymphadenopathy and acute respiratory distress syndrome. The first suspected diagnosis was a lymphoproliferative syndrome and bacterial infection. The second possibility was a hemophagocytic syndrome in a patient recovering from COVID-19. He was treated with broad spectrum antibiotics because the differential diagnosis was difficult, and we removed them when the microbiological screening was negative. During the course of the disease he presented with severe biventricular dysfunction, probably due to the cytokine storm, so we used inotropic drugs (adrenaline, levosimendan). Infection with Salmonella species group B was diagnosed later, when the patient was in the Internal Medicine ward, although he was asymptomatic. Conclusion: The severity of COVID-19 infection ranges from mild to severe, causing serious disease in some people. Although the pathophysiology is not well known, it seems that in some cases an immune storm is triggered, and it is related to more serious and prolonged disease. In our case, heart failure was important, because it could have worsened the prognosis. Fortunately, the response to levosimendan and corticosteroids was adequate and he recovered favorably until discharge.",
"keywords": [
"COVID-19",
"myocarditis",
"multiorganic failure",
"levosimendan",
"case report."
],
"content": "Introduction\n\nThe first cases of acute respiratory syndrome caused by COVID-19 were diagnosed in Hubei, China, in December 2019. The high rate of infectivity of the microorganism has triggered a pandemic. Symptoms include dry cough, headache, dyspnea, diarrhea, or fever. However, COVID-19 may also cause respiratory failure, kidney failure, cardiac injury, and central nervous system damage. Patients with comorbidities such as hypertension, obesity, or diabetes are at a higher risk of developing severe symptoms1.\n\nAlthough the pathophysiology of the virus remains unknown, several studies have associated COVID-19 with a cytokine storm quite similar to that occurring in hemophagocytic syndrome (macrophage activation syndrome). This syndrome is characterized by elevated levels of interleukins (IL-1b, IL-6, IL-10, IL-12), interferon (alpha, gamma), and tumor necrosis factor (TNF-alpha); hypertriglyceridemia; hyperferritinemia; hemophagocytosis in the bone marrow, cerebrospinal fluid, or lymph nodes; and manifests in the form of fever, hepatosplenomegaly, hemorrhagic diathesis, cutaneous rash and alterations of consciousness2.\n\nThe myocardial depressant effect of cytokines, an oxygen deficit generated by a prothrombotic state and coronary vasospasms could cause cardiac injury and dysfunction in other organs.\n\nIL-6, cardiac troponins (cTnI/T), and the amino-terminal fraction of the cerebral natriuretic propeptide (NT-proBNP) have been documented to be elevated in patients with cardiac failure secondary to COVID-193.\n\nViral myocarditis is a widely described condition, with symptoms such as heart failure. It usually develops within one to three weeks of COVID-19 infection. Potential COVID-19 myocarditis therapies are based on inotropic drugs and extracorporeal life support4. Levosimendan should be valued as a useful therapy in this type of patients due to its inotropic effects maintained over time and its associated organ protective effects5, which are essential for cardiocirculatory support in cases such as the one reported in this paper.\n\nOur case is unique because the differential diagnosis was quite difficult and interesting. First, it seemed the patient had septic shock and a lymphoproliferative syndrome. Then we thought about hemophagocytic syndrome as well, so he is probably one of the few patients with such an exhaustive study at the immune and hematological level, which could help to understand COVID-19.\n\nBesides that, we follow therapeutic guidelines that differ from the usual, using levosimendan as an inotropic agent6 with very good results and corticosteroids7 without tocilizumab8 due to suspected hemophagocytic syndrome, which helped to modulate the autoimmune response due to the cytokine storm without the need for more immunosuppression with monoclonal antibodies.\n\n\nCase presentation\n\nThe patient was a 16-year-old Spanish adolescent, Caucasian, with no allergies, with extrinsic asthma treated with corticosteroids and aerosols occasionally. He has no relevant past interventions and no medical, family or psychosocial history (including genetic) of interest. He presented with general discomfort, asthenia and fever (38°C) for three days and was treated with paracetamol 1g/8 hours and azithromycin 500mg/24 hours for three days at home. After seven days, he came to the emergency department with persistence of symptoms, shortness of breath, arthromyalgia and diarrhea.\n\nPhysical examination revealed a bad general condition. Blood pressure was 70/30 mmHg, heart rate was 110 bpm, respiratory rate was 18 bpm, and axillary temperature was 38.5°C. Lung auscultation found bibasilar crackles and heart auscultation found no murmurs. He had hepatosplenomegaly, oliguria, no edemas, no cutaneous rash and no arthritis. He had diuresis of 170 ml in 12 hours. The results of laboratory testing were: white blood cell count 102009/L, with 84.2% neutrophils, red blood cell count 4.212/L, hemoglobin 12.5 g/L, platelet count 1040009/L, serum C-reactive protein level 269.4 mg/L, alanine aminotransferase level 81 U/L, aspartate aminotransferase level 71 U/L, total bilirubin level 3.30 mg/dL, direct bilirubin level 2.73 mg/dL, cardiac troponin I 1135 pg/ml, blood urea nitrogen 48 mmol/L, creatinine 2.72 μmol/L, erythrocyte sedimentation rate of 12 mm/h, procalcitonin 1.96 ng/ml., arterial pH of 7.32, pCO2 of 50.2 mmHg, pO2 of 68 mmHg, HCO3 23 mmol/L, SO2 94%, lactic acid 2.2 mmol/L, ferritin 655.4 ng/mL, triglycerides 161 mg/dL, uric acid 11.3 mg/dL, prothrombin activity 64.7%, international normalized ratio 1.28, activated partial thromboplastin time (aPTT) 28.9 seconds, aPTT ratio 1.16 and D-dimer 7.500 ng/ml. The evolution of laboratory parameters during admission to the Intensive Care Unit (ICU) is shown in Table 1.\n\nA nasopharyngeal swab and reverse transcriptase-polymerase chain reaction (RT-PCR) for COVID-19 was negative, but COVID-19 serology was IgM negative and IgG positive. Microbiological screening (urine, blood, sputum and stool culture), serological tests (virus, parasites, fungi and bacteria), and a Mantoux test were carried out. His thoracoabdominal CT scan showed multiple para-aortic and peri-pancreatic lymphadenopathy (compatible with lymphoproliferative syndrome as the most likely diagnosis) and acute respiratory distress syndrome (ARDS). There was no sign of pulmonary thromboembolism, but there were signs of pulmonary hypertension. He was admitted to the ICU and treated with broad spectrum antibiotics (imipenem 1g/8h, linezolid 600mg/12h) and a low dose of norepinephrine (0.05 mcg/kg/min).\n\nAn investigation of lymphoproliferative syndrome considering the possibility of hemophagocytic syndrome secondary to COVID-19 was carried out, including autoimmune tests. Protein electrophoresis showed an inflammatory pattern and a direct Coombs test was negative. A bone marrow biopsy showed reactive cells, without atypical cellularity, discarding lymphoproliferative or hemophagocytic syndrome. Tests for autoimmune diseases revealed a low level of C3 and positivity for lupus anticoagulant. The rest of the antibody tests were negative.\n\nMicrobiological screening, serological test and Mantoux were all negative, supporting the theory of an exaggerated systemic inflammatory response due to COVID-19. Septic shock was ruled out, so we decided to withdraw antibiotics. Only a rectal swab was positive for COVID-19.\n\nDuring his time in hospital, the patient presented with acute confusion and agitation. He had no meningeal signs on examination. Cranial CT scan was normal and symptoms remitted within 24 hours.\n\nAn electrocardiograph showed atrial fibrillation and diffuse T wave inversion. Transthoracic echocardiography (TTE) was performed regularly, due to elevated cardiac enzymes. The first TTE was normal, but on the third day of admission demonstrated moderate biventricular dysfunction that progressed to severe in the following 24 hours, and atrial fibrillation. The evolution of echocardiographic parameters during admission to the ICU is shown in Table 1.\n\nFrom the beginning our patient was treated with a nasal cannula at 3 liters/minute for five days and a venturi mask at 40% FiO2 for four days. Also, broad spectrum antibiotics (at the beginning, 1g/8h imipenem and 600mg/12h linezolid for six days, and on the third day of admission, 500mg/24h daptomycin and 200mg/24h fluconazole were added to the regimen) and a low dose of norepinephrine (0.05 mcg/kg/min) were administered.\n\nWhen the possibility of a septic shock was ruled out, antibiotics were withdrawn and 8mg/24 hours dexamethasone was started to try to contain the cytokine storm due to COVID-19. The dose was increased to 12 mg when he suffered with confusion, agitation and heart failure. The patient was treated with adrenalin up to 0.1 mcg/kg/min, 12.5mg/24 hours levosimendan and 20mg/8-12 hours furosemide for eight days. A bolus of 150 mg amiodaron followed by an infusion of 600mg in 24 hours was administered when atrial fibrillation was targeted. He was given enoxaparin 60mg/24 hours during the first days and then it was increased to 60mg/12 hours.\n\nA new TTE that was performed four hours after levosimendan was initiated showed a moderate improvement in left ventricular function and a slight improvement in right ventricular function. In 12 hours, the cardiac function returned to normal and sinus rhythm was recovered (Table 2).\n\nHemodynamic support therapy was withdrawn, and oxygen therapy, furosemide and dexamethasone were progressively reduced. He didn´t have any adverse events with the medication; it was well tolerated.\n\nIn a few days, the clinical picture resolved and the patient was discharged to the Internal Medicine ward. The evolution of his condition was very favorable. He was afebrile, hemodynamically stable, with good food tolerance and without other clinical symptoms. Microbiological screening was repeated by Internal Medicine and a stool culture was positive for group B Salmonella species. The patient had no symptoms, but ciprofloxacin was administered for seven days and then he was discharged hemodynamically stable, eupneic and with oxygen saturation of 99% with oxygen supply of 0.28%. Two weeks later he left the hospital.\n\nA timeline with information from the current episode of care is shown in Table 3.\n\nCT, computed tomography; RT-PCR, reverse transcriptase polymerase chain reaction; ICU, Intensive Care Unit.\n\n\nDiscussion\n\nThe Systemic inflammatory response syndrome (SIRS) may be caused by sepsis of bacterial origin, but sometimes it is difficult to substantiate and the differential diagnosis from non-infectious conditions is frequently a challenge. Definitive diagnosis requires isolation of a microorganism, but occasionally this is not possible9. On the other hand, the ability of some viruses to trigger a secondary autoimmune condition is well known. As we said before, on many occasions it is difficult to find out what has been the true trigger of the SIRS. During the COVID-19 pandemic, cases of cardiac involvement have been described10-12 and in many cases autoimmune diseases secondary to infection have been triggered. Elevated levels of IL-6 have been detected in these patients, but we are unable to determine them in our hospital13,14. The diagnosis of the disease can be complicated, and many times it is not possible to have absolute certainty, although due to possible complications, in cases of high suspicion, it is still necessary to treat.\n\nIn this case, cardiac failure especially contributed to the severity of the patient’s condition. Myocarditis is an inflammatory disease of the heart muscle caused by viruses mainly, although bacteria, toxic drugs and autoimmune diseases can produce it too. The exacerbation of the inflammatory response along with the cytokine storm and its associated cardio-depressor and prothrombotic effects could be the cause of alterations in the coronary circulation (microcirculation and vasospasm), myocardial dysfunction, and increased oxygen consumption15. Cardiac magnetic resonance imaging is useful for diagnosis but only endomyocardial biopsy can establish the etiological diagnosis16. We did not perform an endomyocardial biopsy due to coagulopathy and the pandemic situation.\n\nThe patient was treated with adrenaline, diuretics, and levosimendan. He was also receiving anti-inflammatory treatment with dexamethasone, for suspicion of a possible immunological disease secondary to COVID-1917. heart function recovered in a couple of days. The benefits of levosimendan in infectious myocarditis have been endorsed by different studies. It has been shown to be superior over dobutamine in terms of mortality in patients with heart failure18,19. It is a novel drug to treat myocardial dysfunction due to sepsis20, myocardial infarction with left ventricular failure21 or cardiac decompensation22. Its cardioprotective effects are because it causes coronary vasodilation, reduces preloading and postloading, and activates mitochondrial-K+ ATP channels. Its inotropic, coronary, antiplatelet, antiapoptotic, and anti-inflammatory effects increases cardiac output and decreases the ventricular filling pressure, pulmonary and systemic vascular resistance23. This was the reason we decided to use levosimendan, after not getting a full response to adrenaline and the progression of the patient was satisfactory.\n\nWhen he was discharged to the Internal Medicine ward, he continued to show favorable progress and clinical improvement. However, they repeated the stool culture again and it was positive for Salmonella species and treated with ciprofloxacin, although the patient remained asymptomatic. In subsequent check-ups the patient had no sequelae of the disease and cardiac magnetic resonance imaging was performed, which was normal. This makes us suspect that the Salmonella infection was probably acquired in hospital and it was not the cause of myocarditis, although we cannot completely rule it out.\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\n\nConsent\n\nWritten informed consent for publication of their clinical details was obtained from the patient.",
"appendix": "References\n\nSilva Júnior JVJ, Lopes TRR, de Oliveira PSB, et al.: Issues on Coronavirus Disease 2019 (COVID-19) Pathogenesis. Viral Immunol.2020 Apr 27 [cited 2020 May 11]. PubMed Abstract | Publisher Full Text\n\nChannappanavar R, Perlman S: Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. Springer Verlag; 2017; Vol. 39, p. 529–39. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBabapoor-Farrokhran S, Gill D, Walker J, et al.: Myocardial injury and COVID-19: Possible mechanisms. Life Sci.2020 Jul [cited 2020 May 11]; 253: 117723. Reference Source. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChow J, Alhussaini A, Calvillo-Argüelles O, et al.: Cardiovascular Collapse in COVID-19 Infection: The Role of Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO). CJC Open. 2020 Apr. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuerrero-Orriach JL, Ariza-Villanueva D, Florez-Vela A, et al.: Cardiac, renal, and neurological benefits of preoperative levosimendan administration in patients with right ventricular dysfunction and pulmonary hypertension undergoing cardiac surgery: Evaluation with two biomarkers neutrophil gelatinase-associated lipocalin and neuronal enolase. Ther Clin Risk Manag. 2016 Apr 21; 12: 623–630. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen QH, Zheng RQ, Lin H, et al.: Effect of levosimendan on prognosis in adult patients undergoing cardiac surgery: A meta-analysis of randomized controlled trials. Crit Care. 2017 Oct; 17; 21(1). PubMed Abstract | Publisher Full Text | Free Full Text\n\nMattos-Silva P, Felix NS, Silva PL, et al.: Pros and cons of corticosteroid therapy for COVID-19 patients. Respir Physiol Neurobiol. 2020 Sep 1; 280: 103492. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPascarella G, Strumia A, Piliego C, et al.: COVID-19 diagnosis and management: a comprehensive review. J Intern Med. Blackwell Publishing Ltd; 2020; Vol. 288: p. 192–206. PubMed Abstract | Publisher Full Text | Free Full Text\n\nProcalcitonin as a diagnostic and prognostic marker for sepsis caused by intestinal infection: a case report.2020 Sep 19. PubMed Abstract\n\nIrabien-Ortiz Á, Carreras-Mora J, Sionis A, et al.: Fulminant myocarditis due to COVID-19. Rev Esp Cardiol. 2020 Jun 1; 73(6): 503–504. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZeng JH, Liu YX, Yuan J, et al.: First case of COVID-19 complicated with fulminant myocarditis: a case report and insights. Infection. 2020. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen C, Zhou Y, Wang DW: SARS-CoV-2: a potential novel etiology of fulminant myocarditis. Herz. Springer Medizin; 2020; Vol. 45: p. 230–2. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcGonagle D, Sharif K, O’Regan A, et al.: The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmunity Rev. Elsevier B.V.; 2020; Vol. 19: p. 102537. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang W, Ye L, Ye L, et al.: Up-regulation of IL-6 and TNF-α induced by SARS-coronavirus spike protein in murine macrophages via NF-κB pathway. Virus Res. 2007 Sep; 128(1–2): 1–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDominguez F, Kühl U, Pieske B, et al.: Update on Myocarditis and Inflammatory Cardiomyopathy: Reemergence of Endomyocardial Biopsy. Rev Esp Cardiol (Engl Ed). 2016 Feb; 69(2): 178–87. PubMed Abstract | Free Full Text\n\nFriedrich MG, Sechtem U, Schulz-Menger J, et al.: Cardiovascular Magnetic Resonance in Myocarditis: A JACC White Paper. J Am Coll Cardiol. 2009; Vol. 53: p. 1475–87. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen RC, Tang XP, Tan SY, et al.: Treatment of severe acute respiratory syndrome with glucosteroids: The Guangzhou experience. Chest. 2006; 129(6): 1441–1452. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCleland JGF, Ghosh J, Freemantle N, et al.: Clinical trials update and cumulative meta-analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO-LIPIDS and cardiac resynchronisation therapy in heart failure. Eur J Heart Fail. 2004; Vol. 6: p. 501–8. PubMed Abstract | Publisher Full Text\n\nFollath F, Cleland JGF, Just H, et al.: Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): A randomised double-blind trial. Lancet. 2002 Jul 20; 360(9328): 196–202. PubMed Abstract | Publisher Full Text\n\nGong B, Li Z, Yat Wong PC: Levosimendan Treatment for Heart Failure: A Systematic Review and Meta-Analysis. J Cardiothorac Vasc Anesth. 2015 Dec 1; 29(6): 1415–1425. PubMed Abstract | Publisher Full Text\n\nMoiseyev VS, Põder P, Andrejevs N, et al.: Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction: A randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J. 2002 Sep; 23(18): 1422–1432. PubMed Abstract | Free Full Text\n\nPacker M, Colucci W, Fisher L, et al.: Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Hear Fail. 2013 Apr; 1(2): 103–111. PubMed Abstract | Publisher Full Text\n\nG L, R A, I P, et al.: Preoperative Levosimendan. A New Way for Organoprotection. Curr Pharm Des. 2014 Sep 15; 20(34): 5476–83. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "97530",
"date": "09 Dec 2021",
"name": "Cecilia Bonazzetti",
"expertise": [
"Reviewer Expertise Infectious 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 case report is well described, at times almost redundant. The description of the clinical case is interesting and complete in all information. However, the discussion should be revised because it lacks a very important etiological entity talking about this topic which is the MIS-C and the most important works regarding this topic are not even mentioned: Feldstein et al., 20201, Jiang et al., 20202.\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? Yes",
"responses": []
},
{
"id": "154671",
"date": "03 Nov 2022",
"name": "Hrvoje Jakovac",
"expertise": [
"Reviewer Expertise COVID-19",
"heat shock proteins",
"oncogenesis",
"autoimmunity",
"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\nThe authors bring an interesting case of a 16-year-old boy with severe COVID-19. Although the authors claim the cytokine storm was an underlying mechanism, there is no clear evidence that this was the scenario in described patients (the authors did not measure plasma cytokine concentration).\nThe following sentence in the Introduction section is not clear: \"The myocardial depressant effect of cytokines, an oxygen deficit generated by a prothrombotic state and coronary vasospasms could cause cardiac injury and dysfunction in other organs\". Can SARS-CoV-2 directly infect the cardiac conduction system and cause arrhythmias? (See and refer to: https://doi.org/10.3390/tropicalmed70300431)\nThe patient's asthma had been treated with corticosteroids and aerosols occasionally. Please provide the treatment regimen and doses in more detail. Could asthma (and corticosteroids) have been a risk factor for the patient described? Please discuss.\nWas SpO2 measured by pulse oximetry immediately at admission? Please provide data on the patient's state of consciousness at admission. Were there any physical signs of dehydration in the patient upon admission (skin turgor, dry mucous membranes)? Please describe the patient's diarrhea (duration, stool frequency, number of stools). Please show normal laboratory values in parentheses for each parameter. Please provide data on the kit/device used for RT-PCR.\n\nThe lack of nasopharyngeal RT-PCR positivity with rectal swabs being positive is the most intriguing detail, but the authors did not discuss it. Please include it in the discussion. What are the potential causes of such findings? Is there any role of ACE2 distribution (see and refer to: https://doi.org/10.1152/ajplung.00119.20202)\nThe discussion section should be more comprehensive, including consideration of the mechanisms of cardiac affection and arrhythmias described (see above).\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? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-244
|
https://f1000research.com/articles/11-1267/v1
|
07 Nov 22
|
{
"type": "Software Tool Article",
"title": "Gene expression data visualization tool on the o²S²PARC platform",
"authors": [
"Hiba Ben Aribi",
"Mengyuan Ding",
"Anmol Kiran",
"Hiba Ben Aribi",
"Anmol Kiran"
],
"abstract": "Background: The identification of differentially expressed genes and their associated biological processes, molecular function, and cellular components are important for genetic diseases studies because they present potential biomarkers and therapeutic targets. Methods: In this study, we developed an o²S²PARC template representing an interactive pipeline for the gene expression data visualization and ontologies data analysis and visualization. To demonstrate the usefulness of the tool, we performed a case study on a publicly available dataset. Results: The tool enables users to identify the differentially expressed genes (DEGs) and visualize them in a volcano plot format. The ontologies associated with the DEGs are determined and visualized in barplots. Conclusions: The “Expression data visualization” template is publicly available on the o²S²PARC platform.",
"keywords": [
"Visualization",
"Gene expression",
"Ontology",
"o²S²PARC"
],
"content": "Introduction\n\nTranscriptome data has been used to understand the local microenvironment, molecular signals, and cell-cell interaction in cells, tissues, and organs in multiple diseases, such as Alzheimer’s disease,1 Parkinson’s disease,2 and much more. In this study, we focus on the gene expression data, particularly the differentially expressed genes (DEGs) and their associated ontologies: (i) the cellular component (CC) that describes the subcellular structures and macromolecular complexes, often used to annotate cellular locations of gene products; (ii) the biological process (BP) that describes the biological programs consisting of multiple molecular activities, such as DNA repair or signal transduction; (iii) and the molecular function (MF) that describes molecular-level activities performed by gene products, such as “catalysis” or “transport”.\n\nThis study was performed during the SPARC FAIR Codeathon in August 2022 organized by the National Institute of Health (NIH) SPARC program. We developed a gene expression data visualization tool created and published on the o2S2PARC, Open Online Simulations for Stimulating Peripheral Activity to Relieve Conditions platform, a simulation and analysis platform aiming to initially perform interactive peripheral nerve system neuromodulation/stimulations and to visualize its physiological impact on organs.3 However, the platform currently hosts tools for multiple biological and physiological analyses but does not provide a tool for transcriptomics and gene expression data analysis or visualization.\n\nThe tool was initially created to visualize the transcriptomics data on the SPARC Portal platform, a fully open-accessible database consisting of a wide variety of datasets across multiple scales, such as organs, species, and datatypes.4 The platform is created and maintained by the Stimulating Peripheral Activity to Relieve Conditions (SPARC) program, funded by NIH. It was initiated to advance the understanding of nerve-organ interactions and to expedite the invention of therapeutic medicine and devices that modulate electrical activity in nerves to promote organ function.5 The SPARC consortium runs under the FAIR data sharing policy (consists of the principle of Findable, Accessible, Interoperable, and Reusable), according to the SPARC Data Structure (SDS).\n\n\nMethods\n\nImplementation\n\nThe tool is created as a template in the o2S2PARC platform. The platform is accessible on all web browsers. It requires pandas 1.4.3, bioinfokit 2.0.8, numpy 1.22.1, matplotlib 3.5.2, seaborn 0.11.2, and goatools 1.2.3. All the requirements are integrated within the tool and automatically installed.\n\nOperation\n\nThe tool includes two pipelines encoded in two separate python jupyterlab notebooks. The first pipeline identifies the DEGs based on the p-value, set to p-value < 0.05 as default, and determines the expression profile of the genes:\n\n• p-value > 0.05: “Not differentially expressed”\n\n• p-value < 0.05 and the LogFC value > 0: “Upregulated”\n\n• p-value < 0.05 and the LogFC value < 0: “Downregulated”\n\nThe pipeline also performs the ontology analysis for the differentially expressed genes, to determine the cellular components, biological processes, and molecular functions associated with these genes. The Biological processes, molecular functions, and cellular component ontologies are represented in six similar separate Barplots, as represented in Figure 1.\n\nThe genes-related ontology data were downloaded from the NCBI database (https://www.ncbi.nlm.nih.gov/). The file for the human species is provided as default. The user needs to provide a file as input if the transcriptomics data correspond to other species.\n\nThe second pipeline takes two CSV files as input. The gene’s expression profile is determined, as in the first pipeline, for the two datasets. The common and uncommon genes count is performed. And the gene expression profiles in the two datasets are compiled in a single csv file for further analysis.\n\nA web browser extension was developed, using HTML and CSS programming, as a user guide. The extension is helpful for the new SPARC platform users. It guides the user step by step from downloading transcriptomics data from the SPARC portal database, providing a raw data analysis workflow, and explaining the “Gene expression data visualization” tool.\n\nThe tool was initially created to visualize the SPARC Portal platform transcriptomics data. However, it could be used to visualize any expression data csv file. The pipeline validation was performed using two datasets from the Gene Expression Omnibus (GEO) database6 corresponding to the early and advanced stages of multiple sclerosis disease (MS) in human patients (GSE 126802 and GSE 10800).\n\nThe early-stage dataset GSE1268027 provides microarray gene expression analysis raw data from the subcortical normal-appearing white matter from 18 MS donors and the white matter of 9 control donors. The advanced stage dataset GSE1080008 provides microarray gene expression data from 7 chronic active MS demyelinated lesions, 8 inactive MS lesions, and white matter of 10 control donors.\n\nThe tool was used to visualize the first dataset data, to determine the genes and pathways implicated in the occurrence of the disease. Then we compared the two datasets to determine the genes and pathways implicated in the disease progression.\n\n\nResults\n\nThe tool includes two pipelines, one to visualize the expression data from a single csv file, and the second to compare two datasets.\n\nThe dataset expression data are visualized in a volcano plot format, as represented in Figure 2.\n\nThe pipeline also determines the ontologies associated with the DEGs: (i) BP associated with upregulated genes; (ii) MF associated with upregulated genes; (iii) CC associated with upregulated genes; (iv) BP associated with downregulated genes; (v) MF associated with downregulated genes; and (vi) CC associated with downregulated genes. The top ontologies are represented in six barplots.\n\nThe second pipeline determines the genes with similar expression profiles in the two datasets and most importantly those with different profiles, which is useful to compare two cells, tissues, or diseases.\n\nIt also generates a table resuming the gene’s count, as represented in Table 1.\n\nThe tool is publicly available for all the o2S2PARC platform users. And the user guide Browser extension is available in the project repository (https://github.com/SPARC-FAIR-Codeathon/Transcriptomic_oSPARC).\n\n\nDiscussion and conclusion\n\nThere are multiple transcriptomic datasets available on the SPARC Portal,9 containing a wide range of species from humans, pigs, mice to rats; anatomical structures include neurons for multiple organs and physiological systems; analysis methods involve RNA sequencing, real-time PCR; small molecule FISH (RNAscope) probes, and multiple others. The SPARC portal datasets provide a wide variety of transcriptomic data, however, there is no automatic gene expression data processing or visualization tool on the SPARC system.\n\nTranscriptomics has been increasingly favored by researchers and clinicians in prioritizing specific systems and networks,2 finding biomarkers,10 developing precision medicine strategies,10 monitoring disease progressions, and predicting treatment effects.11\n\nThe tool is useful in helping transform the transcriptome data into visualizable DEGs and gene ontology (GO) analysis in a one-step standardized format. Nowadays, DEGs and GO are commonly utilized tools in detecting potential key pathways, molecules, and cells related to target tissues, organs, and diseases.10–13\n\nThe “Gene expression data visualization” tool represents a fast and easy online visualization tool, that does not require any coding skills, to identify the gene expression changes among any target objects, such as species, tissues, and diseases. The browser extension represents an easy and detailed guide for the whole procedure. Currently, the tool requires processed data files as input. Future versions could include the expression raw data analysis.",
"appendix": "Data availability\n\nNo data is associated with this article.\n\n\n\n• Software available from the o2SPARC platform: https://osparc.io\n\n• Source code available from: https://github.com/SPARC-FAIR-Codeathon/Transcriptomic_oSPARC\n\n• Archived source code at the time of publication: https://doi.org/10.5281/zenodo.7265589 14\n\n• License: MIT\n\n\nAcknowledgements\n\nThe authors thank the Stimulating Peripheral Activity to Relieve Conditions (SPARC) program and the National Institutes of Health (NIH) for their immense support during the SPARC FAIR codeathon.\n\n\nReferences\n\nChew P: Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis. Genes. 2019 Oct 12; 10(10): 798. PubMed Abstract | Publisher Full Text\n\nMroczek M, Desouky A, Sirry W: Imaging Transcriptomics in Neurodegenerative Diseases. J. Neuroimaging. 2021 Mar; 31(2): 244–250. Publisher Full Text\n\nthe o2S2PARC modeling and simulation platform:[cited 2022 Aug 10].Reference Source\n\nQuey R, Schiefer MA, Kiran A, et al.: KnowMore: an automated knowledge discovery tool for the FAIR SPARC datasets. F1000Res. 2021 Nov 9; 10: 1132. Publisher Full Text\n\nStimulating Peripheral Activity to Relieve Conditions: National Center for Advancing Translational Sciences.2016 [cited 2022 Aug 10].Reference Source\n\nBarrett T, Wilhite SE, Ledoux P, et al.: NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res. 2013 Jan; 41: D991–D995. PubMed Abstract | Publisher Full Text\n\nMelief J, Orre M, Bossers K, et al.: Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis. Acta Neuropathol. Commun. 2019 Apr 25; 7(1): 60. PubMed Abstract | Publisher Full Text\n\nHendrickx DAE, van Scheppingen J , van der Poel M , et al.: Gene Expression Profiling of Multiple Sclerosis Pathology Identifies Early Patterns of Demyelination Surrounding Chronic Active Lesions. Front. Immunol. 2017; 8: 1810. PubMed Abstract | Publisher Full Text\n\nSPARC Portal:[cited 2022 Aug 11].Reference Source\n\nZhang L, Chen D, Song D, et al.: Clinical and translational values of spatial transcriptomics. Sig. Transduct. Target Ther. 2022 Dec; 7(1): 111. PubMed Abstract | Publisher Full Text\n\nCartwright H, editor. Artificial Neural Networks. New York, NY:Springer US;2021 [cited 2022 Aug 12]; vol. 2190. . Methods in Molecular Biology. Publisher Full Text\n\nZhang L, Sun L, Zhang B, et al.: Identification of Differentially Expressed Genes (DEGs) Relevant to Prognosis of Ovarian Cancer by Use of Integrated Bioinformatics Analysis and Validation by Immunohistochemistry Assay. Med. Sci. Monit. 2019 Dec 24; 25: 9902–9912. PubMed Abstract | Publisher Full Text\n\nBardsley EN, Davis H, Ajijola OA, et al.: RNA Sequencing Reveals Novel Transcripts from Sympathetic Stellate Ganglia During Cardiac Sympathetic Hyperactivity. Sci. Rep. 2018 Dec; 8(1): 8633. PubMed Abstract | Publisher Full Text\n\nDing M, Aribi HB, Nickerson D, et al.: SPARC-FAIR-Codeathon/Transcriptomic_oSPARC: v1.0.0-beta (v1.0.0-beta). [Software]. Zenodo.2022. Publisher Full Text"
}
|
[
{
"id": "155907",
"date": "13 Dec 2022",
"name": "Joost B. M. Wagenaar",
"expertise": [
"Reviewer Expertise Data management",
"timeseries analysis",
"fair-sharing"
],
"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 this article, the authors describe a tool that runs on a platform called O2S2PARC. This tool allows users to visualize gene expression data using some standardized interactive approach. The authors mention that this tool could make it easier for investigators to analyze data in a one-step approach. The authors mention that the tool currently requires processed data files, but that this tool can be expanded to use raw data.\nI am having a bit trouble understanding the need for this tool or some of the platforms and workflows it describes. It would be helpful for the authors to describe the SPARC platform, and the O2S2PARC platform in a bit more detail and explain how they are related to the python jupyter notebooks that were used to run the analysis.\n\nFigure 1 shows an example of a barplot but it doesn't mention how this plot was generated or how users should interpret the data although this might not be a real concern as the focus of the manuscript is on the tool itself.\nIt is a bit unclear what the browser extension that is described in the article does or where it is available. The authors do provide access to a Github repository which has more extensive documentation on how to use the tool.\n\nOverall, I think there could be a bit more information in the article to detail more specifically how the tool interacts with the other platforms that were mentioned and what problem it solves. The authors conclude that there is a need for better tools for visualizing DEGs and GO analysis and it is clear that this tool is a step in that direction.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Partly\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? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "9236",
"date": "06 Feb 2023",
"name": "Jessica Ding",
"role": "Author Response",
"response": "We are grateful for the advice and questions raised by reviewer 1. Here are our revisions and replies for each point s/he had made. 1. I am having a bit trouble understanding the need for this tool or some of the platforms and workflows it describes. It would be helpful for the authors to describe the SPARC platform, and the O2S2PARC platform in a bit more detail and explain how they are related to the python jupyter notebooks that were used to run the analysis. Reply: We thank the reviewer for pointing this out. We have added details on SPARC platform and the O2S2PARC platform in the introduction section (second and third paragraphs). The use of the python jupyter notebooks is explained in the “Methods” section under the “Operation” subtitle (first paragraph). Changes are made as follows: “This study was performed during the Stimulating Peripheral Activity to Relieve Conditions (SPARC) FAIR Codeathon in August 2022 organized by the National Institute of Health (NIH) SPARC program15. The SPARC program was initiated to advance the understanding of nerve-organ interactions and to expedite the invention of therapeutic medicine and devices that modulate electrical activity in nerves to promote organ function. It runs under the FAIR data sharing policy (consists of the principle of Findable, Accessible, Interoperable, and Reusable), according to the SPARC Data Structure (SDS). Currently, there are multiple transcriptomic datasets available on the SPARC Portal9, containing a wide range of species from humans, pigs, mice to rats; anatomical structures include neurons for multiple organs and physiological systems; analysis methods involve RNA sequencing, real-time PCR; small molecule FISH (RNAscope) probes, and multiple others. The expression data visualization tool was initially created to visualize the transcriptomics data on the SPARC Portal platform, and was created and published via the o²S²PARC (Open Online Simulations for Stimulating Peripheral Activity to Relieve Conditions) platform, a simulation and analysis platform aiming to initially perform interactive peripheral nerve system neuromodulation/stimulations and to visualize its physiological impact on organs3. The o²S²PARC platform provides simulations in animal/human anatomical models with emulational organ and tissue-specific properties in the permission of conducting experiments from molecules to a body level3.” “We used the Jupyterlab, as recommended by the o²S²PARC platform, because it provides interactive exploration, along with the possibility of providing guidance and instructions in line with scripted analyses.” 2. Figure 1 shows an example of a barplot but it doesn't mention how this plot was generated or how users should interpret the data although this might not be a real concern as the focus of the manuscript is on the tool itself. Reply: We thank the reviewer for pointing this out. Indeed, the ontology analysis and result visualization, in barplots, are performed using the Goatools Python package. The methodology to generate the barplot and how it should be interpreted are described in “Methods” - “Operation” section paragraph 2 (“The DEGs are represented in a volcano plot generated using the visuz.GeneExpression.volcano() function from the bioinfokit Python package.”) and in the “Results” section paragraph 3 (“The y-axis corresponds to the statistically significant ontology names. Also, the x-axis represents the percentage of the genes associated with the ontology per total genes (upregulated or downregulated).”) respectively. 3. It is a bit unclear what the browser extension that is described in the article does or where it is available. The authors do provide access to a GitHub repository which has more extensive documentation on how to use the tool. Reply: We thank the reviewer for pointing this out. A brief introduction about the extension was added in the “Methods” - “User guide extension” section. Indeed, the browser extension serves as a user guide, from downloading the dataset from the SPARC portal to using the tool on the o2S2PARC platform and analyzing the data. The changes are made as follows: “The extension code could be downloaded from the project GitHub repository and the extension could be installed using the developer mode on any browser. The steps from downloading the code to using the extension are provided in the GitHub repository: https://github.com/SPARC-FAIR-Codeathon/Transcriptomic_oSPARC/blob/main/Install%20the%20extension/README.md.” 4. Overall, I think there could be a bit more information in the article to detail more specifically how the tool interacts with the other platforms that were mentioned and what problem it solves. Reply: We thank the reviewer for pointing this out. We explained the functions and roles it plays in the \"Discussion\" section by the following: \"The tool is build-in/hosted on the o²S²PARC platform. No direct bridge leading the tool from the SPARC portal platform currently exists. The browser extension plays an intermediate role in guiding the users from the SPARC portal toward the tool on the o²S²PARC platform, which is also available on GitHub. Our work enhances the usability of the transcriptomics data on the SPARC portal by providing a specific data analysis and visualization tool that does not require any coding skills, to identify the gene expression changes among any target objects, such as species, tissues, and diseases. It also represents an example of how to use and contribute to the development of the o2S2PARC platform.\" It is also reusable for future transcriptomic analysis on other platforms and portals."
}
]
},
{
"id": "155905",
"date": "21 Dec 2022",
"name": "Esra Neufeld",
"expertise": [
"Reviewer Expertise Computational Life Sciences",
"EM-tissue interactions",
"Computational Modeling"
],
"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 paper discusses a series of workflows established to analyze genetic expression data. They integrate different tools to produce intuitive visualization, help with interpretation, and provide basic statistics. The workflows are made available through an open, online platform (o2S2PARC) established as part of the NIH SPARC Program, which has also generated and published corresponding gene expression data. A particular aspect of interest concerns the platform and technologies used to support the creation, sharing, publication, and execution of such workflows.\nThe paper is kept short, but provides relevant illustrations and information. This reviewer is not sufficiently knowledgeable to provide qualified feedback on the innovativeness and adequacy of the selected data analysis methodology, but will focus on the implementation and innovative aspects thereof.\nIn general, seeing that the form of producing and sharing such an openly accessible workflow was far from standard – it involved a hackathon and the use of a novel and open platform for collaboratively establishing FAIR, sustainable, and reproducible computational modeling and data analysis – it would be desirable to provide more information about that process and its benefits/weaknesses/potential.\nMinor feedback:\nAbstract:\n“In this study, we developed an o²S²PARC template representing an interactive pipeline for the gene expression data visualization and ontologies data analysis and visualization.” -> “In this study, we developed an o²S²PARC template to instantiate an interactive pipeline for gene expression data visualization, ontological mapping, statistical evaluation.”\n\n“The ontologies associated with the DEGs are determined” -> “Ontologies associated with the DEGs are assigned”\n\nIntroduction:\n“and much more” -> “and many more”\n\n“We developed a gene expression data visualization tool created and published on the o2S2PARC, Open Online Simulations for Stimulating Peripheral Activity to Relieve Conditions platform, a simulation and analysis platform aiming to initially perform interactive peripheral nerve system neuromodulation/stimulations and to visualize its physiological impact on organs.” -> “We developed a gene expression data visualization tool and published it on the o2S2PARC, Open Online Simulations for Stimulating Peripheral Activity to Relieve Conditions, platform – a simulation and analysis platform designed to study peripheral nerve system neuromodulation/stimulations and its physiological impact on organs.”\n\n“However, the platform currently hosts […], but does not” -> “While the platform currently hosts […], it does not”\n\nMention already in the introduction that SPARC has generated and published gene expression data (not only in the discussion).\n\n“open-accessible” -> “open-access” or “openly accessible”\n\n“across multiple scales” -> “across multiple dimensions”\n\nSPARC is mentioned repeatedly, before introducing it. Move that SPARC introduction sentence up.\n\n“to expedite the invention of therapeutic medicine and devices” -> “to expedite the development of innovative therapies and devices”\n\n“runs under” -> “has adopted”\n\n“consists of the principles of Findabile, Accessibile, Interoperabile, and Reusabile” -> “encompasses the principles of Findability, Accessibility, Interoperability, and Reusability”\n\nImplementation\n“template in the” -> “template on the”\n\n“on all” -> “on all common”\n\n“It requires” -> “The tool makes use of”\n\n“All the requirements are integrated within the tool” -> “The required runtime environment is bundled along with the tool”\n\nOperation\nExplain why JupyterLab is used (it provides interactive exploration, along with the possibility of providing guidance and instructions in line with scripted analyses)\n\n“The first pipeline identifies the DEGs based on the p-value, set to p-value < 0.05 as default,“ -> “The first pipeline identifies the DEGs based on statistically determined p-values (by default, a threshold of 5% is applied to determine significance)”\n\n“the LogFC” -> “LogFC”; twice; and introduce that abbreviation (log-fold change on a basis of 2, I assume)\n\n“in six similar separate” -> rephrase and provide more detail\n\n“genes-related” -> “gene-related”\n\n“as input if the transcriptomics data correspond to other species” -> “as input, if the transcriptomics data relates to other species”; or “pertains”\n\n“The second pipeline takes two CSV files as input.” What are these two CSV files? Two datasets for which the gene expression is to be compared?\n\n“The gene’s expression profile is determined, as in the first pipeline, for the two datasets.” -> “The gene’s expression profiles are determined, as in the first pipeline, for the two datasets.”\n\n“The common and uncommon genes count is performed.” Please, rephrase.\n\n“And the gene expression profiles in the two datasets are compiled in a single csv file for further analysis.” -> “Finally, the gene expression profiles in the two datasets are compiled in a single csv file for further analysis.” Is this file only a merged version of the original data, or does it include results of the analysis?\n\n“as a user guide” -> “to guide users”\n\n“for the new” -> “for new”\n\n“It guides the user step by step from downloading transcriptomics data from the SPARC portal database, providing a raw data analysis workflow, and explaining the “Gene expression data visualization” tool.” -> “It guides the user step-by-step from the download of transcriptomics data from the SPARC portal database, through a raw-data analysis workflow, to the explanation of the “Gene expression data visualization” tool.”\n\nResults\nAre the results of the application to the multiple sclerosis data new/insightful? How are they to be interpreted?\n\nWhat are the “top ontologies”?\n\n“useful to compare” -> “useful for the comparison of”\n\n“resuming” -> “summarizing”\n\n“in the project repository” -> “in a project repository”\n\nDiscussion and conclusion\n“analysis methods involve” -> “analysis methods include”\n\nIs “favored” the right word?\n\n“and gene ontology (GO) analysis” -> “and gene ontology (GO) analyses”\n\n“standardized format” -> “standardized process and form”\n\n“changes among any target objects, such as species, tissues, and diseases” -> “differences between species, healthy or diseased population groups, individual subjects, and tissues”\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Partly\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? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "9242",
"date": "06 Feb 2023",
"name": "Jessica Ding",
"role": "Author Response",
"response": "We here represent our sincere gratitude toward the reviewer’s advice and corrections. Our replies and amendments were made point-by-point according to the review’s proposals. 1. In general, seeing that the form of producing and sharing such an openly accessible workflow was far from standard – it involved a hackathon and the use of a novel and open platform for collaboratively establishing FAIR, sustainable, and reproducible computational modeling and data analysis – it would be desirable to provide more information about that process and its benefits/weaknesses/potential. Reply: We thank the reviewer for pointing this out. In the “Introduction” section, we mentioned that the work was performed during a hackathon (“This study was performed during the Stimulating Peripheral Activity to Relieve Conditions (SPARC) FAIR Codeathon in August 2022 organized by the National Institute of Health (NIH) SPARC program\"). The hosting platforms were also introduced in the following 2 paragraphs. In the “Discussion” section ( last section), we discussed the benefits, weaknesses, and potentials of the tool in the last four paragraphs of the paper. 2. Minor feedback: Abstract: “In this study, we developed an o²S²PARC template representing an interactive pipeline for the gene expression data visualization and ontologies data analysis and visualization.” -> “In this study, we developed an o²S²PARC template to instantiate an interactive pipeline for gene expression data visualization, ontological mapping, and statistical evaluation.” Reply: We thank the reviewer for pointing this out. We have made the changes accordingly. “The ontologies associated with the DEGs are determined” -> “Ontologies associated with the DEGs are assigned”. Reply: We thank the reviewer for pointing this out. We have made the changes accordingly. Introduction: “and much more” -> “and many more” Reply: We thank the reviewer for pointing this out. We have made the changes accordingly. “We developed a gene expression data visualization tool created and published on the o2S2PARC, Open Online Simulations for Stimulating Peripheral Activity to Relieve Conditions platform, a simulation and analysis platform aiming to initially perform interactive peripheral nerve system neuromodulation/stimulations and to visualize its physiological impact on organs.” -> “We developed a gene expression data visualization tool and published it on the o2S2PARC, Open Online Simulations for Stimulating Peripheral Activity to Relieve Conditions, platform – a simulation and analysis platform designed to study peripheral nerve system neuromodulation/stimulations and its physiological impact on organs.” Reply: We thank the reviewer for pointing this out. We made the following changes: “We developed a gene expression data visualization tool to visualize the transcriptomics data on the SPARC Portal platform and created and published it on the o²S²PARC, Open Online Simulations for Stimulating Peripheral Activity to Relieve Conditions, platform – a simulation and analysis platform designed to study peripheral nerve system neuromodulation/stimulations and its physiological impact on organs.” “However, the platform currently hosts […], but does not” -> “While the platform currently hosts […], it does not” Reply: We thank the reviewer for pointing this out. We made the following changes: “While the platform currently hosts tools for multiple biological and physiological analyses, it does not provide a tool for transcriptomics and gene expression data analysis or visualization.” Mention already in the introduction that SPARC has generated and published gene expression data (not only in the discussion). Reply: We thank the reviewer for pointing this out. We made the changes by putting emphasis on introducing the SPARC in the “Introduction” section. “open-accessible” -> “open-access” or “openly accessible” Reply: We thank the reviewer for pointing out this error. We have made the changes. “across multiple scales” -> “across multiple dimensions” Reply: We thank the reviewer for pointing out this error. We have made the changes so the error no longer exists. SPARC is mentioned repeatedly, before introducing it. Move that SPARC introduction sentence up. Reply: We thank the reviewer for pointing this out. We have moved the SPARC introduction sentence up to the “Introduction” section- paragraph 2. “to expedite the invention of therapeutic medicine and devices” -> “to expedite the development of innovative therapies and devices” Reply: Thank you and we have made the changes accordingly. “runs under” -> “has adopted” Reply: Thank you and we have made the changes accordingly. “consists of the principles of Findabile, Accessibile, Interoperabile, and Reusabile” -> “encompasses the principles of Findability, Accessibility, Interoperability, and Reusability” Reply: Thank you and we have made the changes accordingly. Implementation “template in the” -> “template on the” Reply: Thank you and we have made the changes accordingly. “on all” -> “on all common” Reply: Thank you and we have made the changes accordingly. “It requires” -> “The tool makes use of” Reply: Thank you and we have made the changes accordingly. “All the requirements are integrated within the tool” -> “The required runtime environment is bundled along with the tool” Reply: Thank you and we have made the changes accordingly. Operation Explain why JupyterLab is used (it provides interactive exploration, along with the possibility of providing guidance and instructions in line with scripted analyses) Reply: We thank the reviewer for pointing this out. The reason for using jupyterLab was defined in the “Methods”- “Operation” section (first paragraph). We made the following changes: “We used Jupyterlab, as recommended by the o²S²PARC platform, because it provides interactive exploration, along with the possibility of providing guidance and instructions in line with scripted analyses. ” “The first pipeline identifies the DEGs based on the p-value, set to p-value < 0.05 as default,” -> “The first pipeline identifies the DEGs based on statistically determined p-values (by default, a threshold of 5% is applied to determine significance)” Reply: Thank you and we have made the changes accordingly. “the LogFC” -> “LogFC”; twice; and introduce that abbreviation (log-fold change on a basis of 2, I assume) Reply: Thank you and we have made the changes accordingly. “in six similar separate” -> rephrase and provide more detail Reply: We thank the reviewer for pointing this out. The information was clarified in the “Methods”- “Operation” section, as follows: “The pipeline also performs the ontology analysis for the differentially expressed genes, to determine the cellular components, biological processes, and molecular functions associated with these genes.“...“The biological processes, molecular functions, and cellular component ontologies are represented in separate Barplots, as in Figure 1. In total six barplots are created, three upregulated genes and three downregulated genes. “genes-related” -> “gene-related” Reply: Thank you and we have made the changes accordingly. “as input if the transcriptomics data correspond to other species” -> “as input, if the transcriptomics data relates to other species”; or “pertains” Reply: Thank you and we have made the changes accordingly. “The second pipeline takes two CSV files as input.” What are these two CSV files? Two datasets for which the gene expression is to be compared? Reply: We thank the reviewer for pointing this out. The required CSV files are specified in the “Methods”- “Operation” as follows: “The second pipeline takes two CSV files as input. The CSV files correspond to gene expression data of a different dataset, to be further compared. Example data files are available in the project GitHub repository.” “The gene’s expression profile is determined, as in the first pipeline, for the two datasets.” -> “The gene’s expression profiles are determined, as in the first pipeline, for the two datasets.” Reply: We thank the reviewer for pointing this out. We made the following changes: “As in the first pipeline, the gene’s expression profiles and the DEGs are determined for the two datasets, separately.” “The common and uncommon genes count is performed.” Please, rephrase. Reply: We thank the reviewer for this advice. We made the following changes: “Then, we identified the common genes between the two datasets and those specific genes to one dataset.” “And the gene expression profiles in the two datasets are compiled in a single csv file for further analysis.” -> “Finally, the gene expression profiles in the two datasets are compiled in a single csv file for further analysis.” Is this file only a merged version of the original data, or does it include the results of the analysis? Reply: We thank the reviewer for this advice. We have made the changes as follows: “Finally, the gene expression profiles in the two datasets are compiled in a single CSV file for further analysis, which includes the expression analysis result of the two combined datasets.” “as a user guide” -> “to guide users” Reply: We thank the reviewer for this advice and we have made the changes accordingly. “for the new” -> “for new” Reply: We thank the reviewer for this advice. We have made the changes accordingly. “It guides the user step by step from downloading transcriptomics data from the SPARC portal database, providing a raw data analysis workflow, and explaining the “Gene expression data visualization” tool.” -> “It guides the user step-by-step from the download of transcriptomics data from the SPARC portal database, through a raw-data analysis workflow, to the explanation of the “Gene expression data visualization” tool.” Reply: We thank the reviewer for this advice. We have made the changes as follows: “It guides the user step-by-step from downloading transcriptomics data from the SPARC portal database, through a raw-data analysis workflow, to explaining the “Gene expression data visualization” tool.” Results Are the results of the application to the multiple sclerosis data new/insightful? How are they to be interpreted? Reply: We thank the reviewer for pointing this out. The data analysis was performed for the unique purpose of validating the pipeline. The datasets are publicly available and thus possibly studied by other researchers. However, to our knowledge, no others studies have compared these two datasets for the same purpose of studying the genes and ontologies implicated in multiple sclerosis disease progression. The results are available as supplementary materials on the project GitHub repository (https://github.com/SPARC-FAIR-Codeathon/Transcriptomic_oSPARC/tree/main/pipeline%20validation). But no interpretation was performed since our article focuses on presenting the tool, and we made the clarification as follows: “Pipeline validation: The data analysis was performed for the unique purpose of validating the pipeline. The data and analysis results are available as supplementary materials on the project's GitHub repository. However, no interpretation was performed since our article focuses on presenting the tool.” What are the “top ontologies”? Reply: We apologize for this error and it was replaced by “statistically significant ontologies”. “useful to compare” -> “useful for the comparison of” Reply: Thank you for pointing out this error. We have made the changes accordingly. “resuming” -> “summarizing” Reply: Thank you for pointing out this error. We have made the changes accordingly. “in the project repository” -> “in a project repository” Reply: Thank you for pointing out this error. We have made the changes accordingly. Discussion and conclusion “analysis methods involve” -> “analysis methods include” Reply: Thank you for your suggestion. We have made the changes accordingly. This sentence has been moved to the second paragraph of the “Introduction”. Is “favored” the right word? Reply: Thank you for your suggestion. We have changed the word to “utilized” accordingly. “and gene ontology (GO) analysis” -> “and gene ontology (GO) analyses” Reply: Thank you for your suggestion. We have made the change accordingly. “standardized format” -> “standardized process and form” Reply: Thank you for your suggestion. We have made the change accordingly. “changes among any target objects, such as species, tissues, and diseases” -> “differences between species, healthy or diseased population groups, individual subjects, and tissues” Reply: Thank you for your suggestion. We have made the change accordingly."
}
]
}
] | 1
|
https://f1000research.com/articles/11-1267
|
https://f1000research.com/articles/12-139/v1
|
06 Feb 23
|
{
"type": "Research Article",
"title": "Anthropometric indicators for obesity and its relationship with depressive symptoms: analysis of a Peruvian national survey",
"authors": [
"Victor Juan Vera-Ponce",
"Jenny Raquel Torres-Malca",
"Jamee Guerra Valencia",
"Rubén Espinoza Rojas",
"Fiorella E. Zuzunaga-Montoya",
"Gianella Zulema Zeñas-Trujillo",
"Liliana Cruz-Ausejo",
"Jhony A. De La Cruz-Vargas",
"Jenny Raquel Torres-Malca",
"Jamee Guerra Valencia",
"Rubén Espinoza Rojas",
"Fiorella E. Zuzunaga-Montoya",
"Gianella Zulema Zeñas-Trujillo",
"Liliana Cruz-Ausejo",
"Jhony A. De La Cruz-Vargas"
],
"abstract": "Background: The association between obesity and depression has been frequently reported. However, it still remains unclear which anthropometric indicators for obesity could be the best measure to explain its linkage with depressive symptoms. Methods: This is a cross-sectional analytical study. Secondary data was analyzed using information from the Demographic and Health Survey of Peru (ENDES in Spanish). Data from the years 2018 to 2021 were reviewed. The outcome of interest was the presence of depressive symptoms, assessed with the Patient Health Questionnaire-9 (PHQ-9). The exposure variable was the presence of obesity, which was evaluated by body mass index (BMI) and abdominal circumference. Crude and adjusted odds ratios (cOR and aOR) were calculated using logistic regression. Both prevalence and association measures were presented with 95% confidence intervals (95% CI). Results: A total of 141,134 subjects were included in the study. Depression was present in 2.51% (95% CI 2.38–2.65). Obesity according to BMI was present in 25.42% (95% CI 24.97–25.88), while abdominal obesity was shown in 41.67% (95% CI 41.19–42.15). In the multivariate analysis, a statistically significant association was found in regard to symptoms of depression in patients with abdominal obesity (aOR: 1.13; 95% CI 1.03–1.24), while no association was found with obesity according to BMI. Conclusions: Abdominal circumference could be a better anthropometric measure than BMI to evaluate the association between obesity and depressive symptoms in the Peruvian population.",
"keywords": [
"obesity",
"depression",
"association",
"body mass index",
"abdominal circumference"
],
"content": "Introduction\n\nDepressive disorder is one of the main causes of disease burden worldwide.1 Depression is estimated to affect around 350 million people globally.2 Furthermore, this is projected to be the largest contributor to the disease burden by 2030, according to the World Health Organization (WHO).3\n\nIn addition to this, the relationship between obesity and depression has been frequently studied in the scientific literature, although how this relationship works is still not fully understood. Some previous studies suggest this mental issue is more common among people with obesity, particularly women, but in contrast, there is some evidence linking obesity with lower levels of depressive symptoms.4,5\n\nMany studies looking for the correlation between both characteristics have used the body mass index (BMI) as a prognostic index of fat accumulation; however, it is known that it has some limitations for indicating how it is distributed throughout the body.6 Therefore, some researchers consider other indicators of obesity, particularly abdominal circumference (AC), to be better indicators of many diseases, including depression.7\n\nEven though the relationship between central obesity and depressive symptoms has been reported,7 the evidence among adults is still scarce. For this reason, examining this anthropometric marker and its role in predicting or indicating depressive symptoms, compared to BMI, could help to clarify the association mechanism between obesity and symptoms of depression in adults.\n\nConsequently, we aimed to explore which obesity anthropometric indicator is more useful for the association between obesity and depression in the Peruvian population.\n\n\nMethods\n\nWe undertook a cross-sectional analytical study. Secondary data were taken from the Demographic and Health Survey of Peru (ENDES, in Spanish), anually executed by Instituto Nacional de Estadística e Informática-Peru (freely available in: https://iinei.inei.gob.pe/microdatos/) covering the years 2018 to 2021, and analyzed. The STROBE guidelines (Strengthening the Reporting of Observational Studies in Epidemiology) were followed for the present study.8\n\nThe ENDES is a nationally representative survey with a two-stage sampling design (Instituto Nacional de Estadística e Informática, 2015). The sample was characterized by being probabilistic of a balanced, stratified, and independent type, at the departmental level and in urban and rural areas. For our research, only the data of the respondents of both sexes and that had the main variables of interest were analyzed.\n\nThe outcome of interest was the presence of depressive symptoms, which was assessed with the Patient Health Questionnaire-9 (PHQ-9) in the Peruvian survey. The questionnaire consists of nine items formulated to assess and monitor the severity of depression for patients in primary care and other environments. It was designed to be self-administered, and collects information on depressive symptoms over the course of the previous 2 weeks. Each item has a score ranging from 0 to 3, with a total maximum of 27 points.9,10 Individuals with a score of 15 or more are considered to have depression.10 The PHQ-9 was previously validated in the Peruvian population11 and its psychometric properties have been recognized as adequate for different population groups.12\n\nThe exposure variable was the presence of obesity, which was assessed by BMI and AC. Anthropometric measurements (weight, height) of all participants were evaluated by trained personnel following standardized techniques based on the WHO and the Instituto Nacional de Salud from Peru.13 Obesity according to BMI was defined with a cut-off point of BMI ≥ 30 kg/m2, while abdominal obesity was defined if there was AC ≥ 104 cm in men and ≥ 88 cm in women, measurements recommended by the Adult Treatment Panel III (CA-ATP-III).\n\nThe factors evaluated were gender (man vs. woman); categorized age (15-34, 35-60, 61-69, and ≥70 years); educational level (primary, secondary and higher); the wealth index (poor, medium, rich and richest), the natural region (Metropolitan Lima, rest of the coast, Andean and jungle), daily tobacco use (yes vs no), physical disability (yes vs no), the self-reported alcohol consumption in the previous 12 months (yes vs no), history of hypertension (yes vs no) and Diabetes Mellitus type 2 (DM2) (yes vs no).\n\nWe used STATA 17 software for analysis and the prevalence of depressive and obesity symptoms was estimated. Bivariate analysis through a Chi-square test was used to analyze each possible factor associated with depression. Finally, the crude and adjusted odds ratio (cOR and aOR respectively) were calculated using logistic regression. Each marker was independently adjusted for sex, categorized age, natural region, educational level, wealth index, daily smoking, alcohol consumption, physical disability, history of hypertension, and history of DM2.\n\nAll analyses were performed considering complex samples. It was considered statistically significant if the p value was <0.05. Both prevalence and association measures were presented with 95% confidence intervals.\n\nThis study was developed with an analysis of survey data sets that are openly published and available online (at http://iinei.inei.gob.pe/microdatos/). In the ENDES survey, run by trained interviewers, informed consent was obtained from all participants. Additionally, in order to ensure data privacy, the responses were anonymized through coding.\n\n\nResults\n\nA total of 141,134 subjects were included in the study. The female sex represented 48.40%; 8.07% were 70 years of age or older. The prevalence of hypertension and DM2 was 9.85% and 4.18%, respectively. See Table 1.\n\nDepression was present in 3,544 individuals (2.51%; 95% CI 2.38–2.65). Obesity according to BMI occurred in 29,923 subjects (25.42%; 95% CI 24.97–25.88), while abdominal obesity was seen in 52,839 people (41.67%; 95% CI 41.19–42.15). See Table 2.\n\n* Analysis performed with the chi square of independence.\n\nThe analysis in Table 2, shows a statistically significant association between depressive symptoms and most of the sociodemographic, health-related and habits variables, except in the case of daily smoking (p=0.812).\n\nIn the multivariable analysis, a statistically significant association was found to connect signs of depression in patients with abdominal obesity (aOR: 1.13; 95% CI 1.03–1.24), while no association was found with obesity according to BMI. See Table 3.\n\n* Each marker has been adjusted independently by sex, categorized age, natural region, educational level, wealth index, daily smoking, alcohol consumption in the last 12 months, physical disability, history of hypertension, and history of DM2.\n\n** Significant p-value <0.05.\n\n\nDiscussion\n\nIn the present study, no significant correlation was found between obesity measured by BMI and depressive symptoms. BMI is a regular and easy tool for the assessment of excess adiposity, but it has restrictions, that include the inability to distinguish between adipose tissue distribution and lean body mass14 and also, there are significant differences in the performance of BMI between ethnic groups.15,16 These limitations may be greater in men due to their greater muscle mass compared to women. This may explain the fact that several studies have reported that BMI is an important predictor of depressive symptoms in women but no in men,17,18 although when the studies are carried out prospectively, the BMI is related to depression.19 According to our findings, Guedes et al.20 suggested that particularly, the body fat percentage and not BMI was related to a greater severity of depressive symptoms.\n\nHowever, other studies that only included BMI as an anthropometric variable reported an association between BMI and depressive symptoms, such as the study by De Godín et al.,21 which documented that a high BMI is considered a risk factor for manifestation of depressive symptoms among older adult subjects in France, compared to normal BMI. Furthermore, Sachs-Ericsson et al.22 reported that BMI was a predictor of depression in old age, and that its effect was stronger in African-Americans than in the white population, regardless of sex. However, differences have also been found in relation to sex, since Anderson et al.23 carried out a prospective longitudinal study to evaluate the association between depression and weight variation in a study carried out from the early years to adulthood, and found out that depression was associated with elevated BMI in women but not in men. Similarly, the systematic review by Luppino et al.19 showed that obesity defined by BMI was related to a major risk of depression in American subjects compared to Europeans, and being overweight was associated with a higher risk of depression in adult populations but not in young ones. Another aspect to consider is that the association between BMI and depression varies depending on the different subtypes of depression, as reported in a recent meta-analysis.5 The differences found between the different studies can be explained by the methodological variation, including population, follow-up, cut-off point in diagnostic tools, and criteria for obesity and depression.\n\nThe evidence seems to indicate that some anthropometric markers have a better explanatory value in regard the association between obesity and depression. An example of this is the study by Zhao et al., which found that abdominal obesity among obese and overweight people was strongly associated with an increase in depressive symptoms.24 Likewise, other works such as that of Hadi et al.,25 in which different anthropometric indicators of obesity were studied, concluded that those related to abdominal adiposity have a better association with depression, compared to BMI. On the other hand, Lee et al. reported that depressed mood in overweight premenopausal women is associated with visceral fat, but not subcutaneous fat.26 The follow-up study by Herva et al.27 argued that in both men and women, abdominal obesity may be closely associated with depression.\n\nA Swiss cohort study by Lasserre et al.28 reported that depressive disorder was an important risk factor for obesity as AC increased in both sexes. Ma and Xiao29 reported that higher waist circumference was associated with depression, regardless of BMI. While Williams et al.30 found out that women with antecedents of depressive issues tended to have higher BMI, weight, waist circumference, and body fat than those without antecedents of mental issues.\n\nAbdominal adipose tissue induces the activation of the immune system, the release of regulatory molecules and citokines that, in turn, unchain inflammatory signaling pathways.31,32 Symptoms of depression can be aggravated by systemic inflammation, so it is relevant to focus on central adiposity when discussing the association between obesity and depression.33 In addition, some mechanisms have been suggested for the linkage between obesity and depression, which includes the hypothalamic-pituitary-adrenocortical axis dysregulation resulting from reduced glucocorticoid receptors and excessive cortisol secretion.34\n\nAmong the limitations of this study, it is important to mention two. First, due to the cross-sectional nature of this work, we were unable to determine the direction of causality between anthropometric measures and depressive symptoms. Secondly, it is not possible to talk about the diagnosis of depression itself, since what was assessed was the presence of depressive symptoms. Likewise, subtypes of depression could not be established.\n\nDespite the limitations, this study has the strength of having benefited from a nationally representative sample, as well as from the methodology used to obtain it. Finally, we emphasize that the present study gives us a first impression about the importance of appropriately selecting the anthropometric marker of obesity used to assess its association with depressive symptoms among the Peruvian population.\n\n\nConclusions\n\nAC could be a better anthropometric marker, compared to BMI, for assessing the relationship between abdominal obesity and depression in the Peruvian population. The steadily rises in worldwide prevalence of overweight and obesity points out that mental health issues should be examined and surveilled in obese subjects, especially those with central obesity.\n\n\nAuthors’ contributions\n\nVíctor Juan Vera-Ponce, Jenny Raquel Torres-Malca, Jamee Guerra Valencia, Rubén Espinoza Rojas, Fiorella E. Zuzunaga-Montoya, Gianella Zulema Zeñas-Trujillo, Liliana Cruz-Ausejo and Jhony A. De La Cruz-Vargas participated in conceptualization, data curation, formal analysis, investigation, methodology, supervision, validation and visualization, as well as the writing of the original draft and the manuscript review & editing.",
"appendix": "Data availability\n\nNo primary data are associated with this article.\n\nThe secondary data used for this research, taken from the Demographic and Health Survey of Peru (ENDES), are freely available from the Peruvian National Institute of Statistics and Information (INEI). In addition, dataset and codes are available at: https://data.mendeley.com/datasets/4rjb88t4mc, and INEI link at: https://iinei.inei.gob.pe/microdatos/.\n\n\nReferences\n\nFerrari AJ, Charlson FJ, Norman RE, et al.: Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013; 10(11): e1001547. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFriedrich MJ: Depression is the leading cause of disability around the world. JAMA. 2017; 317(15): 1517. Publisher Full Text\n\nWorld Health Organization: The global burden of disease: 2004 update.2008; 146.\n\nBaldini I, Casagrande BP, Estadella D: Depression and obesity among females, are sex specificities considered? Arch. Womens Ment. Health. 2021; 24(6): 851–866. PubMed Abstract | Publisher Full Text\n\nSilva DA, Coutinho E d SF, Ferriani LO, et al.: Depression subtypes and obesity in adults: A systematic review and meta-analysis. Obes. Rev. 2020; 21(3): e12966. PubMed Abstract | Publisher Full Text\n\nVanderwall C, Eickhoff J, Randall Clark R, et al.: BMI z-score in obese children is a poor predictor of adiposity changes over time. BMC Pediatr. 2018; 18(1): 187. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEsmaeilzadeh S, Farzizadeh R, Kalantari H-A, et al.: Central or overall obesity: Which one is a better predictor of depressive symptoms in children, adolescents, and youths? Eat. Weight Disord. 2018; 23(1): 117–123. Publisher Full Text\n\nvon Elm E , Altman D, Egger M, et al.: Declaración de la Iniciativa STROBE (Strengthening the Reporting of Observational studies in Epidemiology): directrices para la comunicación de estudios observacionales.2008; 22(2): 144–150.Reference Source\n\nReview T: Patient Health Questionnaire–9 (PHQ-9). Rehabilitation Counseling Bulletin. 2014; 57(4): 246–248. Publisher Full Text\n\nKroenke K, Spitzer RL, Williams JB: The PHQ-9: Validity of a brief depression severity measure. J. Gen. Intern. Med. 2001; 16(9): 606–613. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCalderón M, Gálvez-Buccollini JA, Cueva G, et al.: Validación de la versión peruana del PHQ-9 para el diagnóstico de depresión. Rev. Peru. Med. Exp. Salud Publica. 2012; 29(4): 578–578, 579. PubMed Abstract | Publisher Full Text\n\nAlvarez EAC, Virú-Flores H, Alburqueque-Melgarejo J, et al.: Validación del cuestionario sobre la salud del paciente-9 (PHQ-9) en internos de medicina humana de una universidad de referencia del Perú durante la pandemia COVID-19. Rev. Fac. Med. Hum. 2022; 22(3): 540–546. Publisher Full Text\n\nCampos-Sánchez M, Ricaldi-Sueldo R, Miranda-Cuadros M: Diseño del Monitoreo Nacional de Indicadores Nutricionales (MONIN), Perú 2007-2010. Rev. Peru. Med. Exp. Salud Publica. 2011; 28(2): 210–221. PubMed Abstract | Publisher Full Text\n\nJayedi A, Rashidy-Pour A, Khorshidi M, et al.: Body mass index, abdominal adiposity, weight gain and risk of developing hypertension: A systematic review and dose–response meta-analysis of more than 2.3 million participants. Obes. Rev. 2018; 19(5): 654–667. PubMed Abstract | Publisher Full Text\n\nJaved A, Jumean M, Murad MH, et al.: Diagnostic performance of body mass index to identify obesity as defined by body adiposity in children and adolescents: A systematic review and meta-analysis. Pediatr. Obes. 2015; 10(3): 234–244. PubMed Abstract | Publisher Full Text\n\nWHO Expert Consultation: Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004; 363(9403): 157–163. PubMed Abstract | Publisher Full Text\n\nWild B, Herzog W, Lechner S, et al.: Gender specific temporal and cross-sectional associations between BMI-class and symptoms of depression in the elderly. J. Psychosom. Res. 2012; 72(5): 376–382. PubMed Abstract | Publisher Full Text\n\nLim W, Thomas KS, Bardwell WA, et al.: Which measures of obesity are related to depressive symptoms and in whom? Psychosomatics. 2008; 49(1): 23–28. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLuppino FS, de Wit LM , Bouvy PF, et al.: Overweight, obesity, and depression: A systematic review and meta-analysis of longitudinal studies. Arch. Gen. Psychiatry. 2010; 67(3): 220–229. Publisher Full Text\n\nGuedes EP, Madeira E, Mafort TT, et al.: Body composition and depressive/anxiety symptoms in overweight and obese individuals with metabolic syndrome. Diabetol. Metab. Syndr. 2013; 5(1): 82. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGodin O, Elbejjani M, Kaufman JS: Body mass index, blood pressure, and risk of depression in the elderly: A marginal structural model. Am. J. Epidemiol. 2012; 176(3): 204–213. PubMed Abstract | Publisher Full Text\n\nSachs-Ericsson N, Burns AB, Gordon KH, et al.: Body mass index and depressive symptoms in older adults: The moderating roles of race, sex, and socioeconomic status. Am. J. Geriatr. Psychiatry. 2007; 15(9): 815–825. PubMed Abstract | Publisher Full Text\n\nAnderson SE, Cohen P, Naumova EN, et al.: Association of depression and anxiety disorders with weight change in a prospective community-based study of children followed up into adulthood. Arch. Pediatr. Adolesc. Med. 2006; 160(3): 285–291. PubMed Abstract | Publisher Full Text\n\nZhao G, Ford ES, Li C, et al.: Waist circumference, abdominal obesity, and depression among overweight and obese U.S. adults: National Health and Nutrition Examination Survey 2005-2006. BMC Psychiatry. 2011; 11: 130. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHadi S, Momenan M, Cheraghpour K, et al.: Abdominal volume index: A predictive measure in the relationship between depression/anxiety and obesity. Afr. Health Sci. 2020; 20(1): 257–265. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee ES, Kim YH, Beck S-H, et al.: Depressive mood and abdominal fat distribution in overweight premenopausal women. Obes. Res. 2005; 13(2): 320–325. PubMed Abstract | Publisher Full Text\n\nHerva A, Laitinen J, Miettunen J, et al.: Obesity and depression: results from the longitudinal Northern Finland 1966 Birth Cohort Study. Int. J. Obes. 2006; 30(3): 520–527. PubMed Abstract | Publisher Full Text\n\nLasserre AM, Glaus J, Vandeleur CL, et al.: Depression with atypical features and increase in obesity, body mass index, waist circumference, and fat mass: A prospective, population-based study. JAMA Psychiat. 2014; 71(8): 880–888. PubMed Abstract | Publisher Full Text\n\nMa J, Xiao L: Obesity and depression in US women: Results from the 2005-2006 National Health and Nutritional Examination Survey. Obesity (Silver Spring). 2010; 18(2): 347–353. PubMed Abstract | Publisher Full Text\n\nWilliams LJ, Pasco JA, Henry MJ, et al.: Lifetime psychiatric disorders and body composition: A population-based study. J. Affect. Disord. 2009; 118(1–3): 173–179. PubMed Abstract | Publisher Full Text\n\nYang H, Youm Y-H, Vandanmagsar B, et al.: Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: Implications for systemic inflammation and insulin resistance. J. Immunol. 2010; 185(3): 1836–1845. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCartier A, Côté M, Lemieux I, et al.: Sex differences in inflammatory markers: What is the contribution of visceral adiposity? Am. J. Clin. Nutr. 2009; 89(5): 1307–1314. PubMed Abstract | Publisher Full Text\n\nStapel B, Jelinic M, Drummond GR, et al.: Adipose tissue compartments, inflammation, and cardiovascular risk in the context of depression. Front. Psych. 2022; 13: 831358. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOyola MG, Handa RJ: Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity. Stress. 2017; 20(5): 476–494. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "284990",
"date": "05 Jun 2024",
"name": "Sangeetha Shyam",
"expertise": [
"Reviewer Expertise nutrition",
"obesity",
"diabetes"
],
"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 describes the association between generalized and central obesity with depressive symptomatology in a nationally representative Peruvian dataset. The authors are commended for the clarity and brevity of their presentation.\nHere are a few suggestions for the authors to consider to improve their manuscript 1.Over 60,000 results are seen in Google Scholar linking obesity with depression, including several systematic reviews and meta-analyses. In the introduction could the authors elaborate on the existence of any previous evidence on this topic in Peru or the lack of it? 2. Diet quality is associated with both obesity and depression. Do the authors account for this in their model? 3. Also the study includes participants over the age of 15. Could a sub-analysis be performed excluding those below 18? The age categorization of 15-34 seems too broad including adolescents and adults. The authors themselves point to varied relationships between obesity and depression in adults vs. younger populations. 4. Alcohol consumption as a yes or no may not capture the quadratic relationship between alcohol consumption and health outcomes. 5. More people seemed to have central obesity rather than generalized obesity in this cohort, which is interesting. Is there literature that points to the utility of BMI or waist circumference with adiposity in Peru? That would be interesting to add. 6. To better understand the relationships, the authors are encouraged to explore other indices including WHR, waist-to-height ratio and ABSI if they possess data. 7. Finally can the authors articulate the public health implications of their findings? How can a cross-sectional association between obesity and depression find use in clinical/ community practice?\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": []
}
] | 1
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https://f1000research.com/articles/12-139
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https://f1000research.com/articles/12-137/v1
|
06 Feb 23
|
{
"type": "Software Tool Article",
"title": "ROOSTER: An image labeler and classifier through interactive recurrent annotation",
"authors": [
"Zhou Tang",
"Yang Hu",
"Zhiwu Zhang",
"Zhou Tang"
],
"abstract": "A large amount of training data is usually lacking at the beginning of system development and labeling such a large number of RGB (red, green, blue) images is laborious. Interactive recurrent annotation is beneficial to incrementally gain training images in the stream of the system development and provides an opportunity to reduce human workload. We developed a software package, ROOSTER, to integrate both labeling and prediction in a single user-friendly graphic user interface with interactive deep learning to reduce the laborious human labeling for fast development of machine vision systems. Predictions can be performed under both single-image mode and batch mode for multiple images. The prediction results can be used as the initial image labeling and manually adjusted under a single image mode. Human labeling and machine predictions are visualized on the same image. ROOSTER provides fully automatic labeling for abundantly available initial images of wheat stripe rust to gain essential predictability. The navigation of integrating prediction with labeling benefits human adjustment to iteratively improve predictability. The development of a detection system for wheat stripe rust was presented as a use case to demonstrate the efficiency of using interactive deep learning to develop machine vision systems.",
"keywords": [
"Machine vision",
"deep learning",
"labeling",
"classification",
"software"
],
"content": "Introduction\n\nImage recognition is a critical part of machine vision. It identifies objects in images, such as specific types of tumor cells or leaves infected by a specific pathogen. Due to the complexity of solving such problems, deep learning (DL) is leveraged to achieve the required results. The challenge of DL is the requirement of a large number of training images before the learning task.1 Because training data is not always available at the beginning, and the new data arrives in the format of sequential stream.2 Furthermore, labeling a large number of images is labor-intensive.3 To reduce the time consumption of laborious human labeling, it is ideal to incrementally label images to train a DL system and let the system label new images.4,5 After human corrections, the new labels can enhance the system further until the required results are achieved.6,7 We developed an open-source Python package named ROOSTER, to fit such a need. ROOSTER not only has a friendly graphic user interface to label images or their sub-images but also accepts any pre-trained models in the format of PyTorch for classification. We demonstrated the usage of ROOSTER in developing a machine vision system to detect wheat stripe rust using images from smartphones and drones.\n\n\nMethods\n\nThe interface of ROOSTER contains a control panel on the bottom and a display panel on the top. An image is imported by clicking the Image button. The number of rows and columns can define tiles. The grids can be hidden or displayed by clicking the Grid button. The image and grids can be zoomed in (+), zoomed out (-), or moved by clicking and dragging. When numbers of rows and columns are defined, the statuses of tiles are set to control by default, indicated by white lines on the top left corners. With a double-click on a tile, its status can be switched between the default status and the alternative status indicated by red lines in the top left corner (see Figure 1). The statuses of all tiles can be reversed by clicking the Reverse button.\n\nThe case image was for wheat stripe rust which can be found in Underlying data.11\n\nROOSTER can load ResNet-18 based neural networks model to make predictions. Prediction is applied to all tiles by loading a pre-trained model or a model trained with part of user-owned images. For example, RustNet is a ResNet-18 based neural network that can be used for wheat stripe rust detection.8 It was pre-trained with wheat stripe rust images from different situations, which can be loaded into ROOSTER to make predictions. Visualization of prediction on a tile is based on its current status. The disagreement between the prediction and the current status is indicated by a dot on the top left of the tile. The dot is in red if the current status is in the default status and white otherwise (Figure 1). ROOSTER outputs include a PNG file for an overview of labeling, images of cropped tiles, and an Excel file (Map) to indicate the statuses of individual tiles. The output Map file can also be used as the input to define the status of an image. This function allows users to save label results and resume labeling later.\n\nROOSTER can process images in two modes: batch mode and single image mode. When the batch mode is checked, clicking Image button defines the image folder. Otherwise, the Image button clicking chooses a single image. Under single image mode, an option is available to use the Map button to apply a pre-classification result (an Excel form) to the current image, including the numbers of rows and columns and statuses of all tiles. If no excel file is attached, users need to define the total number of tiles by specifying the number of rows and columns and click the Grid button to draw the grids. Users can switch the status between the default and the alternative for each tile. Prediction can be performed for either multiple images with the batch mode or the single image by clicking the Predict button. In either case, a window will pop out for users to attach a classification model, e.g., RustNet.pth. The labels can be saved by clicking the Export button. The exported result can be imported through the Map button to continue the customization of labels.\n\nROOSTER is developed with Python 3.6 for 64-bit processors on Mac OS, Linux, and Windows with a minimal 16 GB memory (the code is available in Software availability12). When numbers of rows and columns are defined, ROOSTER can load ResNet-18-based models to predict tiles before human labeling is involved. Human laborers can correct labels by double-clicking the tile. The disagreement between the prediction model and human labeling would be shown with a two-color dot in the top left corner. With ROOSTER, users can start with labeling part of images and train the initial version of the prediction model. The initial version of the model can be reloaded to predict the rest of images in the ROOSTER and retrain the model with the updated dataset, which could increase the labeling efficiency and gradually improve the model accuracy.\n\n\nUse case\n\nWe used ROOSTER to automatically label 200 images of plants containing no infection as the default status and 200 images of plants with all leaves infected as the alternative status (Stage 1 in Figure 2). These images are available in Underlying data.11 We used them for this initial training stage of RustNet, which was modified with a pre-trained ResNet-18.9 The testing on a published independent set of images (5,818 diseased tiles and 14,542 non-diseased tiles) that were previously labeled manually (see Underlying data10) suggested the two types of abundantly available images are beneficial to establishing essential predictability. The area under the receiver operating characteristic curve of true positive rate against false discovery rate is 0.23 compared to 0 for the random guess. Similarly, the area under the receiver operating characteristic curve of true positive rate against false positive rate is 0.64 compared to 0.5 for the random guess.\n\nA large number of images11 that were automatically labeled in control status (uninfected in a) and case status (all leaves infected by wheat stripe rust in b) were used to initialize the RestNet18 (Stage 1). Images with all leaves infected were initially labeled with case status at Stage 2 and predicted by the model trained from Stage 1 (c) to navigate humans to correct labels (d). Images with plants partially infected were initially labeled as control status (e) and predicted by the model from Stage 2 to navigate humans to correct labels (f). The performances at different stages were examined by 20,360 published tile images labeled manually (5,818 diseased and 14,542 non-diseased) in an independent study (see Underlying data10). Two receiver operating characteristic (ROC) curves with false discovery rate (g) and false positive rate (h) were used to compare performances. Random guess has AUC (area under curve) of 0 for ROC of false discovery rate (g) and 0.5 for ROC of false positive rate (the diagonal dash line in h). See Underlying data11 for the raw data associated with the use case.\n\nThe labels of the images with all leaves infected in Stage 1 contained errors as some tiles do not contain leaves. We made the prediction on 20 new images8 with all leaves infected, and manually corrected the prediction errors. The manual corrections with prediction navigation are much easier than labeling the raw images. The training (Stage 2) with the 20 new images dramatically boosted prediction accuracy (0.54 and 0.78 compared to 0.23 and 0.64 at Stage 1 for ROC of false discovery rate and false positive rate, respectively). Similarly, we made the prediction on 61 images with partial leaves infected, manually corrected the prediction errors, and added to the training data in Stage 2 to form Stage 3 training. The prediction accuracy was further improved (0.66 and 0.87 compared to 0.54 and 0.78 at Stage 2 for ROC of false discovery rate and false positive rate, respectively).\n\n\nConclusions\n\nROOSTER combines functions including automatic labeling, label prediction, and manual labeling in a user-friendly GUI (graphical user interface) to label and classifies images using any outsourced models in the format of PyTorch. The navigation of integrating prediction with labeling benefits human adjustment to iteratively improve predictability to use interactive deep learning to develop machine vision systems.",
"appendix": "Data availability\n\nThe independent data used to test ROOSTER was sourced from Schirrmann et al., 10 see here: https://doi.org/10.3389/fpls.2021.469689). Please contact the corresponding author of this article (mschirrmann@atb-potsdam.de) to request access to the test data if interested.\n\nZenodo: ROOSTER underlying dataset. https://doi.org/10.5281/zenodo.7530460. 11\n\nThis project contains the following underlying data:\n\n- RawImages.zip (400 input training images used to develop the model, and captured by the authors of this article).\n\n- UseCase.zip (use case output files).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nRussakovsky O, et al.: ImageNet Large Scale Visual Recognition Challenge. Int. J. Comput. Vis. 2015; 115: 211–252. Publisher Full Text\n\nSahoo D, Pham Q, Lu J, et al.: Online Deep Learning: Learning Deep Neural Networks on the Fly. Proceedings of the Twenty-Seventh International Joint Conference on Artificial Intelligence, {IJCAI-18} 2660–2666 (International Joint Conferences on Artificial Intelligence Organization). 2018. Publisher Full Text\n\nAdhikari B, Huttunen H: Iterative bounding box annotation for object detection. 2020 25th International Conference on Pattern Recognition (ICPR) 2021; pp. 4040–4046.\n\nChai C, Li G: Human-in-the-loop Techniques in Machine Learning. Bull. IEEE Comput. Soc. Tech. Comm. Data Eng. 2020; 37: 37–52.\n\nMonarch RM: Human-in-the-Loop Machine Learning: Active learning and annotation for human-centered AI. Simon and Schuster;2021.\n\nLe TN, Akihiro S, Ono S, et al.: Toward interactive self-annotation for video object bounding box: Recurrent self-learning and hierarchical annotation based framework. Proceedings - 2020 IEEE Winter Conference on Applications of Computer Vision, WACV 2020. 2020; pp. 3220–3229. Publisher Full Text\n\nLutnick B, et al.: An integrated iterative annotation technique for easing neural network training in medical image analysis. Nat. Mach. Intell. 2019; 1: 112–119. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTang Z, et al.: Affordable High Throughput Field Detection of Wheat Stripe Rust Using Deep Learning with Semi-Automated Image Labeling. Preprints. 2022; 2022: 2022040177. Publisher Full Text\n\nHe K, Zhang X, Ren S, et al.: Deep Residual Learning for Image Recognition. Proc. IEEE Comput. Soc. Conf. Comput. Vis. Pattern Recognit. 2015; 2016-Decem: 770–778.\n\nSchirrmann M, Landwehr N, Giebel A, et al.: Early Detection of Stripe Rust in Winter Wheat Using Deep Residual Neural Networks. Front. Plant Sci. 2021; 475.\n\nTang Z, Hu Y, Zhang Z:ROOSTER underlying dataset (1.0). [Dataset]. Zenodo. 2023. Publisher Full Text\n\nHu Y, Zhou T:12HuYang/Rooster: ROOSTER (v1.0) [Software]. Zenodo. 2022. Publisher Full Text"
}
|
[
{
"id": "171116",
"date": "16 May 2023",
"name": "Michael Schirrmann",
"expertise": [
"Reviewer Expertise Precision Agriculture",
"Remote Sensing"
],
"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: The authors introduce \"Rooster,\" a software designed to assist in human data labeling for training deep learning image classification models. Rooster features an intuitive graphical user interface (GUI) that includes a selection tool. This tool utilizes a grid overlaid on the image, allowing users to easily select tiles corresponding to specific content, such as distinguishing between diseased and non-diseased areas. Users can load an existing deep learning model to pre-select tiles based on its predictions. The selected tiles can be confirmed or modified as needed, enabling an iterative optimization process for training the model effectively.\nThe manuscript provides a straightforward description of the software with a case study. Software and source code are provided as well as the data to follow the use case. The software could help especially in specific fields were data is sparse such as in many agricultural related tasks for improving image classification models. Before publication, some information needs to be added and/or limitations discussed.\nRegarding limitation please discuss the following questions:\nCan the tool provide also multi-class training data and optimize multi-class models? Or is it restricted to binary models?\nCan the system also be extended for object detection models or is it clearly restricted to classification models? How does Rooster compete with other labeling software already available?\nPlease add or change the following in the manuscript:\nHow is the testing of the model achieved internally for model optimization? Did you split data in training and test set, e.g., is it possible to upload specific test data, or do you perform cross validation?\nIn the use case, training data needs to be shortly described. In Figure 2, it is unclear what Marquardt data means.\nDoes Rooster also show the quality of the re-trained model with some performance statistics for fast assessment during the labeling update within the GUI?\nWhat does the threshold button do shown in Figure 1 in the GUI?\nSuggest to write rather “human data labeling” than “human labeling”\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? Partly\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-137
|
https://f1000research.com/articles/11-1197/v1
|
19 Oct 22
|
{
"type": "Method Article",
"title": "The effect of the scale of grant scoring on ranking accuracy",
"authors": [
"Peter M. Visscher",
"Loic Yengo",
"Loic Yengo"
],
"abstract": "In this study we quantify the accuracy of scoring the quality of research grants using a finite set of distinct categories (1, 2, …., k), when the unobserved grant score is a continuous random variable comprising a true quality score and measurement error, both normally distributed. We vary the number of categories, the number of assessors that score the same grant and a signal-to-noise ratio parameter. We show that the loss of information of scoring a small number of categories (k > 5) compared to scoring on a continuous scale is very small, so that increasing the number of scoring categories is unlikely to lead to an improvement in the outcomes of scoring systems. In addition, we model the effect of grant assessors scoring too close to the mean and show that this results in only a very small reduction in the accuracy of scoring.",
"keywords": [
"grant scoring",
"multiple threshold model",
"grant quality",
"grant ranking"
],
"content": "Introduction\n\nGrant funding bodies use different ways to obtain a final ranking of grant proposals. The number of items that are scored can vary, as well as the scale on which each item is scored and the weighting scheme to combine the individual items scores into a single overall score. This note only concerns the matter of the scale of scoring.\n\nScoring scales differ widely among grant funding bodies. For example, in Australia, the National Health and Medical Research Council (NHMRC) uses a scale of 1-7 whereas the Australian Research Council (ARC) uses 1-5 (A:E), and other funding bodies use scales such as 1-10. One question for the funding bodies, grant applicants and grant assessors is whether using a different scale would lead to more accurate outcomes. For example, if the NHMRC would allow half-scores (e.g., 5.5), expanding the scale to 13 categories (1, 1.5, …, 6.5, 7), or the ARC would expand to 1-10, then might that lead to a better ranking of grants? This is the question we address in this note. Specially, we address two questions that are relevant for grant scoring: (1) how much information is lost when scoring in discrete categories compared to scoring on a scale that is continuous; and (2) what is the effect of the scale of scoring on the accuracy of the ranking of grants?\n\n\nMethods\n\nTo quantify the effect of grant scoring scale on scoring accuracy, a model of the unknown true distribution of grant quality has to be assumed, as well as the distribution of errors in scoring the quality of a grant. We assume a simple model where an unobserved underlying score (u) is continuous (so no discrete categories) and the error (e) is randomly distributed around the true quality (q) of the grant and that there is no correlation between the true quality of the grant and the error,\n\nWe now define the way in which the grants are actually scored by assessors. Assume that there are k mutually exclusive categories (e.g., k = 7) which correspond to (k-1) fixed thresholds on the underlying scale and k discontinuities on the observed (Y) scale. We also assume that the scores on the Y-scale are linear and symmetrically distributed, so for an even number of categories, there will be a threshold on the u-scale located at zero (formally, if there are k categories then threshold tk/2 = 0). This is an example of a multiple threshold model. In the extreme case of k = 2 (assessors can only score 1 or 2), the threshold on the underlying u-scale is 0 and when u < 0 then the observed score Y = 1 and when u > 0 then the observed score Y = 2. The mean on the observed scale in this model is simply (k + 1)/2.\n\nIn summary, we assume that the actual observed score is a response in one of several mutually exclusive categories (1, 2, …, k), which arise from an unobserved underlying continuous scale. For a given number of categories (k), the (k-1) thresholds were determined to maximise the correlation between the observed Y-scale and the unobserved continuous u-scale, while fixing the inter-threshold spacing on the u-scale to be constant. This ensures symmetry on the observed Y-scale and appears to be the optimal solution in that it gave identical results to a general optimisation of the thresholds (results not shown). Figure 1 gives a schematic for k = 5. To get the thresholds requires a numerical optimisation, which was done through a purpose-written program using the statistical software package R version 4.2.0 (see Software availability section). The question on the loss of information by using a finite versus continuous (infinite) scoring scale was addressed by calculating the correlation between Y (observed) and u (continuous) with increasing values of k from 1 to 100. For a given set of thresholds ti and assuming that the variance on the underlying scale (u) is 1, this correlation (Rk) was calculated as,\n\nThe x-axis shows the unobserved continuous scale in standard deviation units and the y-axis the density. The position of each of the 4 thresholds is shown as a vertical red line.\n\nThe expression for the correlation between the observed and underlying scale under the multiple threshold model is known from the genetics literature (Gianola, 1979). The square of the correlation in Equation [1] is the proportion of variation on the continuous scale that is captured by the discrete scale. For k = 2, t1 = 0, z1 = 0.3989, p1 = p2 = ½, Y1 = 1 and Y2 = 2, giving var(Y) = ¼ and R2 ~ √0.637 = 0.798. This is a known result for a threshold model with two equal categories, where the binary scale captures 63.7% of the variation on the continuous scale (Dempster and Lerner, 1950).\n\nTo address the question on the effect of scoring on the ranking of grants we need to estimate the signal-to-noise ratio of the Y-scale and u-scale. Thresholds models with two random effects on the underlying scale have been studied in the genetic literature (e.g., Dempster and Lerner, 1950; Gianola, 1979; Gianola and Norton, 1981). Gianola (1979) also deals with the case where the errors (e) are exponentially distributed, but this distribution was not considered here.\n\nWhen the observed scores are 1, 2, …, k, Gianola (1979) showed that the ratio of signal-to-noise on the observed Y-scale and unobserved u-scale is Rk2, the square of the correlation in Equation [1]. Therefore, the ratio of signal-to-noise parameters (Rk2) does not depend on the signal-to-noise value on the underlying scale (s) itself. However, the effect of scaling on the ranking of grants does depend on the signal-to-ratio effects, and to address this question we need to also specify the number of assessors (m). Given m (e.g., m = 4, 5, 6), the correlation (Corr) between the true score of a grant (qi) and the mean score from m assessors on the u-scale or Y-scale can be shown to be,\n\nFinally, we can express the loss of information in ranking grants when m assessor score on the Y-scale instead of on the continuous scale as,\n\nEquations [1] and [3] can also be used to compare different values for k against each other. For example k = 7 versus k = 13 can be compared by calculating R7/R13 and L(m,13,s)/L(m,7,s).\n\nGrant assessors might not use the entire scale that is available to them or score too few grants in the extreme categories (categories 1 and k, respectively). The effect of such a scoring approach is to change the proportions in each of the k categories and thereby change the variance on the Y-scale and the covariance between the u and Y variables. These changes lead to a lower correlation between Y and u than given by Equation [1] and, consequently, reduce the ranking accuracy of grants. We simulated this scenario by using the same model as before, but now assuming that the proportions of scores in each category follow from a normal distribution with smaller variance (σ2us) than the variance of 1 which is assumed to be the true unobserved variance (when σ2us = σ2u = 1). When σ2us < 1, this model leads to more scores around the mean and fewer in the tails (the lowest and highest category).\n\n\nResults\n\nWe first quantify the correlation between the observed categorical score (Y) and the underlying continuous score (u), as a function of the number of categories. Figure 2 shows the results from Equation [1], for k = 2 to 100. It shows there is very little loss of information when the number of categories is five or more. For example, the correlation is 0.958, 0.976, 0.987 and 0.992, for k = 5, 7, 10 and 13, respectively. The association between the correlation and the number of categories can be approximated by the simple equation, R(k) ≈ 1 – 0.7k-1.7, which fits almost perfectly.\n\nThe x-axis is the number of discrete categorical scores (k) and the y-axis shows the correlation between the observed categorical score (Y) and the underlying continuous score (u). The red horizontal line denotes a correlation of 0.95.\n\nGiven the correlations in Figure 2 we calculated the correlation between the true quality of a grant (q) and the mean score on the categorical scale from m assessors. Figure 3 shows the results from Equation [3], for m = 3,4,5,6; k = 5,7,10,13; and s from 0.1 to 0.9. It shows that that loss of information on the correlation between true quality of the grant and its mean assessor score is very small – typically 2% or less.\n\nEach panel shows the loss of information (Equation [3]) when scoring a finite number of categories relative to the continuous score, as a function of the number of assessors (panels a to d) and the proportion of variation in scores due to the quality of the grant (x-axis).\n\nWe next explored the scenario where grant assessors do not sufficiently use the entire scale available to them, by simulating σ2us < 1, which leads to a deficiency of scores in the tails of the distribution. For example, the proportion of scores for k = 5 in categories 1-5 (Figure 1) are 10.3%, 23.4%, 32.6%, 23.4% and 10.3%, respectively, when the distribution underlying scores has a variance of σ2us = 1, but 3.7%, 23.9%, 44.8%, 23.9% and 3.7% when that variance is σ2us = 0.5. In this extreme scenario, the proportions in the tails are nearly 3-fold (10.3/3.7) lower than they should be yet decreasing σ2us from 1 to 0.5 induces only a small reduction of Rk from 0.958 to 0.944. Figure 4 shows Rk for a scoring scale with 2 to 10 categories when the variance of underlying distribution is σ2us = 0.5, 0.75 or 1.\n\nThe x-axis is the number of discrete categorical scores (k) and the y-axis shows the correlation (Rk) between the observed categorical score (Y) and the underlying continuous score (u). The correlation Rk is calculated under three scenarios defined by the variance (σ2s) of the distribution of underlying scores. The grey horizontal line denotes a correlation of 0.95 or 0.99.\n\n\nDiscussion\n\nIntuitively one might think that scoring with a broader scale is always better, but the results herein show that this can be misleading. Above k = 5 categories there is a very small gain in the signal-to-noise ratio compared to a fully continuous scale, and the effect on the accuracy of the ranking of grants is even smaller.\n\nComparing k = 5 with k = 10 categories and k = 7 with k = 13 categories shows a theoretical gain of 3% (0.987/0.958) and 1.6% (0.992/0.976) in the correlation between observed and continuous scales (Figure 2). These very small gains predicted by doubling the number of categories scored will have to be balanced with the cost of changing the grant scoring systems.\n\nThe effect of ranking grants on their quality is even smaller. Figure 3 shows that, for most existing Australian grant scoring schemes, the loss in accuracy of scoring a grant using discrete categories compared to a truly continuous scale is trivial – nearly always less than 1%. As shown in the methods section, the squared correlation between the true quality of a grant and the average score from m assessors is m/(m + λY), with λY = (1-Rk2s)/(Rk2s). Since Rk2 is close to 1 (Figure 2), the squared correlation is approximately equal to m/[m + (1-s)/s]. Therefore, even if the signal-to-noise ratio parameter s is as low as, say, 1/3, the squared correlation between the true quality and the mean assessor score is m/(m + 2), or 3/5, 2/3 and 5/7 for m = 3, 4 and 5, respectively, hence correlations ranging from 0.77 to 0.85.\n\nThe results in Figure 4 are to mimic a situation where assessors score too closely to the mean. As expected, Rk decreases when fewer grants are scored in the tails of the distribution of categories. However, the loss of information is generally very small. For example, for k = 7 and the most extreme case considered (σ2us = 0.5), Rk = 0.966, which is only slightly lower than 0.976, which is the correlation when the distribution of assessor scores is consistent with the underlying true distribution with variance of 1.\n\nWe have necessarily made a number of simplifying assumptions, but they could be relaxed in principle, for example different statistical distributions of the quality of the grant and the errors could be used. We have also assumed no systematic bias in scorers so that the true quality value of a grant on the observed scale is the mean value from a very large number of independent scorers. Departures from these assumptions will require additional assumptions and more parameters to model. However, assuming a multiple threshold model with normally distributed random effects on an underlying scale is simple and flexible and likely both robust and sufficient to address questions of the scale of grant scoring.\n\n\nData availability\n\nThe data underlying Figures 1-3 are generated automatically by the provided R scripts.\n\n\nSoftware availability\n\nSource code available from: https://github.com/loic-yengo/GrantSCoring_Figures\n\nArchived source code at the time of publication: https://zenodo.org/record/7141342\n\nLicense: Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nThe authors would like to think Adrian Barnett for helpful discussions and for the prompt.\n\n\nReferences\n\nDempster ER, Lerner IM: Heritability of threshold characters. Genetics. 1950; 35: 212–236. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGianola D: Heritability of polychotomous characters. Genetics. 1979; 93(4): 1051–1055. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGianola D, Norton HW: Scaling threshold characters. Genetics. 1981; 99(2): 357–364. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "153690",
"date": "07 Nov 2022",
"name": "Rachel Heyard",
"expertise": [
"Reviewer Expertise Statistics",
"Grant peer review",
"Research evaluation"
],
"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 by Peter Visscher and Loic Yengo addresses a crucial question for funding bodies: how large is the effect of the scoring scale on the proposal ranking accuracy. The manuscript is concise and well-written. R-code is available on github and computationally reproducible, which is wonderful! My main concern with the paper as it is currently presented, is that it is not well integrated in the literature on grant peer review (so far only three papers from Genetics, all from before 1990, are cited).\nIntroduction:\nThe introduction is a bit short and the whole paper has only three references, which are also very old. There has been a lot of research on the reliability and accuracy of grant peer review scores which the authors could at least mention.\n\nFunding decisions are based on the rankings of grant proposals. Therefore the accuracy of the ranking of grant proposals is so important. For a general audience, less familiar with grant peer review, some more insights into the motivation of the work could be relevant.\n\nMethods:\nI applaud the authors for uploading their R-code on github, which helped me a lot in understanding of the methods. From the methods section in the paper itself it was rather hard to grasp all the details. Therefore reconsider reworking the methods section and give more details: e.g. how are pi and zi computed?\n\nThe ordering of the presentation of the methods could be changed to make the section more reader-friendly: for example, does the third paragraph start with explaining how the thresholds can be computed by maximising the correlation between Y and u while this correlation is only defined at the very end of the paragraph when explaining the loss of information problem.\n\nThe multiple threshold model is set in a way that most weight is on the average score (3 for a 5-point scale). From the literature on grant peer review we know however that the actual distributions are most often skewed towards higher scores (see for example the plots in doi:10.1126/sciadv.aaz48681). Can your multiple threshold model be updated to such a more realistic scenario?\n\nOften in grant peer review the same experts might score more than one proposal which will affect the error structure of your normal distributions, as all scores by expert xyz are correlated with each other. Could such a scenario be included in your multiple threshold model?\n\nDiscussion:\n\nI believe the discussion is also lacking more context. What do your results mean for funding decisions? for funding agencies?\n\nThe thresholds of the model are chosen in a way to maximise the correlation between the observed and the continuous scale. How realistic is this? Isn't it this exact subjective choice made by the reviewers which often makes grant peer review unreliable? If a 4 in a 5-point scale means the same for all reviewers (as it is the case in your model, right?), grant peer review would be almost perfectly reliable. However it is a very subjective choice. Can you comment on this? at least as a limitation in the discussion.\n\nGeneral Comment:\n\nThe title suggests that you are interested in ranking of grant proposals, but in the article you are actually interested in the correlations between the scoring and the true quality (!= not a rank) of the proposals. The relationship between the effects on the scoring and the subsequent ranks of proposals should be explained more clearly.\n\nCode:\nAll four R-scripts for the four figures re-define the function 'CorrEquiSpaced'. It is common practice to instead write an R-script (called functions.R) with all the functions and very detailed description. All scripts could benefit from more comments, also the Readme file is not very informative.\n\nIs the rationale for developing the new method (or application) clearly explained? Partly\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Partly\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "9237",
"date": "06 Feb 2023",
"name": "Peter Visscher",
"role": "Author Response",
"response": "The paper by Peter Visscher and Loic Yengo addresses a crucial question for funding bodies: how large is the effect of the scoring scale on the proposal ranking accuracy. The manuscript is concise and well-written. R-code is available on github and computationally reproducible, which is wonderful! My main concern with the paper as it is currently presented, is that it is not well integrated in the literature on grant peer review (so far only three papers from Genetics, all from before 1990, are cited). We thank the reviewer for their time, comments and suggestions. We thank the reviewer in particular for pointing us to a number of relevant publications which was most helpful because peer review research is not our normal area of research. We have revised the manuscript taking those comments and suggestions into account. Introduction: The introduction is a bit short and the whole paper has only three references, which are also very old. There has been a lot of research on the reliability and accuracy of grant peer review scores which the authors could at least mention. We thank the reviewer for this comment and have now expanded the Introduction and have cited a number of relevant papers and reports. Funding decisions are based on the rankings of grant proposals. Therefore the accuracy of the ranking of grant proposals is so important. For a general audience, less familiar with grant peer review, some more insights into the motivation of the work could be relevant. We have now included a statement about the motivation. Methods: I applaud the authors for uploading their R-code on github, which helped me a lot in understanding of the methods. From the methods section in the paper itself it was rather hard to grasp all the details. Therefore reconsider reworking the methods section and give more details: e.g. how are pi and zi computed? We have tweaked the Methods section and have specified how, in R, pi and zi are computed. The ordering of the presentation of the methods could be changed to make the section more reader-friendly: for example, does the third paragraph start with explaining how the thresholds can be computed by maximising the correlation between Y and u while this correlation is only defined at the very end of the paragraph when explaining the loss of information problem. We thank the referee for this comment. We have now added a few sentences for clarification and define the correlation earlier. The multiple threshold model is set in a way that most weight is on the average score (3 for a 5-point scale). From the literature on grant peer review we know however that the actual distributions are most often skewed towards higher scores (see for example the plots in doi:10.1126/sciadv.aaz48681). Can your multiple threshold model be updated to such a more realistic scenario? We thank the referee for this comment. We note that the distribution of the Overall Impact Score in Erosheva et al. 2020 (Fig2), on which the ranking is based, is much less skewed than the individual component scores and furthermore that the distribution is a mixture because two groups of grants are compared. The distribution of scores when adjusted for the fixed effect may be (even) more normal. In any case, as we mention the Discussion, in principle the effect of the scale can be investigated with other statistical distributions, for example assuming that the continuous scale is log-normal (skewed) or kurtotic. Non-normal distributions of the quality and error term will make the results less generalisable because the of thresholds will depend on the specific parameters of the chosen non-normal distribution. For example, Gianola (1979) showed that for an exponential distribution, the threshold values depend on the densities of q and e, and therefore each signal-to-noise ratio will have its own set of thresholds. A full exploration of a wide range of statistical models will in our opinion require extensive computer simulations and we judged that to be outside of the scope of our study. Often in grant peer review the same experts might score more than one proposal which will affect the error structure of your normal distributions, as all scores by expert xyz are correlated with each other. Could such a scenario be included in your multiple threshold model? We thank the referee for this question. For our theoretical calculations, the variance due to assessor (as a random effect) is also noise and we have clarified this in the revision. For real data analysis we agree with the reviewer that an assessor effect should be fitted (as, for example, done in Erosheva et al., Science Advances 2020), if only to quantify how much variation in scores is due to some assessors scoring systematically lower or higher than others. Discussion: I believe the discussion is also lacking more context. What do your results mean for funding decisions? for funding agencies? We have now expanded the Discussion significantly. The thresholds of the model are chosen in a way to maximise the correlation between the observed and the continuous scale. How realistic is this? Isn't it this exact subjective choice made by the reviewers which often makes grant peer review unreliable? If a 4 in a 5-point scale means the same for all reviewers (as it is the case in your model, right?), grant peer review would be almost perfectly reliable. However it is a very subjective choice. Can you comment on this? at least as a limitation in the discussion. We thank the reviewer for this question. We agree that in the absence of measurement error (or subjective choices) the reliability of scoring would be perfect, but there is strong evidence that assessors do not always score the same even if the category descriptors are well-defined. We give examples of why assessors might score differently in the revised manuscript. The choice of our thresholds was just to make a link between a true continuous scale and the actual scale of scoring and this choice seems reasonable to us. The main assumption is that the true distribution is continuous. General Comment: The title suggests that you are interested in ranking of grant proposals, but in the article you are actually interested in the correlations between the scoring and the true quality (!= not a rank) of the proposals. The relationship between the effects on the scoring and the subsequent ranks of proposals should be explained more clearly. We thank the reviewer for this point. We have now specified that our parameters are directly related to single-rater reliability and reliability based upon the mean from multiple assessors. In addition, from our simulations we compared the Spearman rank correlations to the Pearson correlations. The Spearman correlations were even larger than the Pearson correlations (Figure for referee below) and therefore re-enforce the conclusion of our study. We have added a paragraph in the Discussion: “Throughout this study we have used the Pearson correlation to quantify the correlation between the score on the underlying and observed scales. We could also have used the Spearman rank correlation, but the conclusions would not change. In fact, the Spearman rank correlations are even larger than the Pearson correlations and they converge at k = 10 categories (results not shown).” See graph here: https://f1000research.s3.amazonaws.com/linked/481471.Visscher_1.png Code: All four R-scripts for the four figures re-define the function 'CorrEquiSpaced'. It is common practice to instead write an R-script (called functions.R) with all the functions and very detailed description. All scripts could benefit from more comments, also the Readme file is not very informative. We thank the reviewer for this comment and have now updated our R script accordingly, added more comments to the code and expanded the Readme file. The github link remains unchanged but the updated version of the Zenodo link is available at https://doi.org/10.5281/zenodo.7519164"
}
]
},
{
"id": "157462",
"date": "21 Dec 2022",
"name": "Alejandra Recio-Saucedo",
"expertise": [
"Reviewer Expertise Research on Research",
"Health services delivery 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\n“The effect of the scale of grant scoring on ranking accuracy” by Visscher and Yengo presents the work of a novel approach to understand the effect of scoring categories/scales (and assessors) on the loss of information/loss in accuracy of grant scoring. The authors developed a multiple threshold model with normally distributed random effects on an underlying scale and showed that doubling the number of categories used to score grant applications does not change the scoring accuracy (as defined by authors), highlighting the importance of assessing the cost of changing grant scoring systems against the benefit it adds to scoring. The authors also studied the correlation between observed categorical scores and continuous scores (as a function of the number of categories) reporting very little loss of information when the number of categories was five or more.\nOverall strengths:\nMethod and data availability: Providing the code to run the analysis reported in this paper is commendable. In doing this, the authors are supporting the principles of research openness and transparency that strengthens science and enhance its value to academia and society. It is a great example of the contribution of meta-research.\nClarity of results: The authors provide a clear description of the main findings of their analysis in a succinct and informative way.\nContribution from conclusions presented: In light of recent work (e.g., Independent Review of Research Bureaucracy Interim Report https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1046070/independent-review-of-research-bureaucracy-interim-report.pdf), the work presented is timely and highly relevant. Changes to the research funding system (from application to delivery and impact) need to be evidence-based. Showing that changes to scoring criteria in funding agencies are not necessarily the solution to issues linked to research funding decisions (which the authors do not necessarily discuss in their literature) is a clear contribution to efforts aimed at reducing unnecessary research bureaucracy.\nAreas for improvement:\nThe work described is not entirely linked to the title of the paper as there is no information on ranking accuracy except for a phrase towards the end of the discussion section: “…the true quality value of a grant on the observed scale is the mean value from a very large number of independent scorers.”\nThey main area to address in this work is represented in the partial response to the question: Is the rationale for developing the new method clearly explained?\nPublished work that reports studies exploring variation in scores touches on one of the issues that the authors are studying, i.e., what is the right number of assessors to ensure a research application is scored fairly/bias-free (through less score variability), whilst ensuring the process is efficient and viable (please see Kaplan D, Lacetera N, Kaplan C. Sample size and precision in NIH peer review. PLoS One. 2008;3(7):e2761. https://doi.org/10.1371/journal.pone.0002761.) This, and other related work on scores inter-reliability (e.g., Sattler DN, McKnight PE, Naney L, Mathis R. Grant peer review: improving inter-rater reliability with training. PLoS One. 2015;10(6):e0130450. https://doi.org/10.1371/journal.pone.0130450.S) highlight the aspect of this paper that is not presented about how this work is contributing to the efforts of enhancing decision-making in research funding. The key assumption of the authors’ model of no-systematic bias in scores provides a ‘place to start’, but the need to include variability because in reality those scenarios are more likely to be the norm leaves a gap in the contribution of the work reported.\nThe model proposed successfully shows that all things being equal, having 13 scoring categories does not enhance an application score, making a case for simplified scoring criteria that have the potential of reducing administrative burden. However, the value of the work will increase if the model showed similar results in the presence of systematic bias in scores.\nOverall, the paper needs to provide context to how their work contributes to the issues that have been identified with research funding allocation for which innovative alternatives have been suggested (see for example Guthrie S, Ghiga I, Wooding S. What do we know about grant peer review in the health sciences? [version 2; peer review: 2 approved]. F1000Research. 2018;6:1335; Guthrie S, Guérin B, Wu H, Ismail S, Wooding S. Alternatives to peer review in research project funding: 2013 Update. Santa Monica: RAND Corporation; 2013. https://www.rand.org/pubs/research_reports/RR139.html.) The results reported are promising, however, without reference to the context and processes that are being targeted to improve, the value of the work is not as evident as it could be.\n\nIs the rationale for developing the new method (or application) clearly explained? Partly\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "9238",
"date": "06 Feb 2023",
"name": "Peter Visscher",
"role": "Author Response",
"response": "“The effect of the scale of grant scoring on ranking accuracy” by Visscher and Yengo presents the work of a novel approach to understand the effect of scoring categories/scales (and assessors) on the loss of information/loss in accuracy of grant scoring. The authors developed a multiple threshold model with normally distributed random effects on an underlying scale and showed that doubling the number of categories used to score grant applications does not change the scoring accuracy (as defined by authors), highlighting the importance of assessing the cost of changing grant scoring systems against the benefit it adds to scoring. The authors also studied the correlation between observed categorical scores and continuous scores (as a function of the number of categories) reporting very little loss of information when the number of categories was five or more. We thank the reviewer for their time, comments and suggestions. We thank the reviewer in particular for pointing us to a number of relevant publications which was most helpful because peer review research is not our normal area of research. We have revised the manuscript taking those comments and suggestions into account. Overall strengths: Method and data availability: Providing the code to run the analysis reported in this paper is commendable. In doing this, the authors are supporting the principles of research openness and transparency that strengthens science and enhance its value to academia and society. It is a great example of the contribution of meta-research. Clarity of results: The authors provide a clear description of the main findings of their analysis in a succinct and informative way. Contribution from conclusions presented: In light of recent work (e.g., Independent Review of Research Bureaucracy Interim Report https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1046070/independent-review-of-research-bureaucracy-interim-report.pdf), the work presented is timely and highly relevant. Changes to the research funding system (from application to delivery and impact) need to be evidence-based. Showing that changes to scoring criteria in funding agencies are not necessarily the solution to issues linked to research funding decisions (which the authors do not necessarily discuss in their literature) is a clear contribution to efforts aimed at reducing unnecessary research bureaucracy. Areas for improvement: The work described is not entirely linked to the title of the paper as there is no information on ranking accuracy except for a phrase towards the end of the discussion section: “…the true quality value of a grant on the observed scale is the mean value from a very large number of independent scorers.” They main area to address in this work is represented in the partial response to the question: Is the rationale for developing the new method clearly explained? Published work that reports studies exploring variation in scores touches on one of the issues that the authors are studying, i.e., what is the right number of assessors to ensure a research application is scored fairly/bias-free (through less score variability), whilst ensuring the process is efficient and viable (please see Kaplan D, Lacetera N, Kaplan C. Sample size and precision in NIH peer review. PLoS One. 2008;3(7):e2761. https://doi.org/10.1371/journal.pone.0002761.) This, and other related work on scores inter-reliability (e.g., Sattler DN, McKnight PE, Naney L, Mathis R. Grant peer review: improving inter-rater reliability with training. PLoS One. 2015;10(6):e0130450. https://doi.org/10.1371/journal.pone.0130450.S) highlight the aspect of this paper that is not presented about how this work is contributing to the efforts of enhancing decision-making in research funding. The key assumption of the authors’ model of no-systematic bias in scores provides a ‘place to start’, but the need to include variability because in reality those scenarios are more likely to be the norm leaves a gap in the contribution of the work reported. We thank the reviewer for these references which we have now cited. We have expended on our Introduction and Discussion sections to place our study in the peer review literature. We also give our motivation for the study. The model proposed successfully shows that all things being equal, having 13 scoring categories does not enhance an application score, making a case for simplified scoring criteria that have the potential of reducing administrative burden. However, the value of the work will increase if the model showed similar results in the presence of systematic bias in scores. We agree with the reviewer that we have focused on precision only and not on bias. The reason is the narrow scope of our paper: what happens if, everything else being the same, the scale of scoring changes? As we now mention, our results are also relevant if there is a random effect of assessor, such that some assessors score on average lower or higher than others. Our motivation for focussing on precision is that there is strong evidence in the literature of lack of precision yet to our knowledge less evidence for systematic biases (e.g., Guthrie et al. 2018). To study systematic bias would require us to model such biases and there are many ways in which this could be done and the necessary assumptions we would need to make could of course be questioned. A full exploration of a wide range of models for bias will in our opinion require extensive computer simulations and we judged that to be outside of the scope of our study. Overall, the paper needs to provide context to how their work contributes to the issues that have been identified with research funding allocation for which innovative alternatives have been suggested (see for example Guthrie S, Ghiga I, Wooding S. What do we know about grant peer review in the health sciences? [version 2; peer review: 2 approved]. F1000Research. 2018;6:1335; Guthrie S, Guérin B, Wu H, Ismail S, Wooding S. Alternatives to peer review in research project funding: 2013 Update. Santa Monica: RAND Corporation; 2013. https://www.rand.org/pubs/research_reports/RR139.html.) The results reported are promising, however, without reference to the context and processes that are being targeted to improve, the value of the work is not as evident as it could be. Is the rationale for developing the new method (or application) clearly explained? We thank the reviewer again for providing these references which we have now cited."
}
]
}
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https://f1000research.com/articles/11-1197
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https://f1000research.com/articles/12-130/v1
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03 Feb 23
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{
"type": "Research Article",
"title": "Toblerone: detecting exon deletion events in cancer using RNA-seq",
"authors": [
"Andrew Lonsdale",
"Andreas Halman",
"Lauren Brown",
"Hansen Kosasih",
"Paul Ekert",
"Alicia Oshlack",
"Andrew Lonsdale",
"Andreas Halman",
"Lauren Brown",
"Hansen Kosasih",
"Paul Ekert"
],
"abstract": "Cancer is driven by mutations of the genome that can result in the activation of oncogenes or repression of tumour suppressor genes. In acute lymphoblastic leukemia (ALL) focal deletions in IKAROS family zinc finger 1 (IKZF1) result in the loss of zinc-finger DNA-binding domains and a dominant negative isoform that is associated with higher rates of relapse and poorer patient outcomes. Clinically, the presence of IKZF1 deletions informs prognosis and treatment options. In this work we developed a method for detecting exon deletions in genes using RNA-seq with application to IKZF1. We developed a pipeline that first uses a custom transcriptome reference consisting of transcripts with exon deletions. Next, RNA-seq reads are mapped using a pseudoalignment algorithm to identify reads that uniquely support deletions. These are then evaluated for evidence of the deletion with respect to gene expression and other samples. We applied the algorithm, named Toblerone, to a cohort of 99 B-ALL paediatric samples including validated IKZF1 deletions. Furthermore, we developed a graphical desktop app for non-bioinformatics users that can quickly and easily identify and report deletions in IKZF1 from RNA-seq data with informative graphical outputs.",
"keywords": [
"cancer",
"RNA-seq"
],
"content": "Introduction\n\nB-cell precursor ALL (BCP-ALL, or B-ALL) is the most common childhood cancer. High risk subtypes of B-ALL include Ph+ (presence of BCR-ABL1 fusion) and Ph-like (similar expression profile to Ph+ without BCR-ABL1 fusion) (Roberts et al. 2014). These subtypes are often characterised by additional focal deletions in IKAROS family zinc finger 1 (IKZF1) gene. IKZF1 consists of 8 exons and encodes a DNA-binding protein and B-cell transcription factor, IKAROS (Mullighan et al. 2009; Boer et al. 2016). The most common IKZF1 alterations that occur in B-ALL are whole gene deletions or deletions of exons 4-7. The focal deletion results in the production of a dominant-negative isoform, IK6, lacking the N-terminal DNA-binding domains of IKAROS (Mullighan et al. 2009; Dörge et al. 2013; van der Veer et al. 2013). Previously, we and others have showed that IK6 could be detected using RNA-seq (Brown et al. 2020; Tran et al. 2022; Rehn et al. 2022). In our work, we did so by adding the deletion transcript to the reference transcriptome and measuring the transcripts per million (TPM) (Brown et al. 2020). Given IK6 lacks exons 4-7 (del4_7) of the canonical IKZF1 transcript, this isoform includes a novel splice junction between exon 3 and exon 8. In our cohort, we found that the splice junction indicating an exon deletion was rarely detected in the cohort in IK6-negative samples, and was increasingly expressed as the purity of the tumour increased as verified by real-time quantitative polymerase chain reaction (RQ-PCR) (Brown et al. 2020). Other isoforms of IKZF1 deletions in the cohort were not as reliably detected. Only one sample was known to have a deletion of exons 2-7 (del2_7) and our previous predictions of increased expression of the del2_7 transcript were unable to be validated. Previous candidates of deletions of exons 2-8 (del2_8) and exons 4-8 (del4_8) were also unable to be reliably validated. Here we develop an improved method for detecting focal deletions that can be applied more broadly to other gene deletions. Prior knowledge of which exon deletions are of interest is not required.\n\nThe key idea in our method is to generate a set of reference transcripts that correspond to all the possible exon deletions in a gene. This idea represents something of a midpoint between using annotated transcripts as the reference transcriptome and using assembly, by pre-defining potential transcripts in the class of whole exon skipping. Essentially, we generate a reference index of possible transcripts based solely on exon deletions of annotated exons, balancing the speed of a reference-based approach while allowing for a certain class of unknown events. We extract reads that support these deletions, test for sufficient coverage (expression) of a deletion, and then infer the relative abundance of deletion reads within a gene.\n\nWe name this method Toblerone and apply it to a B-ALL cohort from the Royal Children’s Hospital (RCH), previously described in Brown et al. We validate the method on the IKZF1 gene and identify additional deletions with high relative expression of the deletion transcript. Toblerone can be applied in both a test and discovery context. Firstly, it can be used to test for known deletion events such as IK6 (exons 4-7 deletion) in IKZF1 or secondly, it can be used for discovery of new genes with exon deleted transcripts, by applying it to any gene with three or more exons. Toblerone is a tool that can quickly and accurately identify skipped exons that may indicate the presence of sub-gene deletions in a cancer sample.\n\n\nMethods\n\nToblerone begins by creating a custom reference. For any candidate gene, e.g., IKZF1, we take the canonical transcript and generate a new transcriptome reference that consists of the original transcript plus a set of deletion transcripts. Deletion transcripts consist of removing combinations of consecutive internal exons, excluding edge exons (first and last). This avoids the lack of splicing events at the ends of genes. A schematic of deletion transcripts for a five-exon gene is shown in Figure 1A, resulting in six deletion transcripts. These deletion transcripts along with the canonical transcript are used as the complete reference for the gene. The new custom reference is then indexed using a De Bruijn graph for pseudoalignment of RNA-seq reads.\n\nA) Using a canonical input transcript, deletion transcripts are generated and indexed into a custom reference. B) Reads are then pseudoaligned to the custom reference. C) reads uniquely supporting a deletion transcript are aggregated into the unique count (UC) for each transcript. All other reads are added to gene total. D) Scaled proportions of unique counts (UC) to totals counts (TC) are calculated for each deletion and saved to the output file.\n\nNext reads are pseudoaligned to the custom reference and quantified at the equivalence class (EC) level based on which of the transcripts they are compatible with. Due to the mutually exclusive construction of the deletion transcripts, there is one EC that is uniquely compatible with each deletion. These correspond to the reads that have splice junctions across the deleted exons. Rather than using the transcript-compatibility count (TCC) (Ntranos et al. 2016) of a deletion transcript, derived from all EC that would support a deletion transcript, the Toblerone approach uses only the count from the EC uniquely supporting that deletion (Figure 1B). We refer to the EC counts for this subset of EC as the unique count (UC) of each deletion transcript. The reads for the remainder of EC, those that support the original canonical transcript for a gene, or support more than one deletion transcript, are used in the sum total of EC counts as an expression measure for the gene. We refer to this as the total EC count for a gene, or simply the total count (TC). Deletion detection requires coverage across the junction including overhang of the exon-exon boundary by at least 5 bp (by default). Any read that does not meet this threshold is not included as a UC, only in the TC. Deletion UC as a proportion of the TC is calculated and scaled by the length of the canonical transcript and the read length to account for the increased number of reads overlapping a splice junction with increased read length. A command line tool is available to generate and index the deletion transcriptome, and perform pseudoalignment.\n\nThe Toblerone transcriptome is generated in several steps, starting from a BED12 definition of the canonical gene(s) of interest that is given to the provided “create_bedfiles.py” Python script. New BED definitions for each Toblerone deletion transcript are then created. For each BED file entry of a transcript of length N exons, the number of deletions transcripts added for a given transcript can be determined using binomial theorem. For N exons, initially N-2 is used to calculate the internal combinations of exon deletions. The method requires continued runs of exons, coincidentally forming a pattern of triangular numbers. These can also be calculated binomially and equal to the binomial coefficient of t+1 and 2 for each t triangle number. Substituting N-2 for t leads to a binomial coefficient of N-1 and 2 for calculating the added Toblerone deletion transcripts. The results of this script are multiple BED files, which are merged, and along with a FASTA file of the canonical transcripts corresponding to the BED12 input, passed to the bedtools (Quinlan 2014) program to create the Toblerone transcriptome FASTA file for indexing.\n\nThe core Toblerone program is an adaptation of a pseudoaligner written in the Rust programming language (2018 edition v1.31.0). This simple pseudoaligner, modified from 10XGenomics, implements concepts from several notable pseudoalignment and RNA-seq publications (Bray et al. 2016; Srivastava et al. 2016, 2019; Ntranos et al. 2016; Limasset et al. 2017; Orenstein et al. 2017; Li and Yan 2015). Two main modes of operation are available: index and map. Index is used to create the de Bruijn index of the Toblerone transcriptome, providing a FASTA file of a generated transcriptome and an output file to store the index.\n\nMap mode is used with either single or paired end reads as input, along with an index, to produce output. For optimal performance, only reads that are likely to match to genes of interest in the input transcriptome should be provided, such as by extracting reads from a prepared genome alignment. Toblerone diverges from the traditional pseudoalignment and template code in several critical ways during the mapping stage. Firstly, for any read, the number of transcripts in the equivalence class is checked; any read matching an EC unique to one transcript is treated differently due to the mutually exclusive nature of the input transcriptome. The coverage of these reads over the input transcript must be complete, excepting the number of allowed mismatches (default: 2). These reads with a unique EC (if trim is enabled, default: 5) are checked for equality between the EC and the EC of a shorter trimmed version of the read.\n\nSecondly, uniqueness is favoured when resolving ambiguity. When comparing the equivalence classes of paired-end reads, the matching EC with fewer transcripts is preferred in such cases ensuring that the read supporting a deletion is used in further processing. Thirdly, only unique EC (UC) are tallied individually in memory against a specific transcript and written to output, with all other reads compatible with more than one transcript assigned only to a gene-level total count (TC). For each deletion, the UC and TC are written to file along with the gene length, nominated read length. The proportion of UC to TC for each deletion-gene combination is also included, as a raw value and with a scaling factor equal to the gene length divided by the read length (paired end reads weighted double). The scaled proportions are then calculated by multiplying the scale factor by the original proportion (Figure 1). These results are written to a CSV file, or standard output, as directed by the user.\n\nA graphical Toblerone app is written in Python (v3) and JavaScript programming languages, and is compatible with Linux, Mac and Windows (using Windows Subsystem for Linux) operating systems. This interface collects the IKZF1 index, core Toblerone program, RCH reference values for deletions and functions for extracting relevant reads into a convenient package. This facilitates single sample analysis via a genome aligned BAM file. Once downloaded, it can be easily run as a desktop app. A gene and cohort must be selected (currently only the IKZF1 gene and the RCH B-ALL cohort) along with an indexed genome aligned RNA-seq BAM file. The relevant IKZF1 reads are extracted and mapped with Toblerone to the IKZF1 deletion transcriptome. Finally, the results are displayed in an interactive format along with the high, medium and low confidence thresholds for clinical deletions, as well as outlier information for those without absolute values of reference. Further cohorts can be added to the app in future.\n\nEthical approval for the cohort was obtained from the Royal Children’s Hospital Human Research Ethics Committee (HREC 34127) as described previously (Brown et al. 2020). The selected B-ALL cohort consisted of children treated at the Royal Children’s Hospital. The Children’s Cancer Centre Tissue Bank undertook biobanking and informed consent for sequencing analysis.\n\n\nResults\n\nWe applied Toblerone to the IKZF1 gene from RNA-seq data from a cohort of 99 B-ALL patients (Figure 2), which included annotations for validated IKZF1 deletion status from microarray and RQ-PCR, as well as other clinical data including fusion status and karyotyping result (Brown et al. 2020). The scaled proportions for each of the 21 IKZF1 deletion transcripts are shown in Figure 2A, and illustrate the different frequencies of exon deletions. The majority of deletions are rarely observed in the cohort, with several notable exceptions. Deletions of exon 4 and exon 6 are commonly observed and are consistent with IKZF1 annotated alternative splicing transcripts attributed to hg38 reference transcripts (ENST00000343574, ENST00000359197, ENST00000439701). The relative expression of these transcripts is variable across samples but does not usually account for more than half of the transcripts based on the calculated proportions. For IK6, the validated del4_7 deletions have proportions that make them clearly identifiable visually, a result consistent with the previous methods applied to this cohort. In order to test for outliers in the proportion of reads indicating a deletion, we transformed the scaled proportion into a Z-score for each deletion. The distribution of Z-scores for deletion transcript with at least one sample with Z-score greater than or equal to three is shown, along with its outliers (Figure 2B). Since low gene expression can lead to high Z-score and therefore outliers with only a small number of counts, we exclude deletions that had outliers due to samples with UC counts of 10 or less. These are however included in Supplementary Figure 1. The validated del4-8 sample is also observed as an outlier of exon 4 deletions. In this case, the signal is indirect as loss of half the exons alters the proportion of splicing events of exon4 relative to the gene expression. Outlier detection identifies two other known IKZF1 deletions; the single known del2_7 deletion in the cohort and a new result of a del3_7 deletion previously only predicted from a low resolution microarray.\n\nA) Box plots of scaled proportions of unique counts (UC) for each transcript of IKZF1 exon deletions. Each row is labelled with the exon numbers that are deleted in that transcript. Each sample is a dot with a size proportional to the UC and coloured by known IKZF1 deletion status (light blue: del2_7, dark blue: del2_8, red: del4_7, pink: del4_7 sub-clonal, yellow: del4_8, purple: del4_8 fusion, green: non-specific deletion from DNA microarray, grey: deletion unknown or undetected). B) Distributions of the scaled proportions transformed into a Z-score within each deletion. Only the IKZF1 deletion transcripts with at least one Z-score outlier ≥ 3 and minimum UC count of 10 are shown, with outliers shown as triangles coloured as in A. C) Scaled proportion scores of IKZF1 del4_7 for the cohort with high, medium and low confidence lines at 0.1 (solid), 0.01 (longdash) and 0.001 (dashed). Samples with two or more counts of the IK6 UC are filled triangles while zero or one count is empty. Many samples including sub-clonal true positives have 0 counts (dotted line).\n\nAlthough outliers can easily identify four of the six IK6 deletions, identifying the remaining two clonal, as well as a further five sub-clonal deletions presents additional challenges. In Figure 2C we show the calculated del4_7 proportions for every sample in the cohort on a log scale. We again observe the high proportion of IK6 UC as outliers and can empirically establish thresholds for high, medium and low confidence calls for the IKZF1 del4_7 deletion. We define high confidence at 0.1 scaled proportion, as most values exceeding this are known IK6 deletions; medium is set at a scaled proportion of 0.01 and a low confidence threshold of 0.001 isolates a cluster of samples that include some sub-clonal IK6 or unresolved microarray deletions as well as many unvalidated samples. The choices of these thresholds are informed by a ROC curve of validated true positives and negatives (Supplementary Figure 2). The area under the ROC of 0.859 confirms that scaled proportions effectively predict true positive del 4-7 samples, and the thresholds to identify when false-positives may be introduced. In the low confidence band especially, many samples have a single read supporting the del4_7 deletion. Low or singular counts are insufficient to identify deletions, and two validated sub-clonal IK6 samples lacked any reads supporting deletion and had counts of 0. Inclusion of the low confidence results may lead to increased false positives due to the possibility of technological or biological artefact, and so would not typically be recommended.\n\nEC counts for Toblerone deletions can be heavily influenced by the alignment of reads across a junction, which is controlled by parameters set at runtime, specifically mismatch and trim. The mismatch parameter controls how many single nucleotides each k-mer can differ from the reference in order to match. Since reads at exon-exon boundaries form the signal of Toblerone, reads that overhang one exon by a small number of bases, equal to the number of allowed mismatches, may be erroneously assigned as supporting a deletion. Conversely, disallowing mismatches can reduce the signal from genuine deletion by excluding any reads that contain genomic variants or mutations. To balance the effects of allowing mismatches, Toblerone includes a trim operator which tests the robustness of read support. For each read that uniquely supports a deletion, nucleotides are removed from the ends of the read and the support checked again. Reads that are still unique and only support the deletion pass the trim test. Otherwise, these reads contribute only to the gene total. The trim operation essentially prevents soft-clipped reads contributing to the UC total, and reduces noise by removing reads with a small overhang of bases at the exon-exon boundary, ensuring that any mismatches are not the sole evidence a read supports a deletion. The trim value must equal or exceed the mismatch value. The effect of Toblerone’s trim and mismatch on the counts, and the effect of the changes in these counts to the scaled proportion, are illustrated in Supplementary figure 3A and 3B, respectively.\n\nThe total number of samples with any read support for IKZF1 del4_7 is shown in Supplementary Figure 3A for combinations of trim and mismatch. With default parameters, 34 samples could be detected with one or more reads. If both trim and mismatch are set to 0, this reduces to 31 samples. The number of samples with observed del4_7 deletion reads are typically reduced by higher trimming values, and increased by allowing more mismatched bases. Although the change in the number of samples is modest, the effect of these parameters is observable in the calculated scaled proportions in some samples (Supplementary Figure 3B). Though the majority of samples are relatively unchanged, notably two validated deletions have an increased proportional expression when including trimming and mismatches.\n\nIn addition to a command line tool, a Toblerone graphical desktop app for non-bioinformatics users was created (Figure 3A). This enhances the command line tool by allowing a user to provide either an hg19 or hg38 genome aligned BAM file. Relevant reads for IKZF1 are extracted and then pseudoaligned against the Toblerone IKZF1 transcriptome using the core Toblerone command line tool that has been integrated into the app. The results are then displayed and compared against the background cohort. The app uses the RCH cohort explored above, as a background, and the same parameters are used as defaults when comparing to new data. The high, medium and low thresholds established for this cohort are also included in the app. We demonstrate the app using a relapse sample from a patient in the RCH cohort (B_ALL16-4). The primary sample was validated as a sub-clonal IKZF1 del4_7 deletion and included in the cohort. The relapse sample was subsequently validated as a full IKZF1 deletion, though not included in the cohort data in Toblerone. The result of submitting this RNA-seq sample within the Toblerone app is shown in Figure 3. Firstly, the app indicates that the del4_7 deletion has been detected in the sample, and assigns it within the high confidence band (Figure 3A) with a scaled proportion of 0.949. Z-scores for this sample for all deletions in IKZF1 are shown in Figure 3B, and outliers are indicated in red. The app also gives details for each deletion in a separate tab, with the background deletion distribution able to be inspected. This is shown for IK6 and the relapse sample in Figure 3C, where it is clear the scaled proportion of the relapse sample is greater than any value seen in the background cohort. This plot can also be viewed as Z-scores if selected by the user.\n\nA) Scaled proportion of the IKZF1 del4-7 for selected ample (blue dot) compared to the previously calculated confidence thresholds and B) the Z-score distributions for all IKZF1 deletion transcripts with the sample indicated dots. Any outliers are shown as red dots; C) detailed view of the del4-7 background distribution in the RCH cohort, with gaussian density estimate line in blue and each cohort value as triangles along the x-axis. The B_ALL16_4 sample is indicated by vertical dotted line, coloured by the confidence value.\n\nWhile Toblerone has been developed and tested on the IKZF1 genes across a cohort of samples, it can also be used with different genes and to compare between samples in paired study design. As a proof of concept, we use data from a recent publication exploring acquired resistance when using CD22 as an immunotherapeutic target for CAR T-cell therapy (Zheng et al. 2022). In that work, RNA-seq data were taken before and after for B-ALL patients undergoing inotuzumab treatment. Notably for the patient with specimen identifier PAVDRV, a decrease in CD22 protein expression after treatment occurred without down regulation of the CD22 transcript. To compare Zheng’s findings with a Toblerone approach, a CD22 index was created and Toblerone was applied to the samples pro- and post- treatment (no replicates). We were able to confirm the study’s result that a transcript with loss of exon 2, specifically the deletion of exons 2-6, was increased after treatment with inotuzumab (Figure 4). Additionally, we ranked and visualised the Toblerone differences in deletion proportions of all transcripts in the Toblerone reference (Supplementary figure 3). This showed that post-inotuzumab treatment, there is an increase in the expression of the transcript with an exon 12 deletion. While the original publication noted this as a known deletion observed in the B-ALL samples of the TARGET cohort, it was not attributed to patient PAVDRV as a possible cause of the loss of CD22 protein.\n\nColoured bars represent the patient sample taken from peripheral blood before (orange) and after (green) treatment with inotuzumab. Selected deletions showed most deviation from pre-treatment results (Supplementary Figure 3).\n\n\nDiscussion\n\nToblerone is a targeted technique for identifying internal exon deletions in specific genes from RNA-seq. Inspired by the detection of deletions in the IKZF1 gene in a study by Brown et al., we have tailored an algorithm to specifically look for these novel isoforms in RNA-seq. A recent approach that performs more comprehensive RNA-seq analysis specific to ALL is RasCALL (Rehn et al. 2022). Toblerone is not intended to be a comprehensive structural variant detection method however, it complements existing RNA-seq analysis tools in cancer such as fusion detection (e.g. JAFFA (Davidson, Majewski, and Oshlack 2015), Aribba (Uhrig et al. 2021), STAR-fusion etc) and SV detection (e.g., MINTIE (Cmero et al. 2020)). These and other tools may be more suitable for broader detection of unusual fusions, transcripts or more complex deletions, especially in situations where atypical events may be missed by standard of care molecular diagnostics (Nardi et al. 2022). Similarity, Toblerone is not intended for comprehensive analysis of alternative splicing from RNA-seq. LeafCutter (Li et al. 2018) and MAJIQ (Vaquero-Garcia et al. 2016) may be more suitable when considering these changes at a whole transcriptome level.\n\nThe Toblerone analysis has been clearly demonstrated for the detection of deletions in IKZF1 including the most commonly seen deletion involving exons 4 to 7 as well as rarer deletions with other combinations of exons. The algorithm can also be extended to discover novel exon deletions in other genes, with some caveats. Toblerone is only applicable to genes with three or more exons where the deletion does not involve the loss of the terminal exons. Loss of terminal exons could potentially be seen in differential expression analysis at the exon or gene level. If these conditions are met, then parallel indexes for additional genes of interest for a given cohort could be executed, e.g., PAX5 in B-ALL (Mullighan et al. 2009). Toblerone indexes can also be created for other organisms, following the same index creation process with substituted reference files and gene definitions. In IKZF1 research, mouse models of Ikzf1 can be used to understand its role in immunity and diseases related to Ikaros (Boast et al. 2021). Example indexes for PAX5 (hg38) and Ikzf1 (mm10) are available with the Toblerone source code.\n\nWhen a deletion transcript is lowly expressed, it is difficult to detect with RNA-seq. Toblerone uses junction read counts to infer the novel junctions produced by a deletion. Even with checks to ensure that reads supporting deletions are not due to minor overlaps at exon boundaries, singular reads for deletions were found in many samples without validated deletions. Conversely, we were not able to detect any supporting reads in several subclonal del4_7 deletions. Determining whether these low counts are a biological or technical artefact remains an open question. With this in mind, we proposed thresholds for high, low and medium confidence deletions to provide a guide to interpreting Toblerone results, as well as establishing the level of background noise for the method. Extending to other genes and cohorts may require validated samples to establish appropriate thresholds between validated samples and remainder of the cohort samples. However, as shown with acquired resistance with CD22 case study, albeit without sufficient replicates for statistical analysis, Toblerone can also be used in case-control studies to compare exon deletions proportions between two groups.\n\nThe generation of the Toblerone transcriptome and pseudoalignment is targeted towards single gene analysis and therefore, is not optimised for a complete transcriptome or competitive pseudoalignment between multiple genes. Results presented here have used extracted reads from genome alignments, and as such, the reads have already been aligned by more conventional approaches such as STAR (Dobin et al. 2013). Conceptually, it is possible to use raw reads and implement the Toblerone approach as part of a competitive pseudoalignment, for single or multiple genes of interest. The Toblerone custom deletion transcriptome can be used with any pseudoaligner that divulges EC counts prior to abundance estimation. So conceptually, a complete pseudoalignment from raw FASTQ data can be performed in programs such as Kallisto (Bray et al. 2016) and Salmon (Patro et al. 2017) with a mixture of reference transcripts and additional deletions transcripts. This approach however stores EC counts compatible with more than one transcript, which is superfluous for the needs of the Toblerone algorithm, and this additional overhead increases with each gene considered and prevents efficient computation across multiple samples. The Toblerone pseudoaligner is designed to only compute the necessary counts, and is optimised to identify reads that support deletions. Future work on Toblerone however, can address these limitations for multi-gene analysis in a competitive alignment, through improvements to the Toblerone pseudoaligner or by reprocessing conventional pseudoaligner results to reduce redundant counts, and removing reads that do not robustly support a deletion.\n\nThe fundamental idea of Toblerone is to modify the transcriptome reference to contain transcripts with all variations for a sequence event of interest. By generating a transcriptome that consists of transcripts with deleted exons, reads that uniquely support that transcript can be identified, inspected and compared. Here, we have modified the reference to represent exon deletions, but there are other possible variants which may be detected. For example, intron retention is a natural extension of the existing algorithm, and exon duplications or inversions could also be identified. Toblerone adds insight into the clinically relevant transcriptional consequences of mutations by extending the analysis of RNA-seq, which is being applied more generally in many malignancies, notably lymphoblastic leukaemia. It can quantify the relative expression of known clinically relevant exon deletions in cancer, and aid in the discovery of new ones.\n\n\nCode availability\n\nThe original template Rust pseudoaligner from 10XGenomics is on GitHub: https://github.com/10XGenomics/rust-pseudoaligner. Source code for the Toblerone (v0.0.9 DOI: 10.5281/zenodo.7563716) adaption is available at: https://github.com/oshlack/toblerone along with instructions for compilation and usage.\n\nSource code for the Toblerone App (v1.05 DOI: 10.5281/zenodo.7563747) is available at: https://github.com/Oshlack/TobleroneApp and binaries can be downloaded directly from http://oshlacklab.com/TobleroneApp/. Software is available under the MIT license.",
"appendix": "Data availability\n\nUnprocessed RNA-seq data for 99 primary RCH cohort samples and selected relapse samples is available from the European Genome-Phenome Archive (Freeberg et al. 2022) (accession number EGAS00001004212). Raw RNA-seq data from the published CD22 resistance patients is publicly available in the Short Read Archive, BioProject ID PRJNA764243.\n\nZenodo: Extended data and images for “Toblerone: detecting exon deletion events in cancer using RNA-seq” (https://doi.org/10.5281/zenodo.7574657) (Lonsdale et al. 2023).\n\nThis repository contains the following extended data:\n\n- Supplementary Figure 1.\n\n- Supplementary Figure 2.\n\n- Supplementary Figure 3.\n\n- Supplementary Figure 4.\n\n- Processed IKZF1 data for the RCH cohort by Toblerone.\n\n- STROBE reporting guidelines for the RCH cohort re-analysis.\n\nExtended data are available under the terms of the Creative Commons Attribution 4.0 International license.\n\n\nAcknowledgements\n\nTumour samples were made available by the Children’s Cancer Centre Tissue Bank at the Murdoch Children’s Research Institute and The Royal Children’s Hospital (www.mcri.edu.au/childrenscancercentretissuebank), made possible through generous support by CIKA (Cancer In Kids @ RCH), The Royal Children’s Hospital Foundation and the Murdoch Children’s Research Institute.\n\n\nReferences\n\nBoast B, de Jesus C , Nunes-Santos HS, et al.: Ikaros-Associated Diseases: From Mice to Humans and Back Again. Front. Pediatr. 2021; 9(July): 705497. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBoer JM, van der Veer A , Rizopoulos D, et al.: Prognostic Value of Rare IKZF1 Deletion in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia: An International Collaborative Study. Leukemia. 2016; 30(1): 32–38. PubMed Abstract | Publisher Full Text\n\nBray NL, Pimentel H, Melsted P, et al.: Near-Optimal Probabilistic RNA-Seq Quantification. Nat. Biotechnol. 2016; 34(5): 525–527. PubMed Abstract | Publisher Full Text\n\nBrown LM, Lonsdale A, Zhu A, et al.: The Application of RNA Sequencing for the Diagnosis and Genomic Classification of Pediatric Acute Lymphoblastic Leukemia. Blood Adv. 2020; 4(5): 930–942. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCmero M, Schmidt B, Majewski IJ, et al.: MINTIE: Identifying Novel Structural and Splice Variants in Transcriptomes Using RNA-Seq Data. Cold Spring Harbor Laboratory. 2020. Publisher Full Text\n\nDavidson NM, Majewski IJ, Oshlack A: JAFFA: High Sensitivity Transcriptome-Focused Fusion Gene Detection. Genome Med. 2015; 7(1): 43. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDobin A, Davis CA, Schlesinger F, et al.: STAR: Ultrafast Universal RNA-Seq Aligner. Bioinformatics. 2013; 29(1): 15–21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDörge P, Meissner B, Zimmermann M, et al.: IKZF1 Deletion Is an Independent Predictor of Outcome in Pediatric Acute Lymphoblastic Leukemia Treated according to the ALL-BFM 2000 Protocol. Haematologica. 2013; 98(3): 428–432. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFreeberg MA, Fromont LA, D’Altri T, et al.: The European Genome-Phenome Archive in 2021. Nucleic Acids Res. 2022; 50(D1): D980–D987. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLimasset A, Rizk G, Chikhi R, et al.: Fast and Scalable Minimal Perfect Hashing for Massive Key Sets. arXiv [cs. DS]. arXiv. 2017.Reference Source\n\nLi YI, Knowles DA, Humphrey J, et al.: Annotation-Free Quantification of RNA Splicing Using LeafCutter. Nat. Genet. 2018; 50(1): 151–158. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLi Y, Yan X: MSPKmerCounter: A Fast and Memory Efficient Approach for K-Mer Counting. arXiv [q-bio.GN]. arXiv. 2015. Reference Source\n\nLonsdale A, Halman A, Brown LM, et al.: Toblerone: detecting exon deletion events in cancer using RNA-seq.2023. Publisher Full Text\n\nMullighan CG, Xiaoping S, Zhang J, et al.: Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia. N. Engl. J. Med. 2009; 360(5): 470–480. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNardi V, McAfee SL, Dal Cin P, et al.: Chemotherapy Resistance in B-ALL with Cryptic NUP214-ABL1 Is Amenable to Kinase Inhibition and Immunotherapy. Oncologist. 2022; 27(2): 82–86. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNtranos V, Kamath GM, Zhang JM, et al.: Fast and Accurate Single-Cell RNA-Seq Analysis by Clustering of Transcript-Compatibility Counts. Genome Biol. 2016; 17(1): 112. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOrenstein Y, Pellow D, Marçais G, et al.: Designing Small Universal K-Mer Hitting Sets for Improved Analysis of High-Throughput Sequencing. PLoS Comput. Biol. 2017; 13(10): e1005777. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPatro R, Duggal G, Love MI, et al.: Salmon Provides Fast and Bias-Aware Quantification of Transcript Expression. Nat. Methods. 2017; 14(4): 417–419. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQuinlan AR: BEDTools: The Swiss-Army Tool for Genome Feature Analysis. Current Protocols in Bioinformatics/Editoral Board, Andreas D. Baxevanis … [et al.]. 2014; 47 (September): 11.12.1–34.\n\nRehn J, Mayoh C, Heatley SL, et al.: Rascall: Rapid (Ra) Screening (Sc) of RNA-Seq Data for Prognostically Significant Genomic Alterations in Acute Lymphoblastic Leukaemia (ALL). PLoS Genet. 2022; 18(10): e1010300. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRoberts KG, Pei D, Campana D, et al.: Outcomes of Children with BCR-ABL1–like Acute Lymphoblastic Leukemia Treated with Risk-Directed Therapy Based on the Levels of Minimal Residual Disease. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2014; 32(27): 3012–3020. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSrivastava A, Malik L, Smith T, et al.: Alevin Efficiently Estimates Accurate Gene Abundances from dscRNA-Seq Data. Genome Biol. 2019; 20(1): 65. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSrivastava A, Sarkar H, Gupta N, et al.: RapMap: A Rapid, Sensitive and Accurate Tool for Mapping RNA-Seq Reads to Transcriptomes. Bioinformatics. 2016; 32(12): i192–i200. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTran TH, Langlois S, Meloche C, et al.: Whole-Transcriptome Analysis in Acute Lymphoblastic Leukemia: A Report from the DFCI ALL Consortium Protocol 16-001. Blood Adv. 2022; 6(4): 1329–1341. PubMed Abstract | Publisher Full Text | Free Full Text\n\nUhrig S, Ellermann J, Walther T, et al.Accurate and Efficient Detection of Gene Fusions from RNA Sequencing Data. Genome Res. 2021 January; 31: 448–460PubMed Abstract | Publisher Full Text | Free Full Text\n\nVaquero-Garcia J, Barrera A, Gazzara MR, et al.: A New View of Transcriptome Complexity and Regulation through the Lens of Local Splicing Variations. elife. 2016; 5(February): e11752. PubMed Abstract | Publisher Full Text | Free Full Text\n\nvan der Veer A , Waanders E, Pieters R, et al.: Independent Prognostic Value of BCR-ABL1-like Signature and IKZF1 Deletion, but Not High CRLF2 Expression, in Children with B-Cell Precursor ALL. Blood. 2013; 122(15): 2622–2629. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZheng S, Gillespie E, Naqvi AS, et al.: Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies. Blood Cancer Discovery. 2022; 3: 103–115. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "163943",
"date": "25 Apr 2023",
"name": "Katherine Pillman",
"expertise": [
"Reviewer Expertise Transcriptome bioinformatics",
"gene regulation."
],
"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 Summary The article describes ‘Toblerone’, an improved targeted method of identifying and quantifying focal deletions of whole internal exons in one or a few genes. The method works without a priori knowledge of which exons will be deleted and was developed to improve the accuracy and sensitivity of detection of exonic deletions for a clinically important gene, IKZF1.\nOverall, I think this is a clearly written and well-explained approach that describes the design and implementation of a solution to the clinically important problem identified in a previous study by the group (Brown et al. 2007). The provided app provides an easy visual way of assessing the results and could also be used as a template when expanding the method to other genes. I think that the approach of creating individual transcripts defining each potential set of exonic deletions is a good one; it deals with some tricky edge cases for mapping reads across splice junctions in a reasonable and transparent way. For example, other solutions wherein one maps reads to only the two junction-flanking exons can raise problems when one of these exons is much shorter than the read length.\nMajor comments None.\nMinor comments Including a brief explanation of any of the following terms would make the paper more widely accessible:\nFocal deletion Pseudoalignment Equivalence Class Level\n\nIn the calculation of Scaled Proportion, it seems to me that the trim value should be part of the equation as it affects the proportion of reads that would be expected to be detected over a junction for a given sequencing depth. Might the solution be to subtract the trim length (=5 by default) from the read length prior to calculation, to account for the loss of the use of the last 5 bases? Would it be correct to think that the length of the part of the read available for counting is what the data should be normalised by?\nI could not find figure legends for the Supp Figures, can these please be explicitly described somewhere.\nIf it is possible, a simple explanation of the meaning of the Scaled Proportion metric would be a great help to the user intuitively understanding their results. Is it “the fraction of reads across a deletion junction relative to what would be expected for a given expression level and read length”? Meaning it is an estimate of the true fraction of transcripts present in Sample X which contain that deletion, with a theoretical maximum of 1.0 (though only in a perfect world where read coverage is not stochastic or biased across a transcript)?\nOn the last line of Page 7, \"Supplementary figure 3\" should be changed to \"Supplementary figure 4\".\nIn Fig3C, I found it confusing that the purple dashed line represents the single sample position, whereas similar lines in other figures (purple lines in Fig3A, dashed lines in Fig2C) were used to describe the thresholds. I think it would help if this line can replaced with a different coloured symbol and/or changed to a new colour.\nI also thought that if a genome-mapped bam was used as the first step, it is important that the mapper used allows soft clipping (like STAR in default mode). A mapper that does not soft clip might discard reads which had a smallish number of bases mapping across a non-canonical junction, which would reduce the sensitivity of Toblerone. This could be worth noting in the text.\nA suggestion: a great use of Toblerone would be in conjunction with an in-clinic capture panel, with probes tiled on the gene specifically so as to avoid capture bias over exon-exon junctions. The huge sequencing depth one gets from capture panels would solve the issues described in determining whether the samples with 0 counts lack the genomic fusion or simply have low sequencing coverage.\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": "192103",
"date": "07 Sep 2023",
"name": "Matt Field",
"expertise": [
"Reviewer Expertise bioinformatics"
],
"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 comments:\nHere Lonsdale et al describe Toblerone, software designed to detect exon deletions in known genes from RNA-Seq. Overall this tool is useful for targeted applications and would likely be of interest to the broader research/clinical community. The manuscript is well written and encouragingly all relevant code and supporting documentation is available enabling other research/clinicians to utilise the framework. My comments below are relevant to the specific sections:\nMethods: “Overview”:\nDefine equivalence class.\n\nWhile the total counts is a useful measure in some contexts, did you think about comparing/reporting the read count supporting the deletion to only the reads that definitively do not support the deletion? For example in a deletion skipping exon 2, supporting reads would span exon 1-3 while non-support reads would be the sum of exons spanning boundaries 1-2 and 2-3.\n\nMethods: Index\nIn some instances, non-canonical forms can be important. Is it possible to input multiple isoforms for the same gene for indexing?\n\nIs there any handling for aberrant read alignments that don’t clearly skip canonical exons? For example supporting reads for a deletions that span a canonical exon boundary and a non-canonical exon boundary might be important to the patient treatment.\nMethods: “app”\nThe app is a great idea and should be useful in targeted cases.\n\nAre there any plans to allow users to request additional applications for other relevant genes? It would be great to see a bit more documentation in the app README on github.\nResults: ALL\nJust to clarify, the exon 4 and 6 deletions are not related to ALL? Might be useful to display the most common non-ALL and ALL-specific isoforms.\nResults: Parameters effect\nDo deletions being in frame and out of frame have any impact on the algorithm?\n\nWhat, if any impact does the length of each alignment segment have on the call? For example, is there any difference between one read that has 140 bases aligned to one exon and only 10 bases aligned across the skipped exon whereas another read has 75 bases aligned to each. Similarly is the mapping score and the uniqueness of each alignment segment factored in?\nResults: CD22\nNice example of another application. While the paper largely describes the application for IKZF1, it’s uptake will largely be determined by how generalisable the framework is. For example, determining the cutoffs in Fig 2C and the placement of the new sample relative to others in Fig 3 is specific to IKZF1 but it would be useful to describe what specifically is required for any new proposed use case.\n\nDo you suspect each application (i.e. gene) will require custom cutoffs/filters?\nDiscussion:\nDo you suspect each application (i.e. gene) will require custom cutoffs/filters?\n\nA specific application would be identifying somatic events in paired tumour / normal samples. Is there any thought to further developments/optimisations around this common use case?\n\nI could imagine scenarios where it is desirable to interrogate a small panel of commonly mutated genes specific to type of cancer (similar to targeted gene panel sequencing). Are there are limitations that might present challenges to this level of scaling?\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/12-130
|
https://f1000research.com/articles/9-1102/v1
|
07 Sep 20
|
{
"type": "Research Article",
"title": "Prevalence and factors associated with anemia among children under five years of age in Rombo district, Kilimanjaro region, Northern Tanzania",
"authors": [
"Innocent B. Mboya",
"Redempta Mamseri",
"Beatrice J. Leyaro",
"Johnston George",
"Sia E. Msuya",
"Melina Mgongo",
"Redempta Mamseri",
"Beatrice J. Leyaro",
"Johnston George",
"Sia E. Msuya",
"Melina Mgongo"
],
"abstract": "Background: Anemia is a severe public health problem affecting more than half of children under five years of age in low-, middle- and high-income countries. We aimed to determine the prevalence and factors associated with anemia among children under five years of age in northern Tanzania. Methods: This was a community-based cross-sectional study conducted in Rombo district, Kilimanjaro region, northern Tanzania in April 2016. Multistage sampling technique was used to select a total of 602 consenting mothers and their children aged 6-59 months and interviewed using a questionnaire. Data were analyzed using Stata version 15.1. We used generalized linear models (binomial family and logit link function) with robust variance estimator to determine factors associated with anemia. Results: Prevalence of anemia was 37.9%, and it was significantly higher among children aged 6-23 months (48.3%) compared to those aged 24-59 months (28.5%). There were no significant differences in anemia prevalence by sex of the child. Adjusted for other factors, children aged 6-23 months had over two times higher odds of being anemic (OR=2.44, 95% CI 1.71, 3.49, p<0.001) compared to those aged 24-59 months. No significant association was found between maternal and nutritional characteristics with anemia among children in this study. Conclusion: Prevalence of anemia was lower than the national and regional prevalence but it still constitutes a significant public health problem, especially among children aged 6-23 months. Interventions such as iron supplementation, food fortification and dietary diversification and management of childhood illnesses in this setting should be targeted towards mothers and children less than two years.",
"keywords": [
"Anemia",
"prevalence",
"risk factors",
"under five children",
"Tanzania"
],
"content": "Introduction\n\nAnemia in children under five years is a significant public health problem in low-, middle- and high-income countries. The world health organization (WHO) defines anemia as a low blood hemoglobin concentration of less than 11g/dl in children under five years of age1–3. Anemia in children is a major cause of adverse health consequences such as stunted growth, impaired cognitive development, compromised immunity, disability and increased risk of morbidity and mortality2–11. Globally, about 43% of children under-five are anemic, and there is a marked variation in the prevalence of anemia between low- and middle-income countries. Over 50% of anemic children live in low- and middle-income countries12. There is also a variation in anemia prevalence within low- and middle-income countries; the highest rate (78%) reported in Ghana and the lowest (26%) in Cuba13,14. According to WHO report, Africa region is reported to have the highest proportion (62%) of children who are anemic12.\n\nA variety of factors causes anemia, but the most common cause is iron deficiency1,3,12. Iron deficiency can result from inadequate dietary intake of iron or poor absorption, increased needs for iron during the high growth periods and increase iron loses due to helminths infection3. Other causes of anemia can be due to infections like malaria, genetic makeup and nutritional deficiencies of vitamins B12, A, C and folate3. Factors reported being associated with anemia also vary from region to region. The factors include area of residence whereby children living in rural areas are reported to be more at risk, low education level of the mother, child’s sex (high among males), child’s age (below 24 months) and history of infections, high birth order and maternal history of anemia1,4,13–20. Unemployment, low family income, low wealth quartile and high poverty index has also been associated with anemia in children under five5,9,15,17. In addition, poor breastfeeding practices and complementary feeding leads to anemia7,14–16.\n\nTo combat anemia in children, WHO recommends combined strategies such as iron supplementation, especially to vulnerable populations, food-based approaches to increase iron intake through food fortification and dietary diversification and management of infectious diseases, particularly malaria and helminth infections21. These strategies are recommended to be built into the primary health care system and existing programs such as maternal and child health, integrated management of childhood illness, adolescent health, safe motherhood, roll-back malaria, deworming and tuberculosis programs21. Improved quality of anemia care is also among key strategies to accelerate progress towards addressing this problem22. Although Tanzania is implementing these strategies23, Demographic and Health Survey (DHS) report shows that there is no improvement in reducing anemia prevalence. For the two consecutive DHS rounds, 2010 and 2015, the prevalence of anemia was 58%. The results of the DHS show that the country is still far from reaching the set target of reducing anemia prevalence to 20% by 2020. In Kilimanjaro region, Same District, anemia prevalence was reported to be 70%19. Since studies show variations in factors that are associated with anemia, there was a need to conduct this study in Rombo district as an important step towards evidence-based decision making when planning for interventions. Geographically Same is semi-arid district while Rombo is located around Mount Kilimanjaro hence having different topographic conditions.\n\n\nMethods\n\nThis study utilized data from a community-based cross-sectional study conducted in Rombo district, Kilimanjaro region, northern Tanzania in April 2016. Rombo district is one of the seven districts of Kilimanjaro region which is located on the north-eastern part of the region. The study aimed to assess the nutritional status of children under five years in the district. The district is bordered to the north and east by Kenya, to the west by Siha and Hai districts and to the south by Moshi rural district. According to the 2012 national population and housing census, Rombo district had a total population of 260,963 of which 124,528 (52.3%) were females while 29,955 were children under five years of which 14,971 (50%) were females24. The largest population of the district depends on agriculture, livestock keeping and small petty business and few people are employed in the public sector. The district has 43 health facilities; 2 hospitals, 4 health centers and 37 dispensaries25.\n\nThe study included consenting mothers and their children aged 6–59 months. Children whose mothers were not available on the day of data collection were excluded from the study as it was not possible to verify child information if next in kin or neighbor was interviewed. We also excluded children with missing information on hemoglobin concentrations. A single proportion formula was used for sample size calculation. Using a standard normal value of 1.96 under 95% confidence interval, a 48% prevalence of anemia among children 6–59 months in Kilimanjaro region2, a margin of error of 5% and multiplying by a design effect of 1.5 to account for cluster design, the minimum required sample size was 575 mother-child pairs.\n\nMultistage sampling technique was used to select 708 mother-child pairs from households with children aged 6–59 months. Villages were randomly selected from a random sample of wards. A listing of households with children under five years was generated with the help of ward/village and street leaders or link persons, followed by a random selection of households. When the visited household had no child under five years of age, the next household was selected until the minimum required sample size was reached. If there were more than one child aged 6–59 months, the younger one was selected to represent the rest of the children in the household. If the child’s mother was not at home, the research team visited the house for a minimum of three times before declaring that the participant could not be reached. After excluding 89 children aged <6 months, 17 children missing hemoglobin concentrations; we analyzed data for 602 mothers-child pairs Figure 1.\n\nA questionnaire, shared as an extended data26, was used to collect data during face to face interviews. Although the questionnaire has not been validated in Tanzania, we adopted questions from the demographic and health survey and added some from previous literature. The following information was collected; maternal reproductive health, breastfeeding history, feeding patterns, initiation of complementary feeding, use of health facilities during pregnancy and anthropometric measurements. Measurement of weight was performed using a SECA weighing scale (SECA GmbH & Co. KG, Hamburg, Germany) while recumbent length was measured for children aged <24 months and standing height was measured for older children using stadiometers. At least two measurements were taken then the average was calculated. Blood samples were drawn among children from a drop of blood taken from a finger prick or heel prick (for children aged 6–11 months) and collected in a microcuvette strip. Hemoglobin (Hb) was measured on-site using a portable HemoCue rapid testing method (HemoCue® Hb 301 Analyzer - HemoCue AB, Kuvettgatan 1, SE-262 71 Angelholm, Sweden). The anemia results were given on-site and children with severe anemia (hemoglobin level <7 g/dL) were referred to the nearby health facilities. Data collection was done by trained medical student at the Kilimanjaro Christian Medical University College under the supervision of the Institute of Public Health.\n\nThe dependent variable in this study was anemia. Anemia was defined as a blood hemoglobin concentration below 11.0 g/dl in children under five years of age1. The independent variables included socio-demographical characteristics such as age of the mother in years (<20, 20–29 and 30+), education level, occupation (Peasant/farmer, Employed and Others), marital status (single, married/cohabiting and divorced/ separated/ widowed), area of residence (rural and urban depending on how the locals define them), alcohol consumption (Yes and No), BMI of the mother (underweight (<18.5Kg/m2), normal weight (18.5–24.9 Kg/m2), overweight (25–29.9 Kg/m2) and obese (≥30 Kg/m2)) and age and sex of the child. Nutritional characteristics included exclusive breastfeeding (Yes and No)27, colostrum feeding (Yes and No), meal frequency per day (≤3 meals and >3 meals), time at initiation of complimentary feeding (<6 months and 6+ months), use of deworming drugs past six months (Yes and No), stunting and wasting (height-for-age and weight-for-height z-score below minus two standard deviations (-2 SD) from the median of the WHO reference population2. Child anthropometric z-scores were calculated using the 2006 WHO child growth standards through the “zscore06” package in Stata28.\n\nData were analyzed using Stata version 15.1, StataCorp LLC. Means and standard deviations were used to summarize numeric variables while frequency and percentages for categorical variables. Chi-square (χ2) test was used to compare prevalence of anemia by participant characteristics. Odds ratio (OR) and 95% confidence intervals (CIs) were used to determine factors associated with anemia in children using generalized linear models (GLM) with binomial family and logit link function adjusted for potential confounding. Akaike information criteria (AIC) was used to select the best model. The GLM model with binomial family and log link function was favored against the log-linear model i.e. Poisson family with log link function hence all the analyses were performed using the former model. Robust variance estimator was used to account for model misspecification hence improve precision of estimates.\n\nEthical approval was obtained from Kilimanjaro Christian Medical University College Research and Ethics Review Committee (KCMU-CRERC). Permission to conduct the study was also sought from the Rombo District Authority. Prior to data collection, logistics meetings were held with ward and village leaders of selected sites to inform them about the study purpose. Mothers were explained the purpose of the study before enrolment. Those who agreed to participant provided written informed consent. To ensure anonymity of participant information, unique identification numbers were used.\n\n\nResults\n\nData were analyzed for a total of 602 mothers and children aged 6–59 months. The mean age (SD) of mothers in this study was 29.9±7.6 years. More than half (52%) of all mothers were aged between 20–29 years, 70% had primary school education level, 81.3% were married or cohabiting with their partners. Prevalence of obesity among women was 14.3%. The median age (IQR) of children in this study was 24 (14, 36) months while more than half (52.5%) were aged between 24–59 months. Also, more than half (52.7%) of all children were males Table 129.\n\n*Variable with missing information.\n\nThe vast majority (96.3%) were given colostrum while the overall prevalence of exclusive breastfeeding up to six months was 40.1%. Less than half (45.2%) of children in this study were given more than three meals per day while 69.7% were initiated complimentary feeding before six months. Also, 70.5% of children in this study were given deworming drugs. Prevalence of wasting and stunting in this study was 10% and 38.5%, respectively Table 229.\n\n*Variable with missing information\n\nThe mean (SD) hemoglobin level of children aged 6–59 months in this study was 11.2±1.6g/dl while prevalence of anemia (hemoglobin level less than 11g/dl) was 37.9%. Prevalence was slightly higher among females (39.7%) compared to 36.2% among males Figure 229, but this difference was not significant (p=0.40). Prevalence was much higher among children aged 6–23 months (48.1%) compared to 28.5% among those aged 24–59 months Figure 329. This differences in the prevalence by age was statistically significant (p<0.001).\n\nWe performed crude and adjusted analysis to determine factors associated with anemia in children aged 6–59 months in this study. In the crude analysis, factors associated with anemia were whether the mother consumed alcohol, exclusive breastfeeding and child’s age Table 329. Lower odds of anemia were observed among children whose mothers consumed alcohol (OR=0.68, 95%CI 0.48, 0.95, p=0.03). Higher odds of anemia were observed among children who were breastfed exclusively (OR=1.53, 95%CI 1.09, 2.14, p=0.02) and children aged 6–23 months (OR=2.34, 95%CI 1.67, 3.28) compared to those aged 24–59 months which showed a much stronger association with anemia (p<0.001). There was a positive association between stunting and the odds of anemia (OR=1.39, 95%CI 0.99, 1.95) but this association was not strong (p=0.06), Table 329.\n\n*COR=Crude odds ratio\n\nAdjusted analysis for factors associated with anemia in children are shown in Table 429. A multivariable model was developed by adding and later removing one variable after another to assess the presence and effect of confounding. Age of the child was the only variable that remained to be strongly (p<0.001) associated with higher odds of anemia. Adjusted for mother’s age categories (years), whether a mother consumed alcohol during pregnancy, exclusive breastfeeding, wasting, stunting and child’s sex, children aged 6–23 months had over two times higher odds of being anemic (OR=2.44, 95%CI 1.71, 3.49) compared to those aged 24–59 months Table 429.\n\n*AOR: Adjusted odds Ratio\n\n\nDiscussion\n\nPrevalence of anemia among children aged 6-59 months in this was 37.9%. Age of the child was the only factor significantly associated with anemia among children. Prevalence of anemia in this study is much lower compared to the national and regional estimates2 and other sub-population studies in Tanzania9,19. One of these studies was hospital-based9 while the other included children aged 1–35 months19 that could explain the differences. Prevalence in this study is also lower that those reported in other countries5,13,15,16,30. High prevalence in other studies could be linked to differences in study population and wider population coverage since most of them utilized the nationally representative data such as DHS data. Prevalence in this study is similar to 38.8% among under-five children in Haiti4 but higher than 26% in Cuba14 although the study found a consistently higher prevalence among children aged 6–23 than 24–59 months. The low prevalence in Cuba was associated to food-fortification interventions among other strategies14. Despite the observed differences, prevalence reported in this study constitutes a significant public health problem12 that needs intensified efforts.\n\nChildren aged 6–23 months had higher odds of having anemia compared to those aged 24–59 months in this study. Infants (<24 months) are consistently reported to be at higher odds of being anemic in other studies2,4,5,13,14,31,32. During this age, children have a higher demand for nutrients needed for their growth, hence are in need of proper complementary feeding. In this setting, there is a practice of giving porridge (a mixture of water, maize flour, and added sugar), cow’s milk and less diversified foods at a younger age33. This practice could be one of the factors that leads to poor anemia status in children33,34. Also, conflicting advice on infant and young child feeding from a range of sources, including close relatives, community members and health care providers affects breastfeeding practices, which has impact on the child’s anemia status34. Mothers of children aged 6–11 months in Australia did not receive quality anemia care, particularly nutrition advice about healthy foods and the minimum acceptable diet to the care giver, and hemoglobin measurement in the past 12 months22. These interventions are critical in reducing anemia burden for this group of children, who are most at risk22.\n\nThe high prevalence of anemia among infants in this study is of concern13. Interventions such as iron supplementation, food fortification and dietary diversification and management of childhood illnesses in this setting should be targeted towards mothers and children less than two years4,13,21. There were no significant differences in the prevalence of anemia by sex of the child in this study which is consistent to findings from other studies13,14,18,30. On the contrary, females have been reported to be less likely to be anemic in Ethiopia16 which is contrary to findings from Kenya where the risk was high in male children (aged 6 months to 14 years)31, which could account for these differences. We did not find association between maternal characteristics such as age categories, education level, occupation and ANC visits among others contrary to other studies. ANC visit and mother’s occupation have been associated with anemia elsewhere7,16. Higher education level of mothers is reported to be protective against childhood anemia15,19,31.\n\nLikewise, there was no association between nutritional characteristics such as uptake of deworming drugs, exclusive breastfeeding (EBF), colostrum feeding, complementary feeding, feeding frequency with anemia. However, other studies reported an association between nutritional characteristics with a higher risk of anemia in under five children4,5,14,18,33. On the contrary, Meinzen-Derr et al.20 reported that, infants who are exclusively breast-fed for six months in developing countries may be at increased risk of anemia, especially among mothers with a poor iron status. Positive association between EBF and anemia was observed in this study but was not statistically significant. The effect of EBF on anemia in children is an area that needs further research. Despite the observed association in this study, nutritional interventions (EBF included) are among the key strategies to reduce the burden of anemia in under five children21,23,27.\n\n\nConclusion\n\nPrevalence of anemia was lower than the national and regional prevalence but it still constitutes a significant public health problem especially among children aged 6–23 months. Children in this age group were more likely to be anemic compared to those aged 24–59 months. No significant differences of anemia prevalence by sex of the child and any of the nutritional characteristics. Interventions such as iron supplementation, food fortification and dietary diversification and management of childhood illnesses in this setting should be targeted towards mothers and children less than two years.\n\n\nData availability\n\nHarvard Dataverse: Anaemia in children under five years of age in rural Tanzania. https://doi.org/10.7910/DVN/KJMNID29\n\nThis project contains the following underlying data:\n\n- anemiaU5_rombo2016data.tab (Data on anaemia prevalence and associated factors among children under five years of age in the Rombo district, Kilimanjaro region, Northern Tanzania)\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: Questionnaire: Nutritional status of children U5 years of age in Kilimanjaro Region, Northern Tanzania. https://doi.org/10.6084/m9.figshare.12553844.v226\n\nThis project contains the following extended data:\n\n- Questionnaire - Nutritional status of children U5 years of age - English.pdf (Study questionnaire - English)\n\n- Questionnaire - Nutritional status of children U5 years of age.pdf (Study questionnaire)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nWe extend our profound appreciation to the Institute of Public Health, Department of Community Health of Kilimanjaro Christian Medical University College for providing the data used in this study. We also acknowledge all the study participants whose consent enabled this study to be successful.\n\n\nReferences\n\nWHO: Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. World Health Organization, 2011. Reference Source\n\nMoHCDGEC, MoH, NBS, etal.: Tanzania Demographic and Health Survey and Malaria Indicator Survey (TDHS-MIS) 2015-16. Dar es Salaam, Tanzania and Rockville, Maryland, USA. 2016. Reference Source\n\nWHO: Global nutrition targets 2025: anaemia policy brief (WHO/NMH/NHD/14.4). Geneva: World Health Organization; 2014. Reference Source\n\nAyoya MA, Ngnie-Teta I, Séraphin MN, et al.: Prevalence and risk factors of anemia among children 6–59 months old in Haiti. Anemia. 2013; 2013: 502968. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhan JR, Awan N, Misu F: Determinants of anemia among 6–59 months aged children in Bangladesh: evidence from nationally representative data. BMC Pediatr. 2016; 16(1): 3. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKumar T, Taneja S, Yajnik CS, et al.: Prevalence and predictors of anemia in a population of North Indian children. Nutrition. 2014; 30(5): 531–7. PubMed Abstract | Publisher Full Text\n\nParbey PA, Tarkang E, Manu E, et al.: Risk Factors of Anaemia among Children under Five Years in the Hohoe Municipality, Ghana: A Case Control Study. Anemia. 2019; 2019: 2139717. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPhiri KS, Calis JC, Faragher B, et al.: Long term outcome of severe anaemia in Malawian children. PLoS One. 2008; 3(8): e2903. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSimbauranga RH, Kamugisha E, Hokororo A, et al.: Prevalence and factors associated with severe anaemia amongst under-five children hospitalized at Bugando Medical Centre, Mwanza, Tanzania. BMC Hematol. 2015; 15(1): 13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTakele K, Zewotir T, Ndanguza D: Risk factors of morbidity among children under age five in Ethiopia. BMC Public Health. 2019; 19(1): 942. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKassebaum NJ, Jasrasaria R, Naghavi M, et al.: A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014; 123(5): 615-24. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWHO: The global prevalence of anaemia in 2011. Geneva: World Health Organization; 2015. Reference Source\n\nEwusie JE, Ahiadeke C, Beyene J, et al.: Prevalence of anemia among under-5 children in the Ghanaian population: estimates from the Ghana demographic and health survey. BMC Public Health. 2014; 14(1): 626. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPita GM, Jiménez S, Basabe B, et al.: Anemia in children under five years old in Eastern Cuba, 2005-2011. MEDICC Rev. 2014; 16(1): 16–23. PubMed Abstract\n\nGoswmai S, Das KK: Socio-economic and demographic determinants of childhood anemia. J Pediatr (Rio J). 2015; 91(5): 471–7. PubMed Abstract | Publisher Full Text\n\nMohammed SH, Habtewold TD, Esmaillzadeh A: Household, maternal, and child related determinants of hemoglobin levels of Ethiopian children: hierarchical regression analysis. BMC Pediatr. 2019; 19(1): 113. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWoldie H, Kebede Y, Tariku A: Factors associated with anemia among children aged 6–23 months attending growth monitoring at Tsitsika Health Center, Wag-Himra Zone, Northeast Ethiopia. J Nutr Metab. 2015; 2015: 928632. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLegason ID, Atiku A, Ssenyonga R, et al.: Prevalence of anaemia and associated risk factors among children in North-western Uganda: a cross sectional study. BMC Hematol. 2017; 17(1): 10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbubakar A, Uriyo J, Msuya S, et al.: Prevalence and risk factors for poor nutritional status among children in the Kilimanjaro region of Tanzania. Int J Environ Res Public Health. 2012; 9(10): 3506–18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMeinzen-Derr JK, Guerrero ML, Altaye M, et al.: Risk of infant anemia is associated with exclusive breast-feeding and maternal anemia in a Mexican cohort. J Nutr. 2006; 136(2): 452–8. PubMed Abstract | Publisher Full Text\n\nWHO, UNICEF: Focusing on anaemia: Towards an integrated approach for effective anaemia control. Geneva, Switzerland: World Health Organization; 2004. Reference Source\n\nMitchinson C, Strobel N, McAullay D, et al.: Anemia in disadvantaged children aged under five years; quality of care in primary practice. BMC Pediatr. 2019; 19(1): 178. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMoHCDGEC: The national road map strategic plan to improve reproductive, maternal, newborn, child & adolescent health in Tanzania (2016 - 2020): One Plan II. Dar es Salaam, Tanzania. 2016. Reference Source\n\nNBS, OCGS: Population Distribution by Age and Sex. Dar es Salaam, Tanzania. 2013.\n\nSwai SJ, Damian DJ, Urassa S, et al.: Prevalence and risk factors for HIV among people aged 50 years and older in Rombo district, Northern Tanzania. Tanzania Journal of Health Research. 2017; 19(2). Publisher Full Text\n\nMboya IB, Mamseri R, John B, et al.: Questionnaire: Nutritional status of children U5 years of age in Kilimanjaro Region, Northern Tanzania. V2 ed: figshare; 2020.\n\nWHO: Global nutrition targets 2025: breastfeeding policy brief. World Health Organization, 2014. Reference Source\n\nLeroy JL: ZSCORE06: Stata module to calculate anthropometric z-scores using the 2006 WHO child growth standards. 2011. Reference Source\n\nMboya IB, Mamseri R, John B, et al.: Anaemia in children under five years of age in rural Tanzania. V1 ed: Harvard Dataverse; 2020.\n\nMenon MP, Yoon SS: Prevalence and factors associated with anemia among children under 5 years of age—Uganda, 2009. Am J Trop Med Hyg. 2015; 93(3): 521–6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNgesa O, Mwambi H: Prevalence and risk factors of anaemia among children aged between 6 months and 14 years in Kenya. PLoS One. 2014; 9(11): e113756. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAssis AMO, Barreto ML, da Silva Gomes GS, et al.: Childhood anemia prevalence and associated factors in Salvador, Bahia, Brazil. Cad Saude Publica. 2004; 20(6): 1633–41. PubMed Abstract | Publisher Full Text\n\nKejo D, Petrucka PM, Martin H, et al.: Prevalence and predictors of anemia among children under 5 years of age in Arusha District, Tanzania. Pediatric Health Med Ther. 2018; 9: 9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMgongo M, Hussein TH, Stray-Pedersen B, et al.: We give water or porridge, but we don’t really know what the child wants:” a qualitative study on women’s perceptions and practises regarding exclusive breastfeeding in Kilimanjaro region, Tanzania. BMC Pregnancy Childbirth. 2018; 18(1): 323. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "84355",
"date": "17 May 2021",
"name": "Indrapal I Meshram",
"expertise": [
"Reviewer Expertise Public Health Nutrition"
],
"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\nGlobally, about 43% of children under-five are anemic, and there is a marked variation in the prevalence of anemia between lowand middle-income countries. Over 50% of anemic children live in low- and middle-income countries 12. There is also a variation in anemia prevalence within low- and middle-income countries; Repetition of sentence\nUnder study design and setting\nNo need to give district profile, better to shift under introduction.\n\nVillages were randomly selected from a random sample of wards. I think the study was done in both urban and rural areas, so while using, use both village/wards.\n\nHow many villages and how many children from each villages/wards were selected is not clear. Also author has mentioned that the survey was done in villages, then wards also mentioned, is it a rural ward or urban, whether urban/rural children were selected is not clear. If so, how these children were selected from urban and rural areas were selected need to be mentioned.\n\nProportionate sampling should be done in order to give equal representation.\nUnder Study population, sample size and sampling-\n\nIt is mentioned that children whose mothers were not available on the day of data collection were excluded from the study as it was not possible to verify child information if next in kin or neighbor was interviewed. But in next para, it is mentioned that If the child’s mother was not at home, the research team visited the house for a minimum of three times before declaring that the participant could not be reached. This is not matching with above statement.\n\nEthical para should be written before analysis.\n\nWhy underweight prevalence is not given when weight has been measured.\n\nIn table 1, age of child mentioned is 6-26, pl correct 6-23.\n\nTable 2, Time at complementary feeding, correct as age at CF.\n\nWhile selecting reference category, positive variable should be consider as reference.\n\nAdjusted analysis, which variables were adjusted in regression is not clear, which variable was removed first should be mentioned.\nUnder discussion\nPrevalence in this study is similar to 38.8% among under-five children in Haiti, but higher than 26% in Cuba. The low prevalence in Cuba was associated to food-fortification interventions among other strategies.\n\nSentence need to rewrite properly such as study by ----- observed 39% prevalence of anemia among under 5 year children in Haiti, while study by -------- observed lower (26%) prevalence of anemia in Cuba which may be due to food fortification being implemented among this study population. This practice could be one of the factors that leads to poor anemia status in children, sentence is not correct it is not poor anemia status but low hemoglobin levels.\n\nMothers of children aged 6–11 months in Australia did not receive quality anemia care, particularly nutrition advice about healthy foods and the minimum acceptable diet to the care givers- this should not be mentioned here as this study is not in Australia.\n\nThe high prevalence of anemia among infants in this study is of concern. Interventions such as iron supplementation, food fortification and dietary diversification and management of childhood illnesses in this setting should be targeted towards mothers and children less than two years. There were no significant differences in the prevalence of anemia by sex of the child in this study which is consistent to findings from other studies- there is no continuity of statement first sentence should deleted as it is there in last para.\n\nSentence writing needs to be changed, should take help from English speaking person who can write fluently.\n\nFrom the study, no other factors except age of child was observed significant, other factors such as type of house, drinking water facility sanitary latrine, morbidities in previous fortnight or one months if studied would have given more information, no new information /variable has been found or studied.\nUnder conclusion\nChildren in this age group were more likely to be anemic compared to those aged 24–59 months-this is of no use in this para first sentence itself is explanatory. In conclusion one has to mention that there is a need to explore other factors contributing to anemia as IFS supplementation, morbidities during previous fortnight, sanitary latrine use and mothers hemoglobin status. In recommendation, it is mentioned IFA supplementation, but whether these children were supplemented IFA has not been studied although this is universal program. So recommendation should also be based on the finding of the study.\n\nSpelling of complementary feeding should be checked.\nIn general\nDiscussion needs to be rewritten properly with continuity of sentence.\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? Yes",
"responses": [
{
"c_id": "7331",
"date": "19 Jan 2022",
"name": "Innocent Mboya",
"role": "Author Response",
"response": "Dear Meshram, Thank you for taking time to review our manuscripts. The manuscript has been revised based on your suggestions as explained below. Comments: Introduction: Globally, about 43% of children under-five are anemic, and there is a marked variation in the prevalence of anemia between lowand middle-income countries. Over 50% of anemic children live in low- and middle-income countries 12. There is also a variation in anemia prevalence within low- and middle-income countries; Repetition of sentence Response: The paragraph has been revised to avoid repetitions. Under study design and setting: No need to give district profile, better to shift under introduction. Response: The district profile is briefly discussed here to give a reader the context with respect to setting where the study was conducted. The background section focused on describing the problem given the current literature and showing the gap that necessitated the conduct of this study. For this reason, the district profile fits best in the methods section than in the introduction. The text has been slightly revised to avoid repetitions. Villages were randomly selected from a random sample of wards. I think the study was done in both urban and rural areas, so while using, use both village/wards. Response: Rombo is considered a rural district of Kilimanjaro region. However, participants were asked whether they considered the place of their residence as urban or rural. Those who resided in urban areas were mostly from the district’s centre (mostly referred by locals as urban or town). The key services such as the district’s commissioner’s office/headquarter, district hospital, among others are in this setting. In addition, wards are largest administrative units and contains several villages. How many villages and how many children from each villages/wards were selected is not clear. Also author has mentioned that the survey was done in villages, then wards also mentioned, is it a rural ward or urban, whether urban/rural children were selected is not clear. If so, how these children were selected from urban and rural areas were selected need to be mentioned. Response: Two villages were randomly selected from a random sample of wards. Also, a systematic random sampling was used to select households. Changes have been made to in the study population, sample size and sampling to make this more specific and clearer. Regarding urban vs rural, please see the response above. Proportionate sampling should be done in order to give equal representation. Response: More than half of all wards in the district were included in this study. For this reason, data from this study are representative of the district population. However, the findings from this study may not be generalized to other districts in Kilimanjaro region and the entire country. This has been added in the last paragraph of the discussion section detailing the study strengths and limitations. Under Study population, sample size and sampling - It is mentioned that children whose mothers were not available on the day of data collection were excluded from the study as it was not possible to verify child information if next in kin or neighbor was interviewed. But in next para, it is mentioned that If the child’s mother was not at home, the research team visited the house for a minimum of three times before declaring that the participant could not be reached. This is not matching with above statement. Response: The reviewer comment is acknowledged. The paragraph has been revised to merge and link this information. Ethical para should be written before analysis. Response: The ethics paragraph has been repositioned. Why underweight prevalence is not given when weight has been measured. Response: Underweight results has been included in the descriptive statistics. In table 1, age of child mentioned is 6-26, pl correct 6-23. Response: Child age categories has been corrected in Table 1. Table 2, Time at complementary feeding, correct as age at CF. Response: Time at complementary feeding changed to Age at complementary feeding in Age 2 and 3. While selecting reference category, positive variable should be consider as reference. Response: We thank the reviewer for this comment. The initial analysis considered the positive category as the reference. Adjusted analysis, which variables were adjusted in regression is not clear, which variable was removed first should be mentioned. Response: Stepwise regression method was used to select variables to include in the adjusted analysis at 10% threshold level. Age of the child remained the only significant predictor of anemia at this stage. Maternal age, alcohol use (statistically significant in the crude analysis), sex of the child, and child’s nutritional characteristics, specifically exclusive breastfeeding, wasting, and stunting were considered potential confounders, hence included in the final model. This information has been added in the data analysis section. Under discussion: Prevalence in this study is similar to 38.8% among under-five children in Haiti, but higher than 26% in Cuba. The low prevalence in Cuba was associated to food-fortification interventions among other strategies. Sentence need to rewrite properly such as study by ----- observed 39% prevalence of anemia among under 5 year children in Haiti, while study by -------- observed lower (26%) prevalence of anemia in Cuba which may be due to food fortification being implemented among this study population. Response: The sentences have been revised accordingly. This practice could be one of the factors that leads to poor anemia status in children, sentence is not correct it is not poor anemia status but low hemoglobin levels. Response: The sentence has been corrected. Mothers of children aged 6–11 months in Australia did not receive quality anemia care, particularly nutrition advice about healthy foods and the minimum acceptable diet to the care givers- this should not be mentioned here as this study is not in Australia. Response: The sentence has been revised and included the recommended best practices from this study. The high prevalence of anemia among infants in this study is of concern. Interventions such as iron supplementation, food fortification and dietary diversification and management of childhood illnesses in this setting should be targeted towards mothers and children less than two years. There were no significant differences in the prevalence of anemia by sex of the child in this study which is consistent to findings from other studies- there is no continuity of statement first sentence should deleted as it is there in last para. Response: The first two sentences have been deleted to ensure continuity of sentences in this paragraph. Sentence writing needs to be changed, should take help from English speaking person who can write fluently. Response: The manuscript has been revised to correct for grammatical errors and structure of sentences. From the study, no other factors except age of child was observed significant, other factors such as type of house, drinking water facility sanitary latrine, morbidities in previous fortnight or one months if studied would have given more information, no new information /variable has been found or studied. Response: The reviewer comment is acknowledged. Determinants of anemia are multi-factorial and are likely to differ across settings. The discussion section has also highlighted numerous other factors that were analysed but had no significant statistical association with anemia in children. Qualitative and quantitative studies, especially the methods employing longitudinal measurements may be relevant in this context to determine the factors associated with anemia in children to inform interventions. This recommendation has been added in the conclusion paragraph. Under conclusion: Children in this age group were more likely to be anemic compared to those aged 24–59 months-this is of no use in this para first sentence itself is explanatory. In conclusion one has to mention that there is a need to explore other factors contributing to anemia as IFS supplementation, morbidities during previous fortnight, sanitary latrine use and mothers hemoglobin status. In recommendation, it is mentioned IFA supplementation, but whether these children were supplemented IFA has not been studied although this is universal program. So recommendation should also be based on the finding of the study. Response: The recommendation has been added as suggested. Spelling of complementary feeding should be checked. Response: The spelling errors have been checked and corrected. In general: Discussion needs to be rewritten properly with continuity of sentence. Response: The discussion section has been revised based also on the reviewer suggestions."
}
]
},
{
"id": "95218",
"date": "08 Oct 2021",
"name": "Tania Supali",
"expertise": [
"Reviewer Expertise 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\nIt is difficult to review the manuscript because the format of manuscript is not in one column with line numbering.\nIntroduction: needs to be rewritten properly\n\nMethods:\nIt should be written systematically. Example: Data collection for Hb measurement (anemia) should be separated from collecting questionnaire data.\n\nThe rural and urban study areas were not described in detail. There are 27 children from urban and 575 children from rural (Table 1). What is the definition of urban and rural?\n\nWhy was the number of urban children only 27 children?\n\nResults:\nPrevalence of anemia based on age and sex – can be combined in one table.\n\nTable 1 and 3 can be combined in one table.\n\nPlease rewrite the results systematically\n\nDiscussion:\nIt is unclear why children below 2 years old showed high prevalence of anemia compared to 24-59 months children. Please explain in more details.\n\nA question about deworming drugs was included in the questionnaire. What was the prevalence of STH in the study area? The impact of intestinal helminth infection should be discussed in this manuscript.\n\nMalaria is prevalent in Tanzania. Why wasn't malaria data included in the study, given that it contributes to anemia?\n\nIn general: The manuscript needs major revision.\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? Yes",
"responses": [
{
"c_id": "7332",
"date": "19 Jan 2022",
"name": "Innocent Mboya",
"role": "Author Response",
"response": "Dear Supali, Thank you for your time to review this manuscript. We have addressed your comments and suggestions as detailed below. Introduction: needs to be rewritten properly Response: The introduction has been revised accordingly. Methods: It should be written systematically. Example: Data collection for Hb measurement (anemia) should be separated from collecting questionnaire data. Response: Information about Hb and other measurements has been shifted to the study variables and measurements section. The rural and urban study areas were not described in detail. There are 27 children from urban and 575 children from rural (Table 1). What is the definition of urban and rural? Response: As also responded to the first reviewer, Rombo is considered a rural district of Kilimanjaro region. However, participants were asked whether they considered the place of their residence as urban or rural. Those who resided in urban areas were mostly from the district’s centre (mostly referred by locals as urban or town). The key services such as the district’s commissioner’s office/headquarter, district hospital, among others are in this setting. In addition, wards are largest administrative units and contains several villages. Why was the number of urban children only 27 children? Response: Please see the response above. Results: Prevalence of anemia based on age and sex – can be combined in one table. Response: The reviewer response is acknowledged. The figures are much preferred against tables for better presentation and for the capturing the reader’s interest. This is also supported by the observed findings in this study where anemia prevalence differed significantly by child’s age groups. Table 1 and 3 can be combined in one table. Response: Tables 1 and 2 focuses on describing the participant background and nutritional characteristics. Table 3 contains slightly different information. It compares the prevalence of anemia by these characteristics and provides results from the crude regression analysis. For these reasons, we would like to retain the current table structure. Please rewrite the results systematically Response: The results section has been revised accordingly. Discussion: It is unclear why children below 2 years old showed high prevalence of anemia compared to 24-59 months children. Please explain in more details. Response: The reviewer comment is acknowledged. The first and second paragraphs of the discussion section has been revised to clearly explain the observed results, which also compare with previous studies and shows the public health implications. A question about deworming drugs was included in the questionnaire. What was the prevalence of STH in the study area? The impact of intestinal helminth infection should be discussed in this manuscript. Response: Unfortunately, the study did not assess the prevalence of STH which may be associated with increased anemia risk, which remains an area for future studies. Malaria is prevalent in Tanzania. Why wasn't malaria data included in the study, given that it contributes to anemia? Response: We thank the reviewer for this comment. Although malaria is prevalent in Tanzania, not all regions are highly affected. At the regional level, malaria prevalence is high in the Southern slopes of Mount Kilimanjaro compared to the highlands[1]. Secondly, the primary study aim was to assess prevalence of anemia in children under five in the Rombo district. A more comprehensive study that capture the social-economic, demographic, behavioral, and clinical determinants of anemia and other child nutritional-related characteristics is essential in this setting. In general: The manuscript needs major revision. Response: The manuscript has been revised accordingly. [1] Kassam, N. A., Kaaya, R. D., Damian, D. J., Schmiegelow, C., Kavishe, R. A., Alifrangis, M., & Wang, C. W. (2021). Ten years of monitoring malaria trend and factors associated with malaria test positivity rates in Lower Moshi. Malaria Journal, 20(1), 1-9."
}
]
}
] | 1
|
https://f1000research.com/articles/9-1102
|
https://f1000research.com/articles/12-125/v1
|
02 Feb 23
|
{
"type": "Research Article",
"title": "‘Glocalizing’ land-use and forest governance in the tropics: examining research partnerships and international forest policies affecting Brazil, DRC and Indonesia",
"authors": [
"Thiago Kanashiro Uehara",
"Florie Chazarin",
"Louise Nakagawa",
"Ariane Favareto",
"Tamara Tobias",
"Arilson Favareto",
"Rigobert Minani",
"Bramasto Nugroho",
"Fitta Setiajiati",
"Silfi Iriyani",
"Damayanti Buchori",
"Chiara Chiavaroli",
"Florie Chazarin",
"Louise Nakagawa",
"Ariane Favareto",
"Tamara Tobias",
"Arilson Favareto",
"Rigobert Minani",
"Bramasto Nugroho",
"Fitta Setiajiati",
"Silfi Iriyani",
"Damayanti Buchori",
"Chiara Chiavaroli"
],
"abstract": "Background: International and market forces are key drivers of deforestation and forest degradation, with transnational and market-based solutions in land-use and forest governance often missing economic, distributive, and environmental targets. Methods: This paper tackles both the framing and effectiveness of transnational initiatives affecting forest lands and peoples in the Global South, and the quality of relationships between institutions in the Global North and the Global South. Through more equitable research partnerships, this paper draws lessons from case studies in Indonesia (legality verification system in different forest property regimes), the Democratic Republic of the Congo (lifting of a moratorium on new logging concession), and Brazil (FSC in the Amazon region and the Amazon Fund). Results: International partnerships have privileged market-based instruments and commodity exchange between Global South and Global North countries, and the benefits of such mechanisms are unevenly distributed. Complementary and alternative policy instruments are discussed for each geography. Conclusions: Glocalizing land-use and forest governance implies in advancing equitable research partnerships between institutions in the Global South and Global North, and strengthening a community of practice for critical enquiry and engagement in partnerships for sustainable development. Land-use, climate and forest governance mechanisms must redress power dynamics, and partnership models, and commit to improving well-being and sustainable livelihood outcomes.",
"keywords": [
"Research partnerships",
"North–South",
"forest governance",
"forest policy",
"transnational initiatives",
"international cooperation",
"Brazil",
"Indonesia",
"Congo",
"DRC"
],
"content": "Introduction\n\nInternational and market forces – particularly industrial-scale commodity markets and large-scale land acquisitions – are key underlying drivers of deforestation and forest degradation, according to the International Panel on Climate Change (IPCC).1 Their latest (2022) assessment comes as international and market-based mechanisms to steer land use in the tropics are continuing apace, and as climate crises compound environmental degradation and systemic poverty. The international community needs to take stock of how it frames and manages land-use, forest and climate policy collaborations: it needs to reflect on lessons learned to date, scale up effective solutions, rethink those that have not worked as intended, and improve the dynamics of transnational collaborations.\n\nA rethink of international collaborations needs to be conducted in an inclusive manner. This includes revisiting Sustainable Development Goal (SDGs) 17 on ‘Global Partnerships for Sustainable Development’, the most central and implementation-focused of all the SDGs and climate targets.2 More inclusive international collaborations entail policy institutes in the ‘Global South’ leading and co-leading on critical analysis of international partnerships, and institutions in the ‘Global North’ acknowledging and learning from diverse perspectives, as well as enabling partnerships for ‘glocal’ land-use and forest governance analysis and solutions.\n\nIn this paper, being ‘glocal’ (or ‘glocalizing’) is not about translating, adapting or implementing Global North (or so-called ‘global’) ideas onto the ‘developing’ world. Rather, ‘glocalizing’ relates to redressing imbalances in the interplay between ‘global’ and ‘local’ imperatives in international collaboration, and between institutions in Global North and Global South countries.\n\nThis publication brings together the results of a research partnership between four policy institutes: CEBRAP Sustentabilidade (Centro Brasileiro de Análise e Planejamento’s sustainability centre) in Brazil, CEPAS (Centre d’Etudes pour l’Action Sociale) in the Democratic Republic of the Congo, CTSS IPB University (IPB University’s Centre for Transdisciplinary and Sustainability Sciences) in Indonesia, and Chatham House (Royal Institute of International Affairs) in the United Kingdom.3 Through a twenty-month collaborative project, the four institutes sought to establish and discuss equitable research partnerships while examining prominent transnational initiatives that are affecting forest lands and peoples in the tropics.\n\nThe results of this work speak to the scientific and international communities – primarily those with an interest or power in reframing international partnerships.4 This paper highlights the importance that should be given to three dimensions of ‘global partnerships for sustainable development’: (i) the quality of the relationships and research partnerships that exist between policy institutes in the Global North and the Global South; (ii) the role of policy institutes headquartered in the Global South in leading or co-leading critical analysis of transnational policy mechanisms that affect the ‘developing world’; and (iii) the need to redress not only power asymmetries but also policy mixes and models to achieve domestic and global priorities for sustainable development, which should go beyond supporting international supply chains, and position well-being and sustainable livelihood outcomes at the core of international partnerships.\n\nThe first section5 frames this publication in terms of policy ideas, proposed solutions for and myths about forest governance. It highlights the growth of voluntary and transnational partnerships centred on commodities and international supply chains. The second section6 discusses the process of establishing research partnerships between policy institutes in the Global North and South, in light of principles of equity, diversity and inclusion (EDI). Led by policy researchers in think-tanks based in the countries with the largest tropical forest areas in the world, the third section presents insights and ‘glocal views’ on the Forest Stewardship Council (FSC) and the Amazon Fund in Brazil,7 on World Bank-led reforms that are affecting logging concessions in the Democratic Republic of the Congo (DRC),8 and on the relevance of a timber verification system for different forest regimes in Indonesia.9 Note that domestic audiences in Brazil, the DRC and Indonesia were reached through policy briefs published in their preferred languages.10 The conclusions revisit the nature of prevalent land-use and forest solutions, with recommendations for the international community of practice and research on climate policy, land-use and forest governance.\n\n\nForest governance solutions\n\nDespite the absence of an effective global agreement on forests, international institutions, transnational banks, philanthropies and donor governments have supported various North–South initiatives aimed at reducing or halting deforestation and forest degradation tout court in the tropics. Such initiatives include those tackling illegal logging and its related trade, sustainable forest management and governance reforms in low- and middle-income countries.11 Multilateral coordination on climate and forests seems to be growing. Some of the latest United Nations Conferences of the Parties (COPs) have launched several voluntary, multiparty pledges, such as the Glasgow Leaders’ Declaration on Forests and Land Use, and the Global Forest Finance Pledge at COP26 in Glasgow, and the Forest and Climate Leaders’ Partnership at COP27 in Sharm El-Sheik.\n\nVoluntary initiatives (self-determined or self-imposed), incentive-based instruments and market-based solutions have been growing as forest governance mechanisms.12 Such initiatives have been on the rise since the 1990s,13 and include the FSC, REDD+,14 Voluntary Partnership Agreements (VPA) between the EU and timber-producing countries, and economic recovery loans by the World Bank conditional on reforms in resource management. The role of the private sector in shaping forest governance solutions further expanded in the 2000s, with the establishment of initiatives such as the Tropical Forest Alliance, commodity roundtables, the Soy Moratorium, and the Consumer Goods Forum deforestation pledge – all of which mirror the evolution of corporate social responsibility and sustainability in supply chains. Corporations (focal firms like Unilever, Nestlé, Cargill, Klabin or Ikea) have for some decades addressed sustainable supply chain management,15 with a growing role for environmental non-governmental organizations (NGOs) in supporting both private and public initiatives for sustainable supply chains.16\n\nGovernments and focal countries have been following suit by complementing or supporting market-based mechanisms and solutions in sustainable supply chains – for instance, through demand or import regulations and due diligence mechanisms for deforestation-free supply chains. The US Lacey Act, as amended in 2008, and the EU Forest Law Enforcement, Governance and Trade (FLEGT) action plan established in 2003 are pioneers in engaging governments in the Global North in supporting ‘sustainable supply chains’.17 All these initiatives, which include the more recent pledges at COP26 and COP27, fall under the umbrella of official development assistance (ODA) and SDG 17.18\n\nSome of the prevalent ‘solutions’ for improving forest governance are frequently not backed up by available scientific evidence, according to a 2020 review by Delabre et al.,19 For instance, one myth is that ‘markets are the solution to deforestation and forest degradation’, with forest politics emphasizing voluntary agreements and market mechanisms20 as prevalent and growing forest governance mechanisms. This myth usually comes with the assumption that market-based mechanisms are more efficient and cost-effective than regulations.21 Yet, the assessment of ‘efficiency’ changes when social indicators such as well-being are prioritized over economic costs.22\n\nIn assessing sustainability in supply chains, the challenge is not only to identify how a commodity is produced, traded and consumed, but mainly to find the convergence of expectations between buyers and suppliers when it comes to defining ‘sustainability’, and distributing benefits across value chains.23 Transparency and open-data enterprises have helped such assessments, particularly when supported by technological innovation, big data24 or participatory and independent monitoring systems.25 These mechanisms facilitate sustainability assessments of industrial modes of production, and export-oriented and import-dependent economies, but rarely address well-being or inequality indicators,26 or risks of leakage27 (collateral effect across governance boundaries).28 For instance, export-oriented production systems (such as financial and industrial forest and agri-food practices) have been better positioned to benefit from sustainability verification systems than domestic or ‘civic’ production systems, when these are based on shorter circuits of commercialization, cooperation or reciprocity logics.29\n\nSolutions also prove inadequate when targets, indicators and metrics of so-called ‘good’ forest governance are oversimplified and overlook dynamics of corruption, oppression and marginalization.30 For instance, another known myth influencing decisions at funding, development and implementing levels, is the assumption that local communities are already included in decision-making.31 Efforts to include smallholders into international and market initiatives have had only limited results and success.32 Heterogeneity and intersectionality are often oversimplified in ‘participatory’ forums, especially beyond the design phase of an initiative.33\n\nIn sum, the results of forest solutions have varied from limited impacts to selective reforms in governance, with the distribution of costs and benefits of prevalent solutions rarely aligning with principles of sustainability and equity.34 Despite the sum of efforts invested in public regulations, private-led initiatives and hybrid forms of forest governance, the world’s forest area continues to shrink. This area includes the countries with the largest expanses of tropical forests – Brazil, the DRC and Indonesia – where rural and forest peoples struggle for autonomy amid varying levels of poverty, inequality and market integration. Selected indicators of the state of forests and the biggest tropical forest countries are summarized in Table 1.\n\n‘Governance responses to addressing the direct and underlying drivers of deforestation have been inadequate to reduce pressures’, according to the 2022 IPCC assessment on forest governance.42 It notes that transformations are needed in several areas, such as the strengthening of environmental laws and policies, better combination of public, private and hybrid initiatives for environmental responsibility, acknowledging land tenure and rights, and enhancing inclusive stakeholder participation to ensure equitable outcomes.43 Also, as remarked by Lambin et al., privately driven mechanisms have the potential to address regulatory gaps in land-use governance in the tropics under ‘appropriate policy mixes’, where ‘various policy instruments perform complementary functions without undermining each other’.44 Notably, ‘public regulations maintain an essential role of protecting basic environmental conditions, as well as providing the enabling conditions for private and hybrid initiatives, and pushing standards upward’.45 In order transform land-use and forest governance responses, it is essential to redress relationships and partnerships between actors across the Global North and South.\n\nPrior to presenting the analysis led by policy researchers with CEBRAP, CEPAS and CTSS in partnership with Chatham House (Section 3), the next section looks at the challenges and lessons learned in establishing research partnerships between these policy institutes. By doing so, we hope to enable greater political accountability and more inclusive governance, which can be seen as part of a ‘transformative lever towards improving environmental governance and resilience of tropical forests’.46\n\n\nNorth–South and South–South research partnerships\n\nEfforts to redress, diversify and enrich local and global perspectives in international cooperation and in research partnerships should pass through the implementation of equitable North–South partnerships. In this section, we argue that the construction of ‘equitable’ research partnerships is a fundamental dimension of the set of North–South relationships to be established in order to improve environmental governance and resilience of tropical forests. The section includes a critical analysis of conventional modes of North–South relationships, as well as the challenges and lessons learned in building a North–South and South–South research partnership between CEBRAP, CEPAS, CTSS and Chatham House. This reflection has the potential to inform good practices in transnational climate and forest collaborations given the limited scholarship that discusses equality, diversity and inclusion in North–South research partnerships in resource governance. An emerging debate on ‘decolonizing’ research invites scholars to employ equitable publication policies and participatory methodologies, and to consider the power relationships that emerge with other researchers and research participants. Yet, neocolonial practices still significantly shape North–South research partnerships, which were avoided in this project.\n\nThe geopolitical power asymmetry between the Global North and the Global South is often mirrored in transnational research partnerships.47 Traditionally, research partners in Global North countries have disproportionate power across several areas of a research partnership, such as: decision-making arrangements; research design; authorship arrangements; and funding management. The asymmetry of power is commonly manifested when Global North partners design and control the entire research process, while their counterparts in the Global South collect data, with limited to no say in research design, methodology and research outputs. The Global South is often treated as ‘a laboratory for the North providing interesting scientific data’, in the words of Maselli et al.,48 with institutions in the Global South not enabled or allowed space to participate effectively in knowledge production. Notably, these research practices lead to efficient and systematic manners to extract and appropriate knowledge from research participants and local partners, with this knowledge rarely reaching or benefiting local participants and national stakeholders.\n\nBefore beginning a collaboration with CTSS, CEPAS and CEBRAP on (g)local forest governance in 2020, Chatham House had worked on global forest governance for two decades. The idea to advance equitable partnerships emerged after discussions at the long-standing series of Global Forums on Forest Governance organized by Chatham House,49 and from the identification of the need to enable and embrace greater diversity as a transformative lever that improves policy analysis and solutions. The opportunity identified was to craft and initiate an innovative work programme to work with and learn from researchers and analysts headquartered in policy institutes in some of the countries with the largest tropical forests in the world. This idea was discussed between Chatham House researchers and funders, and implemented in the 20 months from March 2020 to the end of 2022. Although some of the institutions were known to Chatham House through other projects, like CEBRAP and IPB University through the Trade Hub/UKRI consortium, the relationships with CEPAS and CTSS were crafted from zero.\n\nA clear set of ground rules on the relationships among partners was established in this project. A first, important step to construct new and more equitable practices was to recognize and openly discuss the asymmetries of power derived from Chatham House’s privileged relationship with funders, which resulted in Chatham House writing and negotiating the proposal, defining its overall scope and allocating budget. Second, an anonymized Equity, Diversity and Inclusion (EDI) survey was conducted in the first months of the partnership, with all researchers involved in the project, to identify how they understood responsibilities and roles in the decision-making process. Arnstein’s ladder of participation50 – a framework that describes and identifies different types of participatory spaces ranging from no participation to effective participation – was used to map current modes of relationship and clarify internal decision-making arrangements. Rather than creating a space of ‘formal’ participation, it was important for all partners to clarify which elements of the project could be negotiated and which could not, since they were already established in the agreement between Chatham House and the funder. Discussing this openly avoided forms of ineffective participation such as ‘tokenism’ and ‘manipulation’.51 Moreover, each participant identified how much decision-making power they were aiming to have in the project and what effective participation meant to them.\n\nOne important outcome of the survey was that partners openly negotiated and agreed on the establishment of independent spaces of decision-making with the aim to preserve the autonomy of each policy institute within the limits of the project proposal. In particular, for researchers based in the Global South, it was important to have the autonomy to select their case studies, research methodologies and key literature including scholars writing in languages other than English, such as Portuguese, French and Indonesian. This practice differs from common processes which limit agency of researchers in the Global South. The agreed balance between dependence and independence varied by policy institute, according to the capacities, traditions and preferences stated by the institutes in the Global South, as well as the limits posed by the terms of references agreed between Chatham House and funders. There was no single solution in partnership management, and adaptability was key for Chatham House to accommodate differences within the limits of the project objectives, budget and timeline. Based on the results of the survey, Chatham House staff adjusted project management practices to support more autonomous decision-making in the project. In particular, it was important for Chatham House (CH) staff to recognize that the partners felt the exercise of subtle coercion (later discovered as unintended) when suggestions and recommendations were made by CH staff. This arose both in light of the privileged relationship of Chatham House with the partners and on the basis of implicit assumptions related to its authority as a renowned institution in the UK and in the Global North in general. CH staff were not aware of the coercion felt by partners, particularly when using the verb ‘to encourage’ in meetings. But this was discussed with the EDI consultant, leading to CH staff revisiting their ‘positionality’,52 rethinking practices when providing comments and suggestions to partners, and understanding the impact they had on partners’ decisions. Notably, partners had a permanent space to raise grievances or complain about decision-making processes in the project.\n\nAt the end of the project, another anonymous survey revealed positive feedback by the partners in the Global South with regards to the management of the project’s decision-making processes, and an appreciation that their inputs and suggestions were collected by an independent consultant and then shared with, and enacted by CH staff. In particular, all participants agreed that decision-making arrangements with Chatham House oscillated between equal decision-making and the co-definition of the research objectives and methodologies, with substantial responsibilities delegated to the partners.\n\nSouth–South collaborations are often overlooked when compared to North–South research partnerships,53 but this project sought to address this gap. In this research, similarities and differences in the political economies of Brazil, the DRC and Indonesia were acknowledged, vis-à-vis domestic development challenges and the international pressures. The overall assessment was that transnational mechanisms have largely benefited international operators (i.e., donors, banks, multinational companies) rather than local or national stakeholders, and that there was a case for this dynamic to be redressed.\n\nAlso, the assumption was that policy institutes in the South would benefit from strengthening ties. For this reason, channels for South–South collaboration with and without mediation by Chatham House were established. Partners in the South engaged in bilateral meetings, presented their results to each other, and exchanged comments on each other’s work. These were important steps to strengthening capacities for collaborations, and to build a collective critique of transnational policies.\n\nThe inclusion of local knowledge is fundamental to socially just environmental policymaking.54 The inclusion of women, Indigenous Peoples (IP) and local communities in knowledge co-production is considered key to tackling the environmental risks related to climate change.55 Mindful of this, research partners engaged in a critical reflection on their positionality and on the ways in which their institutional identity could frame project outputs by privileging certain voices over others. It was important to recognize how the political and religious identity of the institutions involved in the project implied the exclusion of certain local voices, and how to deal with this within the research process, and to acknowledge both personal and institutional positionality.\n\nIn terms of frameworks and guidance, the researchers discussed diversity and inclusion in research methodology, inclusive terminologies and classifications of agents in forest governance, and the need to use gender-sensitive focus groups or to include questions on gender, ethnicity and age as determinants of access to natural resources. This also implied critically assessing the extent to which the project participants who consulted in the research represented the diversity of local stakeholders. Finally, in the process of analysing the research results, particular attention was given to the distributive aspects of forest governance initiatives.\n\nAn effort was made in relation to the adaptation of the research outputs to formats that allowed more incidence in domestic contexts and among diverse stakeholders. This was attempted by producing policy briefs in different languages (Bahasa Indonesia, French and Portuguese) and audio-visual materials to share the project results with important stakeholders who do not belong to elites.\n\nTo conclude, addressing power asymmetries in research partnerships is necessary for implementing socially just practices of knowledge production. Openly discussing project management practices helped advance equitable collaborations, opening up an important space of reflexivity for institutions and researchers working in transnational agreements. Finally, an EDI toolkit on establishing equitable research partnerships can be found as a publication in the Chatham House Forest Governance and Legality website.56\n\n\n(G)local views on transnational policy instruments\n\nThis section examines transnational forest governance mechanisms followed by insights and recommendations from policy researchers in the Global South, with CEBRAP, CEPAS and CTSS. Each policy institute examined transnational mechanisms understood as influential and paradigmatic57 (cases that highlight general characteristics of transnational mechanisms affecting land-use and forest governance).\n\nThe FSC and the Amazon Fund are investigated in Section 3.1, led by Louise Nakagawa and CEBRAP colleagues in Brazil. The implications of a World Bank economic recovery loan to the DRC, conditioned on new regulations on forests and logging concessions are discussed in Section 3.2, led by Rigobert Minani with CEPAS. Indonesia’s timber legality and sustainability assurance system, which was co-sponsored by the EU, is discussed in Section 3.3, led by Bramasto Nugroho and CTSS IPB University colleagues.\n\nThe FSC is an international non-profit, multi-stakeholder organization created in 1993 in response to the failure of the 1992 UN Earth Summit in Rio de Janeiro to reach a global agreement to stop deforestation.58 As an alternative to boycotting forest products, the FSC proposed a voluntary market-based instrument (eco-certification) to improve forest management. The FSC gained a reputation as an ecolabel and certification programme.59 Of the total FSC-certified area, 4% is owned by smallholders.60\n\nPrimarily funded by Norway and Germany, the Amazon Fund is one of the first UN REDD+ mechanisms.61 The notion of REDD – Reducing Emissions from Deforestation and forest Degradation – first emerged in climate negotiations. The role of conservation, sustainable forest management and forest carbon stocks in developing countries were added to become REDD+, in 2008.62 REDD+ is ‘the largest payment for ecosystem services initiatives worldwide’,63 and it provides incentives for countries to seek and obtain results-based payments based on carbon dioxide (CO2) metrics.\n\nForest concession is a contractual arrangement for the temporary allocation of public forest resources to another party, such as companies, communities and NGOs.64 Forest concessions have been widespread across tropical regions,65 including the DRC, but in 2002 a moratorium (which is a legal temporary prohibition or suspension of an activity) was imposed on new concessions.66 The moratorium, which was encouraged by the World Bank, was expected to help the DRC to control land use, collect revenues and repay debts.67\n\nDue diligence and verification mechanisms are gaining popularity as part of the commercialization of forest and agricultural commodities. Indonesia's national timber sustainability assurance system, SVLK (Sistem Verificasi Legalitas Kayu), is one of the first of its kind. Launched in 2009, SVLK is a key component of the FLEGT Voluntary Partnership Agreement established between Indonesia and the EU. It aims to ensure that timber is harvested, transported and processed legally.68\n\nNotably, the FSC, Amazon Fund, the moratorium on concessions, and verification mechanisms have international or transitional origins; they tackle commodity markets (i.e., timber and carbon); and were adapted and implemented in multiple countries. FSC-member organizations are present in 89 countries; 69 16 countries submitted REDD+ action plans to the United Nations Framework Convention on Climate Change (UNFCCC);70 Central African countries have followed the World Bank’s conditionalities on reforming forest codes; and 15 countries are implementing or negotiating FLEGT Voluntary Partnership Agreements with the EU, which requires the establishment of a timber legality verification system. The analysis that follows should by no means be generalized but is particular to each specific context, and it should be read in the context of the glocalization of forest governance analysis and solutions.\n\n\nRevisiting community and governance impacts of the FSC and Amazon Fund in Brazil\n\nThe Amazon is a natural heritage region for humanity. It plays a vital role in regulating the global climate system,71 besides being responsible for the rainfall regime covering a sizeable portion of Brazil.72 Its forests contain the highest biodiversity on the planet,73 and are home to numerous peoples and ethnic groups.74 However, over the past decades, the biome has suffered severe impacts due to uncontrolled and illegal use of its natural resources, resulting in the advance of deforestation. Between 2005 and 2012, deforestation rates decreased in the Amazon thanks to the combination of strong public policies and voluntary market mechanisms. But the situation has reversed since 2012, and in 2021, under Jair Bolsonaro’s presidency, the biome had its largest forest loss since 2006.\n\nIn addition to the negative impacts on the environment and the climate, the Amazon region has the highest concentration of poverty in Brazil.75 It is the only region in the country where inequality indicators, such as electricity and health access, deteriorated during the first decade of this century.76 In light of the increasing deforestation rates, the escalation of conflicts over land, the increased vulnerability of rural and forest peoples, and the impoverishment of the most vulnerable populations, what paths have been built to strengthen forest governance for the Brazilian Amazon?\n\nThis section revisits two of the most influential mechanisms affecting land use and livelihoods in and around forests: the Forest Stewardship Council (FSC) and the Amazon Fund as a REDD+ mechanism. The first is primarily focused on promoting better forest management practices, and the latter on reducing emissions and carbon markets or payment for environmental services.77 Notably, multiple sources show that the causes of long-term deforestation or the promotion of the well-being of forest peoples have not been sufficiently tackled through such instruments.78 Examining such mechanisms is even more important under current circumstances – namely, rising deforestation rates and inequality in the Brazilian Amazon79 – as well as for the lessons learned that can inform the next mandate of Lula da Silva’s presidency. Thus, considering the governance structures, achievements of and controversies relating to the FSC and Amazon Fund in the region, what can we learn and recommend for the future of international cooperation on forest governance?\n\nTo explore this question, we conducted a literature review, workshops and key informant interviews with representatives of the government, NGOs, funding agencies, groups of IP holding FSC certification, and beneficiaries of the Amazon Fund.80 On the basis of this, we reached a few conclusions and observations about both mechanisms.\n\nThe FSC contributes to material well-being and productivity of certified units managed by IP and forest peoples, helping to boost incomes and structure non-timber forest product (NTFP) chains. However, the FSC has several limitations, particularly for smallholders, Indigenous Peoples and local communities. The FSC is a privately led initiative, and its effectiveness in forest enterprises led by forest communities and other marginalized groups depend substantively on external support, which is often absent. In our research, we verified that smallholders are dependent on supporting entities (either government or more recently private sector) to obtain and maintain FSC certification. Besides lack of support for minoritized groups, interviewees stated that smallholders face constant threats and incursions by land grabbers – a situation that has worsened during Bolsonaro’s presidency, due to weaknesses in monitoring, command and control mechanisms, and government inertia (or in some cases, encouragement of illicit deforestation and illegal logging). It is indeed very challenging for IP, local communities and smallholders to obtain and maintain FSC certification, since its standards and procedures are not easy to navigate or comply with. The insufficient levels of credit and financing for smallholders do not help them to finance FSC certificates. The low levels of support to smallholders in Brazil stands in stark contrast to the budget allocated by the federal government to agribusiness, mining and major infrastructure works.\n\nThe Amazon Fund, which received donations from the governments of Norway and Germany, and to a lesser extent from Petrobras (Brazilian oil and gas company), has enabled grassroots organizations, NGOs and community associations to build and strengthen capacities to network and partner in international cooperation. The Amazon Fund contributed to strengthening environmental agencies at the subnational (state) and national (federal) levels. Even when Bolsonaro froze the Fund and dismantled its participatory governance aspect, the legacy of the Amazon Fund was noticeable through the continued efforts made by institutions that it had strengthened in the past. One of the most important impact areas of the Fund81 is the combination of positive outcomes for both forest conservation and the promotion of community well-being and safety of forest peoples. Amazon Fund initiatives are often associated with the inclusion of women and traditional communities – such as IP and Quilombola communities – in decision-making processes, which have been more respectful of their livelihoods, cultures, knowledge and values.\n\nWhen both cases are analysed, using the Institutional approach,82 we observe that the effectiveness of forest governance is compromised in two ways. These are when stakeholders’ participation is limited, such as by excluding the government, as in the case of the FSC; and when peasant family farmers, IP or local communities are further marginalized. In circumstances where there are low levels of participation, autonomy and empowerment among local stakeholders, a discontinuity of initiatives, dependency and marginalization linked to poor well-being outcomes can be expected, not only in terms of productivity, access to markets and public policies, and income, but also in health, education, institutional capacity, safety, and food and land security.\n\nBoth the FSC certification and the Amazon Fund have been important forest governance mechanisms for the Amazon. However, they cannot be considered as unique or sufficient solutions. Both have generated positive impacts on people’s lives, albeit in different domains, but there is still much room to discuss new strategies and actions that governments, funders and investors can enact at national and international levels.\n\nDespite efforts to implement forest governance mechanisms that address sustainability and inclusion at the same time, specific topics still require more attention. Capacity-building is one of them. Actors and institutions depend on knowledge, networks, visibility and capacity for engagement in order to compete and get access to technical and financial support.\n\nAnother topic relates to participation. It is crucial to place local and minoritized groups at the centre of decision-making. Listening to local communities, NGOs and subnational governments have meant that funds are directed and spent in a way that respects and values the cultures and livelihoods of diverse populations – who feel more empowered and able to improve their living conditions. At the same time, this approach, which was embedded in the Amazon Fund, has contributed to the enforcement of important instruments of command and control. With Lula returning as president, and the prospects that the Amazon Fund could be co-managed by the central and subnational governments in collaboration with civil society, Norway has committed to resume donations to the Fund.\n\nCoordination between state and non-state actors is therefore key to designing, implementing and improving policies that integrate the social and environmental agendas, promoting sustainability and inclusiveness in the biome. In this sense, international cooperation has a great role to play, helping to build an open, trusting and pragmatic space for negotiation between governments, the private sector, funders, banks, investors, grassroots and civil society organizations.\n\nTo achieve this, we recommend that international development funders such as the EU and UK governments create the necessary conditions to enable and broaden out forums for equitable, diverse and inclusive participation of Global South agents and institutions in their forest governance programmes. These should include language interpretation, the right to veto and consideration of local priorities such as food and land security, or the development of solidarity and well-being economies in and around tropical forests. We recommend that government funders also negotiate the implementation of glocal mechanisms that consider and respect national sovereignty.\n\nTo banks and investors, our recommendations are: i) to support local/regional initiatives that respect, value and promote sustainable livelihoods and local knowledge as a premise, as well as the inclusion of marginalized populations in just and sustainable supply chains, to the extent that such populations want to engage in such markets; and ii) to halt investments and financing of activities that impact negatively on forest conservation and put at risk the livelihoods and human rights of those in and around the Amazon.\n\nMoreover, we recommend international cooperation to update theories of change and monitoring, evaluation and learning (MEL) processes. The social dimensions of forest governance should be thoroughly integrated in theories of change and MEL plans, with the establishment of appropriate indicators and metrics capable of measuring inclusion and well-being, as suggested by Shaafsma and others.83 Reconsidering sustainable livelihoods frameworks linked to political economy analysis could also help rethink and reshape international cooperation.84 The expected impacts, outcomes and targets of forest governance mechanisms must go beyond the legal, biophysical or environmental dimensions.\n\nTo achieve successful glocal forest governance, ‘global’ initiatives must explicitly incorporate local perspectives through inclusive and participatory design and implementation. International organizations would benefit from ‘glocalizing’ their approach and operations, recognizing the complexities of diverse biomes, and encouraging, sponsoring and listening to independent platforms that convene different economic sectors and groups in society. Our recommendations would contribute to better coordination and deliberation processes. Notably, this will only lead to fair and sustainable outcomes if done through an inclusive coalition that works on territorial or place-based development agendas to address root causes of deforestation.\n\nFinally, we highlight three considerations for policymakers in international cooperation. First, integrate bottom-up and top-down mechanisms into policy strategies. Dialogues must consider the pluralities of situations and local realities. Second, foster and strengthen forest governance arrangements built on inclusive and transformative coalitions. And last, but not least, develop strategies and actions that transcend environmental sustainability or legality, adding the much-needed elements of inclusiveness and socio-economic targets and indicators to the international cooperation agenda.\n\n\nRegulating logging concessions and the moratorium in the DRC\n\nIn July 2021, the government of the Democratic Republic of the Congo lifted a ‘temporary prohibition’ – or a moratorium – on the allocation of new industrial logging concessions, which had been in place for 19 years, since 2002. Different stakeholders – whose views we explore in this section – saw this as both an opportunity and a risk.\n\nThe moratorium on new logging concessions was intended to put an end to ‘widespread looting, exploitation, and destruction of the country’s vast forests’.85 It proved to be largely ineffective, given the current levels of deforestation and illegal logging.86 One could ask, therefore, whether the moratorium should be continued or lifted?\n\nTo put this policy change in context: the DRC negotiated a peace agreement to end the Second Congo War in 2002, along with financial support from the World Bank, for a post-conflict economic recovery plan. This financial support was conditioned on reforms over the regulation of mining and forests,87 which the DRC government quickly responded to, having promulgated new codes in 2002.88, 89 This change mirrored what other Congo basin countries had gone through in previous years, such as Cameroon in 1994, following conditionalities by the World Bank. Limited consideration was given to the impacts of such changes on IP, local communities or the environment.90 Capacities of local governments were perceived to be at risk.91 Nevertheless, legal reforms were made, with the 2002 forest code expected to promote sustainable forest management, contribute to increased government revenues, and help the country to ‘develop’ and build capacity to repay debts.\n\nThe conditions for lifting the moratorium were only established in 2015, after a presidential decree. The conditions were three: i) conversion of old logging titles into forest concession contracts; ii) deployment of transparency mechanisms on forest concessions; and iii) plan for a phased lifting of the moratorium.\n\nIn 2021, although these conditions had not been fulfilled, the government announced the lifting of the moratorium. In 2022 the government also announced the auction of new oil exploration blocks, which would affect forests and peatlands. As articulated by international NGOs, these government decisions were at odds with the DRC’s stated aim to become a ‘climate crisis solution country’.92 Among these perceived contradictions, we examined the views of different stakeholders about the moratorium on industrial logging concessions in the DRC, in order to find ways forward in terms of national and international policy work. We gathered the perspectives of various stakeholders in workshops and interviews in Kinshasa and in the province of Tshopo, including representatives from IP, Congolese civil society, international NGOs and the DRC government.93 Their views should all contribute to advancing the glocalization of forest governance solutions and analysis.\n\nFor the DRC government, one of the main reasons to lift the moratorium on industrial forest concessions is that maintaining a 20-year-old moratorium is ‘irresponsible’.94 DRC officials emphasize the potential for land resources to contribute to revenue collection for the government, to the development of infrastructure, and to the benefit of people. According to the DRC’s General Director of Forests, the DRC ‘is home to 60% of forests in the Congo basin, with strong timber potential – of above 10 million cubic metres per year, and a huge farming potential, of around 80Mha of arable land’.95 These resources should be mobilized, the General Director argues, which would be crucial to fulfil the needs of a growing population and infrastructure development. Biodiversity conservation or mitigation of climate change are not evident in this viewpoint.\n\nInternational NGOs and Congolese civil society differ from the government. Some international NGOs denounced a contradiction between the DRC’s climate and forest commitments and its plan to lift the moratorium on new logging concessions.96 International NGOs called attention to the fact that the main beneficiaries of new industrial concessions in the DRC would be foreign companies, and that this would not necessarily create a trickle-down effect. Greenpeace Africa and Rainforest Foundation UK, for instance, submitted a petition to ‘the international community’ calling for action to stop the lifting of the moratorium.97\n\nCongolese civil society groups, such as the Groupe de Travail Climat REDD+ Rénové (GTCRR) and the National Coalition Against Illegal Logging (CNCEIB), argue that the DRC still needs to design and define a phased programme to progressively (and responsibly) lift the moratorium – as per the third conditionality created in the 2015 Presidential Decree. This option would respect the rule of law. Congolese civil society has also called for this process to be done through participatory and multi-sectoral means.\n\nAmong representatives of IP, some expressed the hope that the allocation of new forest concessions could be helpful if logging companies contributed to the provision of services to local communities, such as education, health, water and transport. Yet grievances against industrial loggers remain widespread, and IP’ representatives underline the need for any new enterprise to respect social obligations and human rights, such as observing Free, Prior and Informed Consent (FPIC). Our research however, did not explore alternatives to industrial concessions, such as community forest concessions, which have legal underpinnings and support from IP and local communities’ advocates.\n\nWe acknowledge that views change, and that differences exist not only between but within groups of actors. This caveat acknowledged, we presented the policy research findings to contribute to the debate in this sector, which is still lacking in data availability, transparency and platforms for dialogue.\n\nForest law enforcement is weak in the DRC.98 Despite the 2002–21 moratorium on the expansion of industrial logging, the DRC’s forest administration granted contracts through bilateral negotiations between entrepreneurs and government officials.99 Not only were these were unlawful, they also lacked transparency, fairness or competition that a public action should provide.\n\nThe General-Inspectorate of Finance (IGF) of the DRC concluded that logging concessions in the two decades between 2000 and 2020 were linked to corruption and benefited personal interests – with consecutive ministers violating the moratorium and failing to facilitate revenue collection.100 Law enforcement has been selective and arbitrary, with some Ministers enforcing certain laws, while others striking deals at their discretion, according to the IGF.101 Unlawful concessions deprived the government of security deposit payments, which would have offered some protection against defaulting operators.102 As a result, logs produced in the DRC – albeit in quantities far below other countries in the Congo basin – are more likely to involve illegality now than at the start of the century.103\n\nThe DRC’s capacity to enact reforms or enforce regulations remains limited. The civil service, for instance, faces numerous challenges, such as poor infrastructure, limited headcount or training on environmental policy, forest resources or land rights. Poor infrastructure limits local capacity for timber processing. There is no political and policy coordination to reconcile risks and opportunities between urbanization, rural development, food, energy and climate security. Regulating control and access to land and natural resources is difficult, in general, and this challenge is even greater in low-income countries with weak governance systems, like the DRC.\n\nThe arguments of different stakeholders in the exploitation of natural resources in the DRC tackle ecological, climate and local development challenges, and these have not yet been addressed in a systemic manner. International stakeholders have prioritized support to environmental protection in the tropics, including in the Central African region. This is at odds with some of the local priorities and most pressing development challenges, such as the need for rural livelihoods to be strengthened, and for infrastructure and institutional capacities to be built. In our view, international partnerships and finance have encouraged or prescribed standardized and unsuitable frameworks for the DRC, having failed to truly collaborate in understanding and addressing basic needs, local priorities and the concerns of the majority in the Congo basin.\n\nFuture international partnerships should aim to, first, learn about the local needs of affected communities, engage with local policy institutes, and then rethink reforms, regulations and action plans. Second, they should encourage coordination between different ministries, for policy coherence. This should be primarily focused on sustainable livelihoods or the well-being of people while also targeting commodity production, trade and environmental targets. Third, international partnerships should support participatory, inclusive, non-partisan design of roadmaps and cross-sectoral plans for sustainable development, and encourage co-management practices for policy delivery with domestic institutions, IP and local communities. Inclusive and deliberative in-country processes, with high levels of quality participation of key stakeholders, including marginalized constituents, should be enabled for the benefit of the forests in the region.\n\nThe moratorium on new logging concessions may have stemmed the authorization of mass industrial exploitation of forest lands but it has not stopped illegal practices. Nor has it paved the way for the kinds of governance reforms that the World Bank expected for the economic recovery of the DRC.\n\nHow the lifting of the moratorium plays out will depend on the rules that govern new concessions – which need to be revised – and the capacity for law enforcement, monitoring and learning at the country level. Several questions will also need answering, for instance, who would be entitled to manage new concessions? There would be a substantial difference in distributive outcomes if regulations encouraged arrangements like community forest concessions, and if the international community supported business developments led by local producers’ associations, small and medium enterprises. What technical standards for sustainable resource management should be embedded in future land and forest allocations? What would be the role of state agents, grassroots and civil society organizations in monitoring and evaluating such policies and practices? These issues should be addressed soon, in open and transparent forums, so as to contribute ideas and solutions to advance the DRC as a true ‘climate crisis solution country’.\n\n\nVerifying legality in different forest regimes in Indonesia\n\nMultilateral frameworks to improve forest law enforcement, governance and associated trade have been supported since the 2000s by the World Bank, the United Nations Forum on Forests, the Group of Eight (G8 – currently the G7), the EU, and the Association of Southeast Asian Nations (ASEAN).104 The hope was that reducing illegal logging and the related trade would halt deforestation and would foster sustainable forest management while improving rural livelihoods and supporting sustainable development.105\n\nIn 2016, Indonesia became the first country in the world to operationalize a Forest Law Enforcement, Governance and Trade (FLEGT) licensing scheme,106 which is supported by a verification system called SVLK (Sistem Verifikasi Legalitas Kayu). The SVLK has had several changes since its inception. The major change accompanied the 2021 Omnibus Law on job creation. This change broadened the scope of the system, to encompass verifications on sustainability (beyond legality), and to cover all timber and non-timber forest products, and all forest property regimes.107\n\nThere are several studies about the SVLK as a whole, or assessing it from the importers’ perspective.108 This section brings more of a glocal perspective to the matter, focusing on the effectiveness of the SVLK for Indonesia in different property regimes: state, customary and private forests.\n\nMost forested areas in Indonesia (93%) are the property of the state. State forests have been primarily exploited by large companies through concessions for industrial logging and timber plantations. Only 0.6% of the country’s forested area is officially registered as customary territories for IP’ land tenure, but this rate should expand, with a potential to reach above 8% of the overall forested area in Indonesia. Private forests account for 7% of forested lands. Private forests are primarily looked after by smallholders and exploited by small-scale operators such as local farmers or farming cooperatives.\n\nRegardless of property regime, SVLK certification is mandatory for all producers, traders and exporters of forest commodities in Indonesia. The system has evolved with time, but actors in different forest property regimes have experienced different incentives, levels of support, or challenges to adapt to such changes. We investigated such issues, which were reported in longer reads.109 In this section, we highlight the differences for SVLK implementation in different forest regimes, and for different actors at the landscape level, before featuring a few policy recommendations.\n\nCompanies exploiting forest concessions perceive government support and the SVLK’s economic benefits to be moderate to weak.110 Yet, concession holders have generally accepted and expressed satisfaction with SVLK rules, procedures and certification costs. For instance, holders of logging concessions were found to prefer the mandatory SVLK to voluntary mechanisms such as the FSC or the IFCC (Indonesian Forestry Certification Cooperation, which is part of PEFC, the Programme for Endorsement of Forest Certification). However, some companies still apply the voluntary mechanism to expand their international market. The SVLK is a government requirement for exporting, but companies obtain FSC certification as well to attract importers and buyers because the SVLK is less well known at international level.111 In 2022, about half of state forest concessions were covered by SVLK certification.112\n\nCustomary forests are forest lands located in the territory of ‘customary law communities’, outside state forests.113 By March 2022, Indonesia’s Ancestral Domain Registration Agency counted 17.6 million hectares (ha) of customary and indigenous territories that could potentially be recognized as such.114 Yet, official recognition has been issued for about 16% of this potential (2.78 million ha), or 0.6% of Indonesia’s forested lands. Most customary forests were recognized by subnational authorities,115 while the national government, through its Ministry of Environment and Forestry, had officially recognized 0.09 million ha as customary territories by April 2022.116\n\nWith such low levels of recognition of land tenure for IP, their communities have enjoyed limited to no benefits from the SVLK. IP and local communities still struggle for autonomy, including the fight for land tenure recognition.117 Moreover, even if they had land security, the SVLK would not accommodate the heterogeneity of IP and local communities. There are 1,331 ethnic groups recognized by the Indonesian government,118 and not all IP want to be integrated into global supply chains.119\n\nIllegal logging in private smallholding forests is virtually unheard of, particularly when compared to illegal practices in state forest concessions.120 Forest products and timber from private smallholding forests can be considered the easiest to control at farm level and the ‘most legal’ timber – when the land is inhabited and closely guarded and protected by smallholders or tenants.\n\nPrivate forests represent 7% of Indonesia’s forested lands. The limited impacts of the SVLK on smallholder private forests had long been assumed,121 and this was confirmed in our original field research between 2021 and 2022. Not surprisingly, the benefits of SVLK are not clearly perceived by smallholders. For instance, most smallholder farmers surveyed in Solo122 either do not know what SVLK is (5% of 21 respondents) or have not perceived its impacts (76%). The respondents who reported SVLK benefits referred to a sense of pride (9%), commercialization facilities (5%) or better pricing for timber (5%).123 For most smallholders, certification costs and complicated bureaucracies are burdensome, and they need to use the land in a way that is economical. Smallholders face challenges related to tree maintenance, capital and selling, so need more facilitation to cope with these matters than legal certification constraints.\n\nAlthough smallholders are allowed to issue a SVLK self-declaration of conformity,124 intermediaries have traditionally brokered declarations, according to focus group discussions and interviews.125 This reduces the potential economic benefit that smallholders could draw from the SVLK.\n\nIndonesia’s FLEGT licensing scheme and SVLK are relatively effective in state forests, but considerably less so in private forests and virtually non-existent in customary forests. This profile of impacts has important distributive implications. Indigenous Peoples, local communities, artisanal producers and smallholders have not enjoyed benefits from the SVLK as much as medium to large operators of logging concessions and timber plantations.\n\nLooking at the profile of benefits distributed, and the effectiveness of the SVLK, it is important to remember its origins and evolution, and to think about its future developments. First, with regards to the origins of the SVLK, it is important to highlight that foreign and international market mechanisms promoted by international agencies and donors have largely informed and motivated Indonesia’s forest policy reforms and integration into global supply chains. Second, on effectiveness, the SVLK has been associated with improving transparency and participation, but there are important misalignments between competing trade, forests policies and sustainable livelihoods. The SVLK took decades to develop (since at least the 2001 Bali Declaration on Forest Law Enforcement and Governance), but its impacts are still not significant enough to lead to more sustainable livelihoods. This has been a particular problem for the most marginalized citizens or populations of Indonesia, such as IP, local communities and smallholders. Third, we understand that the development of such regulations primarily serves the interests of traders, importers and actors in global supply chains, while not necessarily benefiting smallholder farmers (i.e. small private forests). All of this makes the glocalization of forest governance analysis and solutions an important avenue to be pursued.\n\nFuture policies and international partnerships should aim to promote sustainable land use and livelihoods, and seriously look at, and prioritize IP, local communities, and smallholders.\n\nWe recommend the maintenance of the full SVLK regime for state forests and large-scale concessions, and the creation of strategies and facilities crafted to benefit peoples and communities in private smallholding and customary forests. In the short term, facilities should be created to enable such groups to autonomously issue Self-Declaration of Conformity (SDoC) as legality and credibility assurance. But reforms in governance should go beyond the commodity market regime and observe the actual needs of forest peoples – to whom access to international markets is secondary to several other priorities. For instance, according to the interviews conducted in this research, the acceleration of recognition of customary territories is a priority for IP, as is better technical assistance, insurance and loans, eradication and prevention of pests and diseases, and facilitation of direct sales to the industry for smallholder farmers. Tackling these fundamental needs will help glocalize forest governance solutions and contribute to reducing poverty and inequality whilst safeguarding the climate and nature.\n\n\nConclusions\n\nBy discussing the challenges in establishing equitable research partnerships between policy institutes across the Global North and Global South, and by featuring policy analysis and recommendations crafted between those institutes, this paper contributes to ideas and methods for the localization and glocalization of solutions and critiques of transnational mechanisms that affect land use, forest lands and peoples in the tropics. Glocalizing forest governance, in this project, implied advancing equitable research partnerships between think-tanks in the Global South and Global North, and strengthening a community of (policy research) practice for critical enquiry and engagement in partnerships for sustainable development.\n\nA starting point was to identify the gaps between ideas of sustainability in international cooperation and localized practices. These have been problematic particularly when ‘solutions’ are crafted and decided away from producing sites and constituencies in the ‘developing’ world. Focal countries and firms in supply chains, primarily in the Global North, have struggled to understand the nuanced, cultural and context-specific issues and priorities in the Global South, and for the populations living in and around forested areas. The expansion of international and market mechanisms has reinforced unsustainable consumption and production patterns (which includes overconsumption in affluent societies) that are known to be underlying causes of deforestation, forest degradation, climate crises and inequality. In turn, institutions in the Global South have struggled for autonomy, for self-determination, for access to just and sustainable markets, and for resources to influence policymaking or conduct independent analysis. Acknowledging and confronting power dynamics of privilege and marginalization, which can be linked to historic colonization of lands and minds, is necessary in any serious enterprise such as international collaboration for sustainable development.\n\nIn this project, we have made efforts to tackle power asymmetries in the research partnership between think-tanks across continents, and to enable critical, glocal analysis of forest governance mechanisms, particularly when it comes to the investigation of their transnational origins, market underpinnings, achievements and challenges, participation profile, distributive impacts, lessons learned and recommendations to improve international partnerships.\n\nAs seen, the principal beneficiaries and the conditions for participation and inclusion vary by initiative, and by country. Notably, in the case of the Amazon Fund, the analysis led by Louise Nakagawa, Ariane Favareto, Tamara Tobias and Arilson Favareto showed that this REDD+ initiative contributed to certain non-monetary well-being indicators, as well as to participatory and more inclusive forums in Brazil. This differs from certain REDD+ experiences in other parts of the world,126 and from the FSC certification for smallholders in the Brazilian Amazon. In the case of land-use regulations in the DRC, predictions that a moratorium on new logging concessions would not benefit the Congolese population, due to high levels of corruption,127 was substantiated by the evidence communicated by Rigobert Minani, who also argues that foreign interventions focused on environmental protection have yet to acknowledge the social and development challenges in the region. In the case of Indonesia’s SVLK, the findings by Bramasto Nugroho, Damayanti Buchori, Fitta Setiajiati and Silfi Iriyani confirm what previous research had identified as a trend, i.e. legality verification systems favouring large companies128 and export markets rather than smallholders and their needs and priorities. Overall, the case studies recognize limitations and challenges in influential North-South forest governance mechanisms – particularly when it comes to the distribution of costs and benefits – which is in line with the recent review by Delabre et al.129\n\nAdditionally, the authors pointed to a set of alternatives for future forest solutions at the international level and at national level, thanks to the strengthening of their influence throughout the course of this project. For instance, all policy institutes had the chance to convene diverse stakeholders in forest governance, and to engage directly with ministers, representatives of marginalized communities, NGOs, entrepreneurs, as well as policy institutes in different continents. One of the lessons learned in the project is that well-crafted partnerships between policy institutes in the Global North and South contribute to enriching, strengthening and embedding transnational and glocal policy discussions at national and international forums. Investment in the establishment of equitable partnerships across regions and continents, and in learning by doing pedagogies (and other participatory action research methods)130 can benefit future international cooperation programmes, particularly in the medium and long terms.\n\nAlongside these procedural yet strategic remarks, donor entities and multilateral organizations would benefit from considering the following recommendations:\n\n• Go beyond supporting legal or sustainable supply chains and their variants, such as in ‘green’, ‘carbon-neutral’, ‘net-zero’ or ‘deforestation-free’ supply chains. The focus on commodity markets has not shown clear benefits for those who are most dependent on tropical forests, and is unlikely to reduce excessive or unsustainable consumption levels in affluent societies, which is an underlying driver of deforestation, forest degradation, and the crises related to climate and inequality. Commodity-centred approaches need to be complemented by stronger environmental policies and regulations, coupled with mechanisms to guarantee human rights and the well-being of all. And this requires renewed theories of change, with greater scrutiny of assumptions, greater ambition for outcomes and impacts, and a strong commitment to learning strategies, as well as to Equality, Diversity and Inclusion mechanisms, through and beyond gender equality, that are wired towards just and sustainable livelihoods and outcomes.\n\n• Work together with policy institutes across the Global South and Global North and develop context-specific, place-based mechanisms with strong participation of IP, local communities, with local knowledge, and with full consideration of local, subnational, national and regional development priorities. Market-based instruments created in the Global North and adapted or translated to ‘producing’ countries have not been a good fit to reverse unsustainable patterns of consumption and production. Co-creation and co-leadership are promising approaches for just and sustainable transitions, and must include equitable partnerships between institutions across the Global South and North. This is key to pave the way for the right kind (non-colonial forms) of glocalization that is needed in forest and land-use governance.\n\n• Design and implement policy mixes and models to achieve global and domestic priorities for sustainable development. This entails balancing out different land uses (i.e. forestry, agriculture, mining, infrastructure) and sectoral policies between and within countries; regulation in domestic and international markets through fiscal, trade, environmental and agricultural policies; and a prioritization of not only poverty eradication, but the provision of multi-dimensional well-being and sustainable livelihoods as outcomes and impacts of international partnerships.131 This relates to the importance of refreshing theories of change, and of promoting and pursuing diversification in land use and livelihood portfolios, which enable families and communities to be more resilient to shocks and disruptions.\n\nThese recommendations present the unequivocal need to build suitable and equitable forest governance mechanisms, through a glocalized approach, for future generations and the environment. The disconnect between theory and practice must be bridged, while mindful that resource governance involves multiple actors and interests at different scales, as well as all their social, ecological and location-specific complexities.\n\nAs it is the most central of all the Sustainable Development Goals, SDG 17 ‘global partnerships for sustainable goals’ must be improved and adapted to redress power imbalances between ‘global’ and ‘local’ imperatives, and between institutions across continents, in the Global North and in the Global South. Reflecting on the glocalization of development goals, and on the glocalization of partnerships for sustainable development will help with the design of innovative policy mixes and effective land-use and forest governance mechanisms.\n\nThis report was built upon two needs that became opportunities. First, the need to rethink North–South research partnerships in international partnerships which required researchers to identify their own degrees of privilege in an unjust world and to redress power dynamics. Second, the need for more inclusive, participatory and transdisciplinary policy research, which would open up ways for diversity and plurality in the analysis of international policy mechanisms. These needs were taken as a springboard for innovation. We are proud of the collaborative approach adopted to produce this paper, and we invite serious consideration of the analysis and recommendations put forward by the authors in the Global South and the Global North to improve international partnership on land use, forests and sustainable livelihoods. The scale of this partnership is relatively small, but this could be scaled up to encompass other geographies and case studies, to promote diversity and mutual learnings in South–South and South–North–South (triangular) collaborations, and to keep advancing on equitable partnerships for sustainable development.\n\nTransnational forest governance mechanisms need renovation. Market-based solutions and hybrid initiatives for ‘sustainable supply chains’ have been prominent since the 1990s, supported by public, private and hybrid initiatives and international partnerships focused on commodity exchange between Global South and Global North countries. These kinds of interventions can be improved and complemented by stronger environmental laws and public regulations (alongside their implementation) to raise standards that would effectively protect peoples and the environment, and contribute to the well-being of all. Notably, as discussed in this paper, innovation in policy instruments for land-use governance must position well-being and sustainable livelihood outcomes at the core of international partnerships, which in turn should be based on, and enhance, inclusive stakeholder participation.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgments\n\nWe thank Paula Bernasconi, Tom Blomley, Paolo Cerutti, Antony Froggatt, Georg Hahn, Alison Hoare, Erin Matson, Thomas Pichet, Henry Throp, and a blind reviewer for comments on the manuscript; we thank Alison also for having co-initiated this project, as well as Charlotte Watts, Kate O’Reilly, Lavina Ranjan and Anum Farhan for project management support. We thank the project advisory board, Isabel Drigo, Jean Mboma, Julia Falconer, Paolo Cerutti, Patrick Kipalu, Pedro Nogueira, Purabi Bose, Rukka Sombolinggi, Soeryo Adiwibowo, Sudarsono Soedomo and Thomas Pichet, especially for their initial inputs to the project, for enriching dialogues and for helping with connections with other key stakeholders. We also thank Jack Barry and Owen Grafham for providing comments on the editorial plan. A special thought goes to Yulius Hero.\n\n\nFootnotes\n\n1 Ometto, J.P. and Kalaba, F.K., (2022). CCP 7 Tropical Forests, Climate Change 2022: Impacts, Adaptation and Vulnerability. Contribution of Working Group II to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change, https://doi.org/10.1017/9781009325844.024.2369.\n\n2 Laumann, F., von Kügelgen, J., Kanashiro Uehara, T. H., & Barahona, M. (2022). Complex interlinkages, key objectives, and nexuses among the Sustainable Development Goals and climate change: a network analysis. The Lancet Planetary Health, 6(5), e422–e430. https://doi.org/10.1016/s2542-5196(22)00070-5.\n\n3 This collaboration was enabled by the Forest Governance, Legality and Climate (FGMC) programme of the UK Foreign, Commonwealth and Development Office (FCDO).\n\n4 We refer to the definitions of these terms given by the Cambridge Dictionary, according to which partnership is ‘an agreement between organisations, people etc. to work together’, which differs from collaboration: ‘the situation of two or more people working together to create or achieve the same thing’; and cooperation: ‘the act of working together with someone or doing what they ask you’.\n\n5 Led by TKU, FC and LN with inputs from the co-authors.\n\n6 Led by CC with FC and TKU with inputs from the co-authors.\n\n7 Led by LN, AF, TT and AF with inputs from the co-authors.\n\n8 Led by RM with inputs from the co-authors.\n\n9 Led by BN, FS, SI and DB with inputs from the co-authors.\n\n10 Policy briefs available at http://forestgovernance.chathamhouse.org/publications/from-theory-to-practice-how-to-disrupt-north-south-research-partnerships\n\n11 Hoare, A., & Kanashiro Uehara, T. (2022). Establishing fair and sustainable forest economies: Lessons learned from tackling illegal logging. Research Paper, London: Royal Institute of International Affairs. https://doi.org/10.55317/9781784135386.\n\n12 Delabre, I., Boyd, E., Brockhaus, M., Carton, W., Krause, T., Newell, P., Wong, G. Y., & Zelli, F. (2020). Unearthing the myths of global sustainable forest governance. Global Sustainability, 3. https://doi.org/10.1017/sus.2020.11; Lambin, E. F., Meyfroidt, P., Rueda, X., Blackman, A., Börner, J., Cerutti, P. O., Dietsch, T., Jungmann, L., Lamarque, P., Lister, J., Walker, N. F., & Wunder, S. (2014). Effectiveness and synergies of policy instruments for land use governance in tropical regions. Global Environmental Change, 28, 129–140. https://doi.org/10.1016/j.gloenvcha.2014.06.007.\n\n13 Koberg, E., & Longoni, A. (2019). A systematic review of sustainable supply chain management in global supply chains. Journal of Cleaner Production, 207, 1084–1098. https://doi.org/10.1016/j.jclepro.2018.10.033.\n\n14 REDD+ is a framework created by the UNFCCC COP to guide activities in the forest sector that reduce emissions from deforestation and forest degradation, as well as the sustainable management of forests and the conservation and enhancement of forest carbon stocks in developing countries.\n\n15 ‘Sustainable supply chain management’ tackles the integration of ‘environmental, social and economic goals across a focal firm’s supply chain processes’, or across a focal country or state, from the perspective of governments. Grabs, J., and Carodenuto, S.L. (2021), Traders as sustainability governance actors in global food supply chains: A research agenda, Business Strategy and the Environment, 30(2), pp. 1314-1332, https://doi.org/10.1002/bse.2686.\n\n16 Wardell, A., Piketty, M. G., Lescuyer, G., & Pacheco, P. (2021). Reviewing initiatives to promote sustainable supply chains: The case of forest-risk commodities. FTA Working Paper. https://doi.org/10.17528/cifor/007944.\n\n17 Hoare, A., & Kanashiro Uehara, T. (2022). Establishing fair and sustainable forest economies: Lessons learned from tackling illegal logging. Research Paper, London: Royal Institute of International Affairs. https://doi.org/10.55317/9781784135386.\n\n18 Laumann, F., von Kügelgen, J., Kanashiro Uehara, T. H., & Barahona, M. (2022b). Complex interlinkages, key objectives, and nexuses among the Sustainable Development Goals and climate change: a network analysis. The Lancet Planetary Health, 6(5), e422–e430. https://doi.org/10.1016/s2542-5196(22)00070-5.\n\n19 Delabre et al. (2020), ‘Unearthing the Myths of Global Sustainable Forest Governance’.\n\n20 Ibid., p. 4.\n\n21 Shapiro-Garza, E., McElwee, P., Van Hecken, G., & Corbera, E. (2019). Beyond Market Logics: Payments for Ecosystem Services as Alternative Development Practices in the Global South. Development and Change, 51(1), 3–25. https://doi.org/10.1111/dech.12546; Gómez-Baggethun, E., & Muradian, R. (2015). In markets we trust? Setting the boundaries of Market-Based Instruments in ecosystem services governance. Ecological Economics, 117, 217–224. https://doi.org/10.1016/j.ecolecon.2015.03.016.\n\n22 Schaafsma, M., Dreoni, I., Ayompe, L. M., Egoh, B., Ekayana, D. P., Favareto, A., Mumbunan, S., Nakagawa, L., Ngouhouo-poufoun, J., Sassen, M., Uehara, T. K., & Matthews, Z. (2022). A framework to understand the social impacts of agricultural trade. Sustainable Development. https://doi.org/10.1002/sd.2379; WCMC (2021), ‘What do we need to make trade more socially sustainable within exporting countries?’, Trade, Development and the Environment Hub blog, 25 November 2021, https://tradehub.earth/2021/11/25/what-do-we-need-to-make-trade-more-socially-sustainable-within-exporting-countries/.\n\n23 Koberg, E., & Longoni, A. (2019). A systematic review of sustainable supply chain management in global supply chains. Journal of Cleaner Production, 207, 1084–1098. https://doi.org/10.1016/j.jclepro.2018.10.033; Kanashiro Uehara, T., and O’Reilly K. (2022). Trade policy and sustainability: The WTO, the international fair trade charter, and five principles for system change. Manuscript submitted for publication.\n\n24 Grabs, J., & Carodenuto, S. L. (2021b). Traders as sustainability governance actors in global food supply chains: A research agenda. Business Strategy and the Environment, 30(2), 1314–1332. https://doi.org/10.1002/bse.2686.\n\n25 Hasyim, Z., Laraswati, D., Purwanto, R. H., Pratama, A. A., & Maryudi, A. (2020). Challenges facing independent monitoring networks in the Indonesian timber legality assurance system. Forest Policy and Economics, 111, 102025. https://doi.org/10.1016/j.forpol.2019.102025; Hoare, A. and Kanashiro Uehara, T. (2022), Forest sector revenues in Ghana, Liberia and the Republic of the Congo: The impact of reforms on collection and disbursement, Research Paper, London: Royal Institute of International Affairs, https://doi.org/10.55317/9781784135188.\n\n26 Marije Schaafsma and others, ‘A Framework to Understand the Social Impacts of Agricultural Trade’, Sustainable Development, February, 2022, 1–13 <https://doi.org/10.1002/sd.2379>.\n\n27 Marcello de Maria, Chris West, and others, ‘How Do We Link Local and National Level Measures with International Policy and Private Initiatives on Sustainable Trade for Agricultural Commodities?’, Trade and Nature Discussion Papers, 1.2 (2022), https://tradehub.earth/wp-content/uploads/2022/10/.\n\n28 See, for instance, Meyfroidt, P., Roy Chowdhury, R., de Bremond, A., Ellis, E., Erb, K. H., Filatova, T., Garrett, R., Grove, J., Heinimann, A., Kuemmerle, T., Kull, C., Lambin, E., Landon, Y., le Polain de Waroux, Y., Messerli, P., Müller, D., Nielsen, J., Peterson, G., Rodriguez García, V., … Verburg, P. (2018). Middle-range theories of land system change. Global Environmental Change, 53, 52–67. https://doi.org/10.1016/j.gloenvcha.2018.08.006.\n\n29 For a classification of social orders of markets related to land use, see: Niederle, P. A. (2017). A pluralist and pragmatist critique of food regime’s genealogy: varieties of social orders in Brazilian agriculture. The Journal of Peasant Studies, 45(7), 1460–1483. https://doi.org/10.1080/03066150.2017.1313238.\n\n30 Gardner, T., Benzie, M., Börner, J., Dawkins, E., Fick, S., Garrett, R., Godar, J., Grimard, A., Lake, S., Larsen, R., Mardas, N., McDermott, C., Meyfroidt, P., Osbeck, M., Persson, M., Sembres, T., Suavet, C., Strassburg, B., Trevisan, A., … Wolvekamp, P. (2019). Transparency and sustainability in global commodity supply chains. World Development, 121, 163–177. https://doi.org/10.1016/j.worlddev.2018.05.025.\n\n31 Fletcher, R., Dressler, W., Büscher, B., & Anderson, Z. R. (2016). Questioning REDD+ and the future of market-based conservation. Conservation Biology, 30(3), 673–675. https://doi.org/10.1111/cobi.12680; Delabre, I., Boyd, E., Brockhaus, M., Carton, W., Krause, T., Newell, P., Wong, G. Y., & Zelli, F. (2020). Unearthing the myths of global sustainable forest governance. Global Sustainability, 3. https://doi.org/10.1017/sus.2020.11.\n\n32 Pokorny, B., Johnson, J., Medina, G., & Hoch, L. (2012). Market-based conservation of the Amazonian forests: Revisiting win–win expectations. Geoforum, 43(3), 387–401. https://doi.org/10.1016/j.geoforum.2010.08.002.\n\n33 Delabre et al. (2020), ‘Unearthing the Myths of Global Sustainable Forest Governance’.\n\n34 Hoare, A., & Kanashiro Uehara, T. (2022). Establishing fair and sustainable forest economies: Lessons learned from tackling illegal logging. Research Paper, London: Royal Institute of International Affairs. https://doi.org/10.55317/9781784135386; Leach, M., & Scoones, I. (2013). Carbon forestry in West Africa: The politics of models, measures and verification processes. Global Environmental Change, 23(5), 957–967. https://doi.org/10.1016/j.gloenvcha.2013.07.008.\n\n35 Chatham House Forest Governance & Legality, http://forestgovernance.chathamhouse.org, country profiles for Brazil, DRC and Indonesia. For global, Ometto, J.P. and Kalaba, F.K., (2022). CCP 7 Tropical Forests, Climate Change 2022: Impacts, Adaptation and Vulnerability. Contribution of Working Group II to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change, https://doi.org/10.1017/9781009325844.024.2369.\n\n36 Forest Governance and Legality (2022). Country profiles. https://forestgovernance.chathamhouse.org/countries.\n\n37 FAO & UNEP. (2020). The State of the World’s Forests 2020. www.fao.org. https://www.fao.org/state-of-forests/en/.\n\n38 Global Forest Watch (2022). Global Deforestation Rates & Statistics by Country. https://www.globalforestwatch.org/dashboards/global/?category=summary. Underlying drivers of deforestation such as international and market forces, insecure land tenure, and the impacts of financialization (e.g., correlation of commodity prices with stock market dynamics rather than pure demand) are not included in this table. For a review on direct and underlying drivers of deforestation, see Ometto et al. (2022).\n\n39 OPHI & UNDP. (2022). Unpacking deprivation bundles to reduce multidimensional poverty. In Global Multidimensional Poverty Index 2022. https://hdr.undp.org/system/files/documents/hdp-document/2022mpireportenpdf.pdf.\n\n40 WID - Wealth and Income Database. (2018). World: Top 10% net personal wealth share. WID - World Inequality Database. https://wid.world/world/; Bajard, F., Chancel, L., Moshrif, R., & Piketty, T. (2022). Global Wealth Inequality on WID.world: Estimates and Imputations. The Source for Global Inequality. https://wid.world/document/global-wealth-inequality-on-wid-world-estimates-and-imputations-world-inequality-lab-technical-note-2021-16/. Net personal wealth share held by the p90p100 group. Net personal wealth is the total value of non-financial and financial assets (housing, land, deposits, bonds, equities, etc.) held by households, minus their debts. The personal or household sector – in the national accounts sense – includes all households and private individuals (including those living in institutions), as well as unincorporated enterprises whose accounts are not separated from those of the households who own them. The population is comprised of individuals over the age of 20. The base unit is the individual (rather than the household) but resources are split equally within couples.\n\n41 Chatham House resourcetrade.earth. (2022). Commodity: Forestry products. Year: 2020. https://resourcetrade.earth/?year=2020&category=3&units=value&autozoom=1.\n\n42 Ometto, J.P. and Kalaba, F.K., (2022). CCP 7 Tropical Forests, Climate Change 2022: Impacts, Adaptation and Vulnerability. Contribution of Working Group II to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change, https://doi.org/10.1017/9781009325844.024.2369.\n\n43 Forest Declaration Assessment Partners. (2022). Forest Declaration Assessment: Are we on track for 2030? Climate Focus (coordinator and editor). https://forestdeclaration.org/wp-content/uploads/2022/10/2022ForestDeclarationAssessment.pdf; Ozinga, S. & Hopkins, D. (2020), Tackling deforestation: the need for regulation. Forest Governance and Legality Blog, 10 August 2020. https://forestgovernance.chathamhouse.org/publications/tackling-deforestation-the-need-for-regulation .\n\n44 Lambin et al. (2014). Effectiveness and synergies of policy instruments for land use governance in tropical regions. p. 137.\n\n45 Lambin et al. (2014). Effectiveness and synergies of policy instruments for land use governance in tropical regions.\n\n46 Ometto, J.P. and Kalaba, F.K., (2022). CCP 7 Tropical Forests, Climate Change 2022: Impacts, Adaptation and Vulnerability. Contribution of Working Group II to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change, https://doi.org/10.1017/9781009325844.024.2369.\n\n47 Tuck, E. & Young, K.W. (2012). Decolonization is not a metaphor. Decolonization: Indigeneity, Education & Society. Vol.1 (1).\n\n48 Maselli, D., Jon-Andri, L., & Schmid, J. (2006). Improving impacts of research partnerships. Swiss Commission for Research Partnerships with Developing Countries KFPE. https://portal-cdn.scnat.ch/asset/1b8a6bc7-2840-5dcf-acb3-4bb086fbe718/KFPE_ImpactStudy.pdf?b=5e0dc39f-2adc-5ad2-96f0-92d97ba881b8&v=61b509e4-3355-5390-a481-5b57f6c1f20e_0&s=jvH2a27MJb7DLMjoA716qWITcPvxKy6yw4UGOQEl3f0xZzd-ApWDT_7Ow5IOSP5w-zXzkffEBzJyZOHDrp-uDAZv5cL3VHNe0bgpwsaOiYPbGnSpbYKVeirSF6YqfSaIT-JqT7IQZbb9KXOiQDkMKBAORnGrPuZwjjCKNLKk1Ec.\n\n49 See, for instance, Forest Governance and Legality (2021). Forest voices: the path forward for strengthening forest governance. Forest Governance and Legality Blog. 14 October 2021. https://forestgovernance.chathamhouse.org/publications/forest-voices-the-path-forward-for-strengthening-forest-governance; Uehara, T. (2022). Takeaways from the Global Forum on Forest Governance 2022. Forest Governance and Legality Blog. 26 July 2022. https://forestgovernance.chathamhouse.org/publications/takeaways-from-the-global-forum-on-forest-governance-2022.\n\n50 Arnstein, S. R. (1969). A Ladder Of Citizen Participation. Journal of the American Institute of Planners, 35(4), 216–224. https://doi.org/10.1080/01944366908977225.\n\n51 Arnstein, S. R. (1969). A Ladder Of Citizen Participation. Journal of the American Institute of Planners, 35(4), 216–224. https://doi.org/10.1080/01944366908977225.\n\n52 ‘Positionality refers to the stance or positioning of the researcher in relation to the social and political context of the study—the community, the organization or the participant group. The position adopted by a researcher affects every phase of the research process, from the way the question or problem is initially constructed, designed and conducted to how others are invited to participate, the ways in which knowledge is constructed and acted on and, finally, the ways in which outcomes are disseminated and published.’ Bourke, B. (2014). Positionality: Reflecting on the Research Process. The Qualitative Report. https://doi.org/10.46743/2160-3715/2014.1026.\n\n53 Bradley, M. (2017). Whose agenda? Power, policies, and priorities in North–South research partnerships. Development in Practice. Vol. 18, No. 6. http://www.jstor.org/stable/27751975; Mougeot, L. J. A. (2017). Putting Knowledge to Work: Collaborating, Influencing and Learning for International Development. Practical Action Publishing, IDRC.\n\n54 Samuel S. 2019. Witsaja iki, or the good life in Ecuadorian Amazonia: Knowledge co-production for climate resilience. In: Ahearn A, Oelz M, Dhir RK (eds.) Indigenous Peoples and Climate Change: Emerging Research on Traditional Knowledge and Livelihoods. International Labour Organization.; Smith, H.A. 2007. “Disrupting the global discourse of climate change: The case of indigenous voices”, in M.E. Pettenger (ed.): The social construction of climate change: Power, knowledge, norms, discourses (Aldershot, Ashgate Publishing).\n\n55 Samuel S. (2019). Witsaja iki, or the good life in Ecuadorian Amazonia: Knowledge co-production for climate resilience. In: Ahearn A, Oelz M, Dhir RK (eds.) Indigenous Peoples and Climate Change: Emerging Research on Traditional Knowledge and Livelihoods. International Labour Organization. https://ccafs.cgiar.org/resources/publications/witsaja-iki-or-good-life-ecuadorian-amazonia-knowledge-co-production.; Smith, H. A. (2006). Disrupting the Global Discourse of Climate Change: The Case of Indigenous Voices. In The Social Construction of Climate Change. Routledge. https://www.taylorfrancis.com/chapters/edit/10.4324/9781315552842-20/disrupting-global-discourse-climate-change-case-indigenous-voices-heather-smith .\n\n56 http://forestgovernance.chathamhouse.org/publications\n\n57 See Bent Flyvbjerg, ‘Five Misunderstandings About Case-Study Research’, Qualitative Inquiry, 12.2 (2006), 219–45 <https://doi.org/10.1177/1077800405284363>. The paradigmatic case is one of four modes of ‘information-oriented selection’ used to maximize the utility of information from small samples, and to develop a metaphor for the domain of transnational policy mechanisms that the cases concern.\n\n58 Forest Stewardship Council. (2022). Our History. FSC United States. https://us.fsc.org/en-us/who-we-are/our-history .\n\n59 Altruwood. (n.d.). Brief History of FSC Certification. Altruwood Blog. http://www.altruwood.com/brief-history-of-fsc-certification\n\n60 Wardell D. and others, Reviewing Initiatives to Promote Sustainable Supply Chains: The Case of Forest-Risk Commodities, FTA Working Paper, 2021 <https://doi.org/10.17528/cifor/007944>.\n\n61 Ortiz, F. (2018). Ten years on, Amazon Fund receives applause, criticism, faces new tests. Mongabay Environmental News. 21 December 2018. https://news.mongabay.com/2018/12/ten-years-on-amazon-fund-receives-applause-criticism-faces-new-tests/\n\n62 Angelsen, A., Brown, S., Loisel, C., Peskett, L., Streck, C., & Zarin, D. (2009). Reducing emissions from deforestation and forest degradation (REDD): an options assessment report. In CIFOR. https://www2.cifor.org/gcs/modules/knowledge-sharing/redd-reducing-emissions-deforestation-forest-degradation/#:~:text=What%20is%20the%20history%20of,reducing%20carbon%20emissions%20from%20deforestation.\n\n63 Garcia-Ulloa, J., & Koh, L. P. (2016). Payment for ecosystem services: the role of REDD + in primate conservation. An Introduction to Primate Conservation, 257–268. https://doi.org/10.1093/acprof:oso/9780198703389.003.0016\n\n64 FAO & EFI. (2018). Making forest concessions in the tropics work to achieve the 2030 Agenda: Voluntary Guidelines (FAO Forestry Paper No. 180). https://www.fao.org/3/i9487en/I9487EN.pdf.\n\n65 FAO & EFI. (2018). Making forest concessions in the tropics work to achieve the 2030 Agenda: Voluntary Guidelines (FAO Forestry Paper No. 180). https://www.fao.org/3/i9487en/I9487EN.pdf.\n\n66 Harris, T. (2021). 5 Points to Understand Congo’s Logging Moratorium. Greenpeace Blog. 10 March 2021. https://www.greenpeace.org/africa/en/blogs/13258/5-points-to-understand-congos-logging-moratorium/#:~:text=Since%202002%2C%20a%20moratorium%20on,rampant%20in%20the%20logging%20sector.\n\n67 OECD. (2020). Towards Sustainable Land Use: Aligning Biodiversity, Climate and Food Policies, Chapter 5: Policy instruments relevant to sustainable land use. OECD Publishing, Paris. https://www.oecd-ilibrary.org/environment/towards-sustainable-land-use_3809b6a1-en\n\n68 Fishman, A., & Obidzinski, K. (2015). Verified Legal? Ramifications of the EU Timber Regulation and Indonesia’s Voluntary Partnership Agreement for the Legality of Indonesian Timber. International Forestry Review, 17(1), 10–19. https://doi.org/10.1505/146554815814725095.\n\n69 FSC Connect. (2022). Facts & Figures: At a glance. https://connect.fsc.org/impact/facts-figures .\n\n70 UNFCCC. (2022). National strategy Fact Sheet. REDD+ Web Platform. https://redd.unfccc.int/fact-sheets/national-strategy.html.\n\n71 Jonathan A. Foley, Gregory P. Asner, Marcos Heil Costa, Michael T. Coe, Ruth DeFries, Holly K. Gibbs, Erica A. Howard, Sarah H. Olson, Jonathan A. Patz, Navin Ramankutty, & Peter K. Snyder. (2007). Amazonia revealed: forest degradation and loss of ecosystem goods and services in the Amazon Basin. Frontiers in Ecology and the Environment, 5(1), 25–32. https://doi.org/10.1890/1540-9295(2007)5; Strand, J., Soares-Filho, B., Costa, M. H., Oliveira, U., Ribeiro, S. C., Pires, G. F., Oliveira, A., Rajão, R., May, P., van der Hoff, R., Siikamäki, J., da Motta, R. S., & Toman, M. (2018). Spatially explicit valuation of the Brazilian Amazon Forest’s Ecosystem Services. Nature Sustainability, 1(11), 657–664. https://doi.org/10.1038/s41893-018-0175-0.\n\n72 Trancoso, R., Carneiro Filho, A., Tomasella, J., Schietti, J., Forsberg, B. R., & Miller, R. P. (2009). Deforestation and conservation in major watersheds of the Brazilian Amazon. Environmental Conservation, 36(4), 277–288. https://doi.org/10.1017/s0376892909990373; Ometto, J. P., Aguiar, A. P. D., & Martinelli, L. A. (2011). Amazon deforestation in Brazil: effects, drivers and challenges. Carbon Management, 2(5), 575–585. https://doi.org/10.4155/cmt.11.48; Leite-Filho, A. T., Soares-Filho, B. S., Davis, J. L., Abrahão, G. M., & Börner, J. (2021). Deforestation reduces rainfall and agricultural revenues in the Brazilian Amazon. Nature Communications, 12(1). https://doi.org/10.1038/s41467-021-22840-7.\n\n73 Heckenberger, M. J., Christian Russell, J., Toney, J. R., & Schmidt, M. J. (2007). The legacy of cultural landscapes in the Brazilian Amazon: implications for biodiversity. Philosophical Transactions of the Royal Society B: Biological Sciences, 362(1478), 197–208. https://doi.org/10.1098/rstb.2006.1979; Fearnside, P. M. (2021). The intrinsic value of Amazon biodiversity. Biodiversity and Conservation, 30(4), 1199–1202. https://doi.org/10.1007/s10531-021-02133-7.\n\n74 Carneiro Da Cunha, M. & De Almeida, M. W. B. (1999). Indigenous people, traditional people, and conservation in the Amazon. Daedalus, 129(2), 315–338; Graubard, S. R. (2000). Brazil: The Burden of the Past; The Promise of the Future. American Academy of Arts & Sciences. https://www.amacad.org/daedalus/brazil-burden-past-promise-future; Carneiro Filho, A., & Souza, O. B. (2009). Atlas de pressões e ameaças às terras indígenas na Amazônia brasileira. São Paulo: Instituto Socioambiental. https://repositories.lib.utexas.edu/handle/2152/17335; Yang, A. Toni, A. Waack, R. & Levy, J. (2021). Rethinking the Brazilian Amazon Sustainable development for a thriving future. Research Paper. Sustainability Accelerator. Chatham House Research Paper. https://www.chathamhouse.org/sites/default/files/2021-10/2021-10-21-rethinking-the-amazon-yang-et-al_0.pdf.\n\n75 Campello, T. (Ed.). (2017). Faces da Desigualdade no Brasil: Um olhar sobre os que ficam para trás. CLACSO. https://doi.org/10.2307/j.ctvtxw2vg.\n\n76 May P.H., Gebara M.F., Barcellos L. M., Rizek M., & Millikan B. (2016). The context of REDD+ in Brazil: Drivers, actors and institutions. 3rd Edition, CIFOR Occasional Paper 160. Bogor, Indonesia: CIFOR. https://doi.org/10.17528/cifor/006338.\n\n77 Sabogal, C., Lentini, M., Pokorny, B., Silva, J.C., Zweede, J.C., Verissimo, A. & Boscolo, M. (2006). Manejo florestal empresarial na Amazônia brasileira: restrições e oportunidades: relatório síntese. CIFOR. https://www.cifor.org/publications/pdf_files/Books/BSabogal0601.pdf; Sparovek, G. (2009). E certificar, faz diferença? ? Estudo de avaliação de impacto da certificação FSC/RAS. https://www.imaflora.org/public/media/biblioteca/3_e_certificar_faz_diferenca.zip; Marcovitch, J., & Pinsky, V. C. (2014). Amazon Fund: financing deforestation avoidance. Revista De Administração, 49(2), 280–290. https://doi.org/10.5700/rausp1146; Van Der Hoff, R., Rajão R., Leroy P., and Boezeman D. (2015). The parallel materialisation of REDD+ implementation discourses in Brazil. Forest Policy and Economics. Vol. 55(C). Pages 37-45. https://doi.org/10.1016/j.forpol.2015.03.005.\n\n78 Fearnside, P.M. (2005). Deforestation in Brazilian Amazonia: History, Rates, and Consequences. Conservation Biology. Vol. 19 (3): 680–688. https://doi.org/10.1111/j.1523-1739.2005.00697.x; May P.H., Gebara M.F., Barcellos L. M., Rizek M., & Millikan B. (2016). The context of REDD+ in Brazil: Drivers, actors and institutions. 3rd Edition, CIFOR Occasional Paper 160. Bogor, Indonesia: CIFOR. https://doi.org/10.17528/cifor/006338; Silva, M. (2013). Políticas públicas e conservação dos recursos naturais: os aspectos socioambientais do programa bolsa floresta no modo de vida das comunidades ribeirinhas de Maués (AM). Dissertation (Master in Society and Culture in the Amazon). Universidade Federal do Amazonas, Manaus; Eula, M.J. (2017). O Fundo Amazônia e o desenvolvimento local sustentável: o caso da cooperativa de hortifrutigranjeiros de Boa Vista. Dissertation (Master in Regional Development), Universidade Federal de Roraima. Boa Vista; Marin, T.I.S, & Silva, L. (2019). Uma avaliação da eficácia operacional do Fundo Amazônia: um olhar crítico sob sua gestão. X Colóquio Organizações, Desenvolvimento e Sustentabilidade – CODS 2019, http://revistas.unama.br/index.php/coloquio/article/view/1851; Viergever, M., & Santos, P. (2019). Relatório de avaliação de Meio termo da Efetividade do Fundo Amazônia. http://www.fundoamazonia.gov.br/export/sites/default/pt/.galleries/documentos/monitoramento-avaliacao/5.avaliacoes-externas/FA-Relatorio-Distribuicao-de-Beneficios.pdf.\n\n79 Cardoso, A.C., & Negrão, M.R.G. (2006). Considerações sobre a pobreza no Considerações sobre a pobreza no Brasil e suas manifestações nas Brasil e suas manifestações nas cidades da Amazônia. Novos Cadernos NAEA. vol.9, n. 1. pp. 95-118. ISSN 1516-6481; Campello, T. (Ed.). (2017). Faces da Desigualdade no Brasil: Um olhar sobre os que ficam para trás. CLACSO. https://doi.org/10.2307/j.ctvtxw2vg.\n\n80 16 key-informant interviews were conducted. Details at https://www.cebrapsustentabilidade.org/assets/files/2022_PolicyBrief_CEBRAP_Nakagawa.pdf\n\n81 For more information see: https://www.fundoamazonia.gov.br/en/home/\n\n82 Which focuses on governance, institutions and the common use of natural resources. Theories of polycentric governance and inclusive coallitions, by Ostrom, Acemoglu, Robinson and Berdegué, for instance, were the theoretical backbone for the analysis.\n\n83 Schaafsma, M., Dreoni, I., Ayompe, L. M., Egoh, B., Ekayana, D. P., Favareto, A., Mumbunan, S., Nakagawa, L., Ngouhouo-poufoun, J., Sassen, M., Uehara, T. K., & Matthews, Z. (2022b). A framework to understand the social impacts of agricultural trade. Sustainable Development. https://doi.org/10.1002/sd.2379.\n\n84 Scoones, I. (2015). Sustainable Livelihoods and Rural Development (Agrarian Change and Peasant Studies). Fernwood Publishing. https://practicalactionpublishing.com/book/2123/sustainable-livelihoods-and-rural-development.\n\n85 Minami, R. (2017). Unmet promises of extractive industries in Africa: corporate social responsibility: case study of Kitwe (Zambia) and Katanga (DR Congo). Nairobi, Kenya: Paulines Publications Africa. https://catalog.libraries.psu.edu/catalog/32173743.\n\n86 Forest Governance and Legality (2022). DRC Country Profile. https://forestgovernance.chathamhouse.org/countries/democratic-republic-of-the-congo.\n\n87 The Inspection Panel (2006), ‘Report and recommendations: Democratic Republic of Congo: Transitional Support for Economic Recovery Credit Operation (TSERO) (IDA Grant No. H 192- DRC) and Emergency Economic and Social Reunification Support Project (EESRSP) (IDA Credit No. 3824-DRC and IDA Grant No. H 064-DRC)’, Report No. 35192, The World Bank, https://documents1.worldbank.org/curated/en/112601468026108254/pdf/35192.pdf.\n\n88 Long, C. (2011). Land Rights in the Democratic Republic of Congo: A New Model of Rights for Forest-Dependent Communities?. in Land Struggles and Civil Society in Southern Africa. pp. 1–28. https://mokoro.co.uk/wp-content/uploads/land_rights_in_the_DRC-2.pdf.\n\n89 Trefon, T. (2007). Industrial logging in the Congo: is a stakeholder approach possible?. South African Journal of International Affairs. 13(2). pp. 101-114. https://doi.org/10.1080/10220460609556805.\n\n90 Mulvagh, L. (2006). The Impact of Commercial Logging and Forest Policy on Indigenous Peoples in the Democratic Republic of Congo. Indigenous Affairs. 4. http://www.iwgia.org/graphics/Synkron-Library/Documents/publications/Downloadpublications/IndigenousAffairs/IA4-2006 articles/DRC.pdf.\n\n91 Tshibwabwa Kuditshini, J. (2008). Global Governance and Local Government in the Congo: The Role of the IMF, World Bank, the Multinationals and the Political Elites’. International Review of Administrative Sciences. 74(2). pp.195–216. https://doi.org/10.1177/0020852308090773.\n\n92 Masudi, E.B. (2022). DRC Pre COP27. https://drcprecop27.medd.gouv.cd/en/\n\n93 Nakagawa, L., Favareto, A., Tobias, T. & Favareto, A. (2023). Forest governance in the Amazon and transition towards sustainable and inclusive use of natural resources: Lessons and challenges since FCS certification and the Amazon Fund. [Unpublished manuscript].\n\n94 Ministère de l’Envirronnement et Développement Durable (2021). Le moratoire pour quel bénéfice 18 ans après. News. 29 September 2021, https://medd.gouv.cd/?s=moratoire.\n\n95 Ir. José ILANGA LOFONGA, General director of forest in DRC ministry of environment Presentation during the national workshop July, 30, 2021.\n\n96 Geopolis Hebdo (2021). COP 26 à Glasgow (Écosse): Félix Tshisekedi confirme le statut de pays-solution de la RDC’. 02 November 2021. https://www.geopolismagazine.net/cop-26-a-glasgow-ecosse-felix-tshisekedi-confirme-le-statut-de-pays-solution-de-la-rdc/.\n\n97 Mavambu, R. (2021). Greenpeace Africa hands over a petition against the lifting of the moratorium with more than 100,000 signatories to the Prime Minister of the Democratic Republic of Congo. Greenpeace press release. 04 November 2021. https://www.greenpeace.org/africa/en/press/49456/greenpeace-africa-hands-over-a-petition-against-the-lifting-of-the-moratorium-with-more-than-100000-signatories-to-the-prime-minister-of-the-democratic-republic-of-congo/\n\n98 Hoare, A. and Kanashiro Uehara, T.H. (2022). Establishing Fair and Sustainable Forest Economies: Lessons Learned from Tackling Illegal Logging. Research Paper. London: Royal Institute of International Affairs. https://doi.org/10.55317/9781784135386.\n\n99 Democratic Republic of the Congo, Presidency of the Republic, General Inspectorate of Finance (2020), Rapport de mission relatif au contrôle de la légalité des allocations et cessions des concessions forestières et des droits dus au Trésor public par les exploitants forestiers formels [Mission report on the control of the legality of the allocations and transfers of forest concessions and rights due to the public treasury by formal loggers], https://medd.gouv.cd/wp- content/uploads/2022/04/Rapport-de-mission-relatif-au-controle-de-la-legalite-des-allocations-et-cessions-des-concessions-forestieres-et-des-droits-dus-au-Tresor-public-par-les-exploitants-forestiers-formels.pdf\n\n100 Ibid.\n\n101 Ibid.\n\n102 Ibid.\n\n103 Forest Governance and Legality (2022). DRC Country Profile. https://forestgovernance.chathamhouse.org/countries/democratic-republic-of-the-congo.\n\n104 TEREA & S-FOR-S. (2016). Evaluation of the EU FLEGT Action Plan (Forest Law Enforcement Governance and Trade) 2004-2014: Final Report Volume 1 (Main Report). https://ec.europa.eu/environment/forests/pdf/FLEGT%20Eval%20Consultant%20Report%20EN.pdf; Hoare, A., & Kanashiro Uehara, T. (2022). Establishing fair and sustainable forest economies: Lessons learned from tackling illegal logging. Research Paper, London: Royal Institute of International Affairs. https://doi.org/10.55317/9781784135386.\n\n105 Hoare, A., & Kanashiro Uehara, T. (2022). Establishing fair and sustainable forest economies: Lessons learned from tackling illegal logging. Research Paper, London: Royal Institute of International Affairs. https://doi.org/10.55317/9781784135386.\n\n106 Fourteen other countries were negotiating or preparing to implement similar schemes in 2022, but Indonesia remained the only one with an operational licensing scheme. FLEGT Independent Market Monitor, Monitoring board, https://stats.flegtimm.eu (last access 19 September 2022)\n\n107 SVLK abbreviation was revised, whereby ‘K’ no longer meant Kayu (timber), but rather Kelestarian (sustainability).\n\n108 Nugroho B., and Tiryana T. 2013. Implications of the private property right to the community forest business formalization through the certification policy. Jurnal Manajemen Hutan Tropika XIX (3): 178 – 186.\n\nMaryudi A, Laraswati D, Sahide MAK, Giessen L. 2021. Mandatory legality licensing for exports of Indonesian timber products: balancing the goals of forest governance and timber industries. Forest Policy and Economics 124: 102384. Doi: https://doi.org/10.1016/j.forpol.2020.102384. Villanueva, F.D.P., Tegegne Y.T., Winkel, G, Cerutti P.O., Ramcilovic-Suominen S., McDermott C.L, Zeitlin J., Sotirov, M., Cashore, B., Wardell, D.A., Haywood A., Giessen, L. 2022. Effects of EU illegal logging policy on timber-supplying countries: A systematic review. Journal of Environmental Management 327 (2023) 116874\n\n109 Data was collected from July 2021 to June 2022, through a combination of interviews, focus group discussions, field visits, observations, and three workshops. Approximately 317 participants were involved as respondents and informants, representing state forest licence holders, smallholder private forests, and customary forests. Nugroho, B., Buchori, D., Setiajiati, F. & Iriyani, S. (2022). Effectiveness of SVLK Implementation in Forest Property Rights Regimes Following Indonesia's Omnibus Law: An Institutional Economic Perspective. [Unpublished manuscript].\n\n110 Survey results of 11 natural forest concessions and nine monoculture timber plantation concessions. Results were confirmed by participants in the second national workshop on 19 April 2022.\n\n111 Nurkomariyah S, Firdaus M, Nurrochmat DR, Erbaugh JT. (2019). Questioning the competitiveness of Indonesian wooden furniture in the global market. IOP Conf. Series: Earth and Environmental Science. 295. https://doi.org/10.1088/1755-1315/285/1/012015.\n\n112 Indonesia has 262 units of natural forest concessions and 293 units of monoculture timber plantation concessions (MoEF website phl.menlhk.go.id/infografis, accessed on 20 September 2022). The total concessions that received the SVLK up to September 2022 were 178 units for natural forest and 152 units for monoculture timber plantation (informed by MoEF Staff at the Directorate General of Sustainable Forest Management). Indonesia's production forests cover 68.82 million ha. Notably, the area of natural forest concessions declined by 69% while industrial plantations increased by 142% in the past two decades. This change can be explained by the political reforms in Indonesia in 1998 and international political economy pressures, which have enabled the expansion of monocultural timber plantations.\n\n113 The customary law community is a traditional community in association with institutions and instruments of customary law, which is still adhered to and which still relates to collecting forest products in the surrounding forest areas, whose existence is confirmed by regional regulations (Regulation of MoEF No. 9 the Year 2021). Previously, the customary forest was part of the state forest (Law no. 41 the Year 1999), no longer has that status since the Constitutional Court decision no. 35/PUU-X/2012.\n\n114 Working Group for ICCAs in Indonesia. (2022, April 22). A five-million-hectare increase in the registered Indigenous territory in Indonesia: New BWRA data. ICCA Consortium. https://www.iccaconsortium.org/index.php/2022/04/12/indonesia-indigenous-peoples-territory-record-update-bwra/.\n\n115 Working Group for ICCAs in Indonesia. (2022, April 22). A five-million-hectare increase in the registered Indigenous territory in Indonesia: New BWRA data. ICCA Consortium. https://www.iccaconsortium.org/index.php/2022/04/12/indonesia-indigenous-peoples-territory-record-update-bwra/.\n\n116 Jong, H. N. (2022). Indonesian government lagging independent effort to recognize Indigenous lands. Mongabay Environmental News. 05May 2022. https://news.mongabay.com/2022/05/indonesian-government-lagging-independent-effort-to-recognize-indigenous-lands/.\n\n117 Jong, H. N. (2022). Indonesian government lagging independent effort to recognize Indigenous lands. Mongabay Environmental News. 05May 2022. https://news.mongabay.com/2022/05/indonesian-government-lagging-independent-effort-to-recognize-indigenous-lands/.\n\n118 Badan Pusat Statistik. “Informasi Terbaru.” 2021. https://bps.go.id/\n\n119 Uehara, T. (2022). Takeaways from the Global Forum on Forest Governance 2022. Forest Governance and Legality Blog. 26 July 2022. https://forestgovernance.chathamhouse.org/publications/takeaways-from-the-global-forum-on-forest-governance-2022.\n\n120 Nugroho B, Buchori D, Iriyani S, Setiajiati F. (2022). Efektivitas penerapan SVLK pada Berbagai Tipe Alas Hak. Policy Brief Pertanian, Kelautan, dan Biosains Tropika. Vol 4 No. 3. https://dpis.ipb.ac.id/wp-content/uploads/2022/08/12.-Efektivitas-Penerapan-SVLK-pada-Berbagai-Tipe-Alas-Hak.pdf.\n\n121 Nurrochmat, D.R., Dharmawan, A.H., Obidzinski, K., Dermawan, A., and Erbaugh, J.T. (2016), Contesting national and international forest regimes: Case of timber legality certification for private forests in Central Java, Indonesia, Forest Policy and Economics, 68: 54 – 64, https://doi.org/10.1016/j.forpol.2014.09.008.\n\n122 The survey and focus group discussion are part of this study, conducted in Solo Raya on 17 March 2022\n\n123 Findings from FGD Solo on 17 March 2022\n\n124 Ministerial Regulation Permenhut 8, 2021.\n\n125 Nugroho B, Buchori D, Iriyani S, Setiajiati F. (2022). Efektivitas penerapan SVLK pada Berbagai Tipe Alas Hak. Policy Brief Pertanian, Kelautan, dan Biosains Tropika. Vol 4 No. 3. https://dpis.ipb.ac.id/wp-content/uploads/2022/08/12.-Efektivitas-Penerapan-SVLK-pada-Berbagai-Tipe-Alas-Hak.pdf.\n\n126 Ece M. (2021). Creating property out of insecurity: territorialization and legitimation of REDD+ in Lindi, Tanzania. The Journal of Legal Pluralism and Unofficial Law. Volume 53. https://doi.org/10.1080/07329113.2021.1900512.\n\n127 Cannon, J. (2018). NGOs seek suspension of forest-related funding to DRC in response to proposed end to logging moratorium. Mongabay Series: Global Forests. 08 March 2018. https://news.mongabay.com/2018/03/ngos-seek-suspension-of-forest-related-funding-to-drc-in-response-to-proposed-end-to-logging-moratorium/.\n\n128 Maryudi, A., Acheampong, E., Rutt, R.L., Myers, R. and McDermott, C.L. (2020). “A Level Playing Field”? – What an Environmental Justice Lens Can Tell us about Who Gets Leveled in the Forest Law Enforcement, Governance and Trade Action Plan. Society & Natural Resources. 33(7), pp. 859-875. https://doi.org/10.1080/08941920.2020.1725201.\n\n129 Delabre, I., Boyd, E., Brockhaus, M., Carton, W., Krause, T., Newell, P., Wong, G. Y., & Zelli, F. (2020). Unearthing the myths of global sustainable forest governance. Global Sustainability, 3. https://doi.org/10.1017/sus.2020.11.\n\n130 See, for instance, David Coghlan and Mary Brydon-Miller, ‘Paulo Freire’, in The SAGE Encyclopedia of Action Research, ed. by David Coghlan and Mary Brydon-Miller (London: SAGE Publications, 2014), pp. 368–71 <https://doi.org/10.4135/9781446294406>.\n\n131 See, for instance, Schaafsma and others; Ian Scoones, Sustainable Livelihoods and Rural Development (Rugby, UK: Practical Action Publishing, 2015); Marcello de Maria, Ilda Dreoni, and others, What Do We Need to Make Trade More Socially Sustainable within Exporting Countries?, Discussion Paper, 2021 <https://tradehub.earth/wp-content/uploads/2021/11/TRADE_Discussion_Paper_5.pdf>. rooks, S., Nicholas, H., West, C., De Maria, M., and Komarudin, H. (2022), Taking responsibility for supply chain impacts: who, why and how?, Discussion Paper 6, Chatham House, UNEP and WCMS, https://tradehub.earth/wp-content/uploads/2022/03/FAQ6-3-003.pdf."
}
|
[
{
"id": "176890",
"date": "30 Jun 2023",
"name": "Peter Kanowski",
"expertise": [
"Reviewer Expertise Forest governance"
],
"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\nI acknowledge the spirit in which the authors and institutions have undertaken and reported this work, and commend them for that. One could not argue with the intentions of strengthening the agency of institutions of the Global South in collaborative research, or of South-South collaboration; and, from the evidence in the paper, it appears that the project has been successful in doing so.\n\nSuch models of research partnership are not new, of course (albeit underrepresented); Australia's ACIAR (www.aciar.gov.au) was established 40 years ago to support research between one country of the Global N and a cohort of those of the Global S. Its original focus on primarily technical issues has broadened over the past decade to a stronger policy focus. Some studies have explored the factors that contribute to the success, or otherwise, of these partnership projects (e.g., Bartlett 20181).\nThe Brazilian and DRC case studies reported here each recommend inclusive, transparent multistakeholder forums as platforms for addressing the forest governance challenges they explore. Such platforms exist, of course, internationally (The Forests Dialogue; theforestsdialogue.org) and in particular countries (e.g., Brazil; dialogoflorestal.org.br).\n\nMethodologically, more information on the actual form of the institutional analysis conducted in Brazil. The analytical approaches adopted in DRC and Indonesia were not clear to me.\nFor the paper as a whole, the results reiterate those of the wider literature (eg Katila et al 2020, DOI: 10.1017/97811087650152). While I don't disagree with the emphasis in the conclusions on reimagining and reforming N-S relationships, I am reminded by each of the case studies of how so much of forest governance outcomes is determined by domestic political economy, which is influenced only to some extent by the N-S dynamics. It would be helpful to see some further thoughts on strategies for change in that arena emerge from each of the cases.\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?\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? Partly",
"responses": []
},
{
"id": "176892",
"date": "04 Jul 2023",
"name": "Felipe Nunes",
"expertise": [
"Reviewer Expertise Environmental science",
"Geoscience and Spatially-explicit modeling"
],
"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\nA well-written manuscript that addresses an important perspective for better understanding the failure of transnational and market initiatives to effectively combat deforestation in the tropics. Small comments and suggestions to the authors above (and highlighted in the pdf document shared).\n\nI suggest citing the European Union Regulation on deforestation-free imports recently approved and especially discussing how it is shaping EU-Mercosul Agreement, which once signed could become the world's largest free trade agreement: https://environment.ec.europa.eu/topics/forests/deforestation/regulation-deforestation-free-products_en; https://www.greens-efa.eu/en/article/study/the-eu-mercosur-free-trade-agreement-its-impacts-on-agriculture\n\nIt is important to discuss the role of private certifications as it they have contributed to expanding market-based solutions despite several cooperative scandals and evidence of insufficient progress toward achieving anti-deforestation targets and greenhouse gas emissions reductions1.\n\nGovernments can also play an important role in providing transparency in high-risk supply chains by addressing compliance with socio-environmental legislation at the farm level.\n\nI suggest the authors include 2 or 3 sentences indicating ways through boundary work and boundary objects literature2-4.\n\nI suggest that the authors also cite critical studies on the effectiveness of the Amazon Fund, e.g., Correa et al., (2019)5.\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?\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": []
},
{
"id": "176883",
"date": "12 Jul 2023",
"name": "Krossy Mavakala",
"expertise": [
"Reviewer Expertise Social and Politicl Science & Forests and Tropical Lands 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\nSummary\nThe article addresses a crucial and topical issue about forest governance in the tropics under the optique of examining partnerships and international forest policies that affect Brazil, the Democratic Republic of Congo and Indonesia. As an introduction, the authors stated that international and market forces are key underlying drivers of deforestation and degradation of forest. Then, the authors call the international community to take stock of how it frames and manages land-use, forest and climate policy collaborations. International collaboration needs to be led in an inclusive manner including revisiting SDGs (Sustainable Development Goals) on ‘Global Partnerships for Sustainable Development’. Authors define ‘global’ or ‘globalizing’ as a way to redress imbalances in the interplay between ‘global’ and ‘local’ imperatives in international collaboration, and between institutions in Global North and Global South countries. The article is a result of a twenty-month collaborative project between Chatham House from the UK, CEBRAP (Centro Brasileiro de Análise e Planejamento) from Brazil, CEPAS (Centre d’Etudes pour l’Action Sociale) from the DRC and CTSS (Centre for Transdisciplinary and Sustainability Sciences) from Indonesia. The project aimed to establish and discuss equitable research partnerships while examining prominent transnational initiatives affecting the forest lands and peoples in the tropics.\nThe article is subdivided into three big parts each with sub-part. Apart from the introduction and the conclusion, the first part of the article talks about Forest governance solutions that need a critical analysis, the second one is about North–South and South–South research partnerships emphasing setting of relationships between research partners while underlying the methodology and the outputs of the research, and the last part is about (G)local views on transnational policy instruments with regard to revisiting community and governance impacts of the FSC and Amazon Fund in Brazil, Regulating logging concessions and the moratorium in the DRC, and Verifying legality in different forest regimes in Indonesia. The article has shown interesting results in the three countries and different domains of reflexions through all the countries object of the study.\n1. Revisiting community and governance impacts of the FSC and Amazon Fund in Brazil\nThe situation of uncontrolled and illegal use of natural resources in Brazil that made the biome suffer severely has been reversed since 2012 until the deforestation become greater recently with impacts on poverty of people from the Amazon region. Therefore, the section about revisiting community and governance impacts of the FSC and Amazon Fund in Brazil aims to revisit two mechanisms affecting land use and livelihoods such as the Forest Stewardship Council (FSC) and the Amazon Fund as Redd+ mechanism. The first mechanism is about promoting better forest management practices while the second one is about reducing emissions and carbon markets on payment for environmental services.\nIt appeared in the context of Brazil that the FSC mechanism had several limitations particularly for smallholders, Indigenous Peoples and local communities as it depends on external support, generally absent. The survey conducted with minoritiy groups shows that smallholders face constant threats and incursions by land grabbers, that makes it challenging for minority groups to obtain and maintain FSC certification. In the other hand, the Amazon Fund contributed to strengthen environmental agencies at the state and federal levels. The legacy of the Amazon Fund was noticeable, particularly by including women and traditional communities, even when unfavorable political decisions were applied.\nTherefore, authors recommended not to consider FSC certification and the Amazon Fund as unique and sufficient solutions; but, to also discuss about new strategies and actions that governments, funders and investors could enact.\n2. Regulating logging concessions and the moratorium in the DRC\nAuthors talk about the moratorium on the allocation of new industrial logging concessions, a process that begun in 2002 and that the government wanted to lift in 2021. Shown as a way to put an end to what Congolese government calls a widespread of looting, exploitation, and destruction of the country, the moratorium itself turned out to be both an opportunity and a failure. Established by a presidential decree in 2015, the moratorium presented three conditions such as the conversion of old logging titles into forest concession contracts, deployment of transparency mechanisms on forest concessions and plan a phased lifting of the moratorium. The lifting of the moratorium has been announced in 2021 while the conditions were not fulfilled, government claiming the DRC as a « climate crisis solution country ». Therefore, authors of the article examined the views of different stakeholders about the moratorium on industrial logging concessions in order to find ways forward in terms of national and international policy work.\nOne of the views from the government shows that maintaining a 20-year old moratorium is irresponsible emphasizing the potential for land resources to contribute to revenue collection for the government, to the development of infrastructure, and to the benefit of people. International NGOs and the Congolese civil society opposed to this point of view the contradiction between the DRC’s climate and forest commitments and its plan to lift the moratorium on new logging concessions, underlying the fact that the main beneficiaries of such a decision would certainly be foreign companies, and not necessarily Congolese communities. Therefore, Congolese government has been asked to firstly design and define a phased programme to progressively lift the moratorium.\n\nDRC’s forest law enforcement has been said weak by the authors, DRC’s administration having granted contracts through bilateral negotiations between entrepreneurs and government officials that were unlawful, lacked transparency, and fairness. Views from the DRC government said that logging concessions were linked to corruption and benefited personal interests. The capacity of the country to enact reforms or enforce regulations shown numerous challenges for the public service.\n3. Verifying legality in different forest regimes in Indonesia\nSeveral International Organization including the World Bank, the United Nations Forum on Forests, the Group of Eight, the EU, and the Association of South-East Asian Nations have supported multilateral frameworks to improve forest law enforcement, governance and associated trade with the aim to reduce illegal logging and the related trade that would halt deforestation and foster sustainable forest management with negative impacts on rural livelihoods and sustainable development.\nBeing the first country in the world to have operationalized the Forest Law Enforcement, Governance and Trade (FLEGT) licensing scheme supported by the SVLK (Sistem Verifikasi Legalitas Kayu), the SVLK had several changes whose the major one is the 2021 Omnibus Law on job creation that broadened the scope of the system, to encompass verifications on sustainability, and to cover all timer and non-timber products, and all forest property regimes. The section talks about the effectiveness of the SVLK for Indonesia in different regimes such as the state, customary and private forests.\nWhile most forested areas belong to the State, with a lesser quantity to the indigenous peoples and a fewer one to privates, companies exploiting concessions perceive government support and the SVLK’s economic benefits to be moderate or weak. Holders, therefore, preferred the mandatory SVLK to voluntary mechanisms like the FSC or the IFCC.\nAuthors give this final remark that licensing scheme and SVLK have relative effect in state forests while effects are minor in privates and non-existent in customary forests with negative implications in Indigenous Peoples, local communities, artisanal producers and smallholders.\nNow, it a place to assess the article by answering to some questions that the F1000Research have organized in a way of peer-reviewing efficiently this work. Here are questions:\nIs the work clearly and accurately presented and does it cite the current literature?\nYes, the work is clear and accurately presented and cited current literature. However, we suggest that the authors give a sufficient place to words from the interviewees as the study has made more than 20 months and included several researchers from several research institutions. Some pages of the article have had a half of citations while we do not see anywhere some quotes showing that what authors say comes from people from the field. Without showing that it is a field study, we are afraid that readers think it is a work done from the library. Our advice is to ask authors to reduce the amount of citations and give more insights and importance to views from people from the field.\nIn the presentation of the work, we observe that the authors have tried to advise others like the international community, that we think could lead to a certain risk of ethnocentrism or egocentrism and lead to a feeling of everything the international community has done is null seen from the Global South. We all know that a lot has been done while a lot has to be done in the future. Sentences like « the international community needs to take stock of how it frames and manages land-use, forest and climate policy collaborations… » or « a rethink of international collaborations needs to be conducted in an inclusive manner » looks like either the international community does not know what they are doing or efforts that the international community have made for decades were not well designed, and, therefore, once they act for advice from authors, everything will drive better. We know that it is useful, or it is a fashionable way of characterizing the international community, but, we think that we should be grateful to what we all have done in the side of conservation to make it move better, even though we know that challenges are still numerous to face. It should be important that we design accurate ways of assessing efforts made since then through metrics that could easily show improvements made in the sector of conservation. And, what does the international community mean for those three countries when the DRC is an international community member when we talk about Brazil and Indonesia, vice-versa. It is obvious that numerous works discuss the role of institutions such as the Word Bank, the IMF, the EU, the UN, and so on in designing programmes that could impact the global challenges. And, the inclusive aspect of the conservation authors seek to be included in the conservation is already elements of the discourse of the international community since decades, and participation of international, national and local communities in efforts to undertake global climate change is not aspect to be ignored. However, it is also obvious that numerous authors, institutions and countries have criticized the way those institutions function. It is however obvious that those institutions and their programmes have impacted the world, including the way we organize conservation responses. What was positive and what is negative are things to be assessed with objectivity. From then, there's still a long way to go.\nOur point of view remains when authors talk about Global South governments. Some sentences address the functioning of governments from the South when it is to say like « there is no political and policy coordination to reconcile risks and opportunities between urbanization, rural development, food, energy and climate security ». I think those are extreme affirmations that could be revisited or relativized as governments from the South have also made sufficient efforts to participate in the fight of sustainable environment.\nIs the study design appropriate and is the work technically sound?\nYes, the study is appropriate and the work sounds technically. I was asking myself what was the transition between both parts of the work that are « Forest governance solutions » and « (G)local views on transnational policy instruments ». Authors succeeded in explaining what is the link between those parts: « four institutes sought to establish and discuss equitable research partnerships while examining prominent transnational initiatives that are affecting forest lands and peoples in the tropics ». However, some questions raise when it is to question the status, functions and rules of members of those institutes according to their involvement in actions and programmes that affect forest lands and peoples of the three countries? Are they just researchers from independent research center or are they government members with related connections to decision-making about forest lands and peoples? In this part, we also question the role of Chatham House in designing the survey. It looks like authors are talking about equitability while Chatham House remains « above » other partners in the research. Indeed, Chatham House has looked for funds to finance the research and has designed a questionnaire that was implemented to researchers in the Global South. It is Chatham House that controlled the budget, that makes it not acting as a partner, but a coordinator of the project with a risk to negatively the equitability criterion it fights for. Authors do not state that either researchers from the South either contributed to budget or researchers from the North responded to the questionnaire. By not doing so, equitability between Global North and Global South remains in a risk of maintaining the imbalance between partners.\nAre sufficient details of methods and analysis provided to allow replication by others?\nPartly. The section on methodology leaves us wanting more. The methodology is not precise about what kind of method (and techniques) were used as in the beginning authors talk about a questionnaire submitted to researchers from the Global South and some focus groups and interviews so far. Author sare not precise if it was quantitative, qualitative or mixed approach of the survey that led to the results that we are acknowledging today. Authors do not talk a lot about the quality of the interviewees, their functions in their respective institutions, their sociological profile, and so on. We don’t know how many researchers they questioned and how many times they had in produce the data and we don’t know if the survey was led in the Global South or in the Global North or if it was an online one. I think some precisions are important to help the survey to benefit from a replication if possible. Being precise about how they produced the data could help why they have chosen to present their results in that way, as I have underlined that those results look like coming from a huge literature source than from a long time field work survey. We need some quotes and some sentences and sociological profiles from people from the ground to make the article feed the voices of people from the Global South.\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable. The style or the methodology applied by the authors have not asked them to use sufficient statistical analysis, which in no way detracts from the quality and nature of the information contained in this article.\nAre all the source data underlying the results available to ensure full reproducibility?\nYes\nAre the conclusions drawn adequately supported by the results?\nYes\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?\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": []
}
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https://f1000research.com/articles/12-125
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https://f1000research.com/articles/12-124/v1
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02 Feb 23
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{
"type": "Systematic Review",
"title": "Endourological versus open cystolithotomy for bladder stone management among children: A systematic review and meta-analysis",
"authors": [
"Randy Fauzan",
"Hendra Herman",
"Wendy Rachman",
"Ardiansyah Periadi Sitompul",
"Ari Astram",
"Hendra Herman",
"Wendy Rachman",
"Ardiansyah Periadi Sitompul",
"Ari Astram"
],
"abstract": "Background: The treatment of choice for bladder stones in children remains debatable. This study aimed to compare the outcomes of endourological and open cystolithotomy for the management of bladder stones in children. Methods: The Medline, Embase, Cochrane controlled trial databases and clinicaltrials.gov were searched for relevant English-language publications from 1 to 30 August 2022. Stone-free rate (SFR), complication rate, length of stay, and procedure duration were compared. Children (male and female) <18 years of age of any ethnicity with bladder stones (single/multiple) were included. Patients with a history of bladder augmentation or diversion were excluded. The quality of studies included was assessed using Cochrane’s Risk of Bias Assessment. The meta-analysis was performed using RevMan. Results: Five articles (436 participants) that compared endourological versus open cystolithotomy were included in qualitative and quantitative analyses. Four were non-randomised, retrospective, and single centre studies. While the other one was a randomised controlled trial. Measure outcome characteristics included SFR, complications, procedure duration, and length of hospital stay. There was no significant difference in the SFR between transurethral cystolithotripsy (TUCL) and percutaneous cystolithotomy (PCCL) (p=0.22). There were also no significant differences in complications (TUCL versus PCCL, p=0.18; TUCL versus open cystolithotomy [CL] and PCCL versus CL, p=0.08). PCCL featured a longer procedure duration than TUCL (p<0.00001), while CL was shorter than TUCL and PCCL (both p<0.00001). Finally, in terms of length of stay, TUCL was superior to PCCL and CL, while PCCL was better than CL (all p<0.00001). Conclusions: Endourological and open surgical management of bladder stones in children showed comparable SFR and fewer complications. Open surgery offers a shorter procedure duration than endourological management, but PCCL features a shorter procedure duration than TUCL. In terms of length of stay, TUCL and PCCL were superior to CL, while TUCL was better than PCCL.",
"keywords": [
"Endourological techniques",
"Open surgery",
"bladder stone",
"children"
],
"content": "Introduction\n\nBladder stones account for 5% of urolithiasis cases, which are traditionally classified as primary idiopathic, secondary, or migrant.1 In some cases, it can occur in children, especially in developing countries, due to the high prevalence of urinary tract infections and poor nutritional status, especially owing to a protein-poor diet. The incidence in male children is 10-fold that in female.2,3 The best option for managing these patients was traditionally open cystolithotomy (CL) owing to its high stone-free rate (SFR); however, it results in significant complications, such as long scars, prolonged catheterisation, extended hospitalisation, and risk of infection.4,5\n\nDue to technological advancements and the application of laser science in medicine, endourological procedures (transurethral cystolithotripsy [TUCL] and percutaneous cystolithotomy [PCCL]) have become popular among urologists.6,7 Large and hard stones can be disintegrated and removed in large fragments to enable a quick intervention. It is also more advantageous than open surgery in terms of cosmetic outcomes and length of hospital stay. Some studies have shown its safety and efficacy; however, more data are still needed.8,9\n\nTo date, only a few studies have compared endourological procedures and open cystolithotomy for the management of bladder stones in children; therefore, we performed this systematic review and meta-analysis. There were no expected sex and/or gender differences in this study.\n\n\nMethods\n\nThe inclusion criteria in this study were as follows: 1) All randomised controlled trials (RCTs) and comparative non-randomised studies (NRSs) comparing open cystolithotomy and endourological procedures for bladder stones; 2) full-text articles published in English; 3) children (male and female participants) <18 years of age of any ethnicity with bladder stones (single/multiple) were included. Patients with a history of bladder augmentation or diversion were excluded. All studies were grouped into three groups: group A (TUCL versus PCCL), group B (TUCL versus CL) and group C (PCCL versus CL).\n\nWe conducted the systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist26 and Cochrane Handbook for Systematic Reviews of Interventions. This study followed the SAGER guidelines for reporting sex and gender.27 The MEDLINE (RRID:SCR_002185), EMBASE (RRID:SCR_001650), and Cochrane Central Register of Controlled Trials (RRID:SCR_006576) databases and ClinicalTrials.gov (RRID:SCR_002309) were searched for relevant English-language publications from 1 to 30 August 2022.\n\nWe used keywords adjusted to search engine specification in the form of (bladder stone OR bladder calculi) AND (transurethral cystolithotomy OR percutaneous cystolithotripsy OR open cystolithotomy) AND (children OR paediatric).\n\nThe PICOS framework was used to trace studies and identify the suitability of any we found.10 Study selection was carried out independently and duplicated by each author, referring to inclusion and exclusion criteria. The decision to study eligibility was determined by each author independently. Any disagreement was resolved by discussion.\n\nData collection was carried out by each author independently and in duplication. We extracted the study’s primary characteristics, including the first author, location, sample size, and publication year. We also extracted patient baseline data and postoperative data, including a SFR, complication rate, procedure duration and length of stay. We used a 2x2 contingency table to obtain each study’s odds ratio (OR) and pooled the overall ORs using RevMan (RRID:SCR_003581) version 5.3.\n\nThe following data were extracted from each study included in the review: study methodology (study design, year); participant characteristics (age, sex, stone size, lithotripsy energy, SFR, complication, procedure duration, catheterisation, hospital stay and follow up); intervention and comparator description (TUCL, PCCL and CL); and outcome measures.\n\nRisk of bias assessment was independently assessed by each author using the risk of bias assessment tool by Higgins et al., (2011)11 including: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias, which were produced via RevMan (RRID:SCR_003581) version 5.3.\n\nThe odds ratio (OR) with 95% CI was used to assess the success of treatment (SFR and complication). The mean duration and mean hospital stay were assessed using mean difference (MD) with 95% confidence intervals (CI).\n\nThe meta-analysis was performed using RevMan (RRID:SCR_003581) version 5.3. The results are described as odds ratios (OR) with 95% confidence intervals (CI) for dichotomous variables and as mean difference with 95% CI for continuous variables. A chi-squared statistic (Cochrane Q) was used to evaluate the level of heterogeneity. The I2 statistic was used to determine the percentage of the total variation in the estimated effect across studies. The data was analysed using the random effect model when I2 >25%, and fixed effect model when I2 is less than 25%. Statistical significance was set at values of p<0.05. For studies that provided the minimum and maximum value instead of standard deviation (SD) for the mean difference analysis, estimated SD were calculated with the formula derived from a study by Walter and Yao (2007).12 Sensitivity analyses were not conducted to explore the effect of study quality as there were too few studies and some studies used different criteria for measuring outcomes.\n\nWe could not use funnel plots of between-treatment effect and its precision on individual studies for publication bias due to the small numbers of studies.\n\nTo assess certainty (or confidence) in the body of evidence for an outcome, this meta-analysis used GRADE score, which has four level of evidence very low, low, moderate, and high.13\n\n\nResults\n\nA total of 2,975 articles were initially retrieved from the database. After removing duplicates and evaluating the title and abstracts, 28 articles were subjected to full-text review. From the 28 article studies screened, 23 studies were excluded due to the following reasons: they were studies on adults (n=16), had an insufficient number of patients (n=2), or did not focus on endourological and open cystolithotomy (n=5). Finally, five studies were included in the analysis: four NRS and one RCT. The article selection process was performed according to the PRISMA statement (Figure 1).\n\nThree of the five studies included in this systematic review were non-randomised studies, retrospective, and single centre.14–16 The other two were prospective, but one was randomised and the other one was not randomised.17–18 The numbers of patients enrolled in the studies did not differ between studies. The total number of patients in this meta-analysis was 436 patients. Two studies compared endourological (TUCL; PCCL) versus open cystolithotomy, two studies compared PCCL versus TUCL, and the last one compared PCCL versus open cystolithotomy. Measure characteristics included intervention type, sex, age, stone size, and lithotripsy energy. Outcomes (SFR, complications, procedure duration, and length of hospital stay) and follow-up were also measured (Table 1).\n\nNRS, non-randomised study; RCT, randomised controlled trials; TUCL, transurethral cystolithotripsy; PCCL, percutaneous cystolithotomy; CL, cystolithotomy; yo, years old; mo, months; NR, not reported; XR, X-ray; USG, ultrasonography; w, weeks; Pneu, pneumatic.\n\nOf the five studies included in this meta-analysis, three had high risk of bias because assessor outcome blinding was not performed.14,15,18 Selection bias in some studies was also considered high because no allocation concealment was performed. In general, the quality of the studies in this meta-analysis varied from low to high. The bias assessment was carried out independently by each author and in duplication, in which all authors were resolved by discussion or consensus. Figure 2 visualizes the summary of bias risk.\n\n(A) Traffic light plot and (B) summary plot.\n\nStone-free rate\n\nGroup A (TUCL versus PCCL)\n\nMahran et al., 2000, Al-Marhoon et al., 2009 and Javanmard et al., 2018 reported SFRs of 100%. All stones were removed successfully.14–16 Mishra et al., 2020 reported both groups (TUCL and PCCL) were comparable with good outcomes. The clearance rate was 100% in the PCCL group, while in the TUCL group it was 86.6%. However statistical significance was not reached.18 Shahat et al., 2022 reported TUCL SFR was 96%, while PCCL 98%. There were no significant differences between both groups (p=1).17\n\nGroup B (TUCL versus CL) and Group C (PCCL versus CL)\n\nMahran et al., 2000, Al-Marhoon et al., 2009 and Javanmard et al., 2018 reported SFRs of 100%.14–16\n\nComplication\n\nGroup A (TUCL versus PCCL)\n\nMahran et al., 2000 reported one (4%) patient who was observed for urethral rupture and extravasation during TUCL and four (15%) patients who developed early and late complications (persistent leakage of urine, acute abdomen, and stricture urethra) for PCCL.16 Shahat et al., 2022 reported that complication for TUCL were persistent haematuria, urethral abrasion, difficulty after catheter removal, and bladder perforation, while PCCL had fever, persistent haematuria, stone entrapped, subcutaneous fluid collection, and intraperitoneal collection.17 Javanmard et al., 2018 reported complications in PCCL included surgical site infection,2 urinary leakage,1 and irritative symptoms,2 while six patients from TUCL group developed haematuria.15 Mishra et al., 2000 reported zero complications in the PCCL group and one patient conversion into open surgery in the TUCL group.18 Al-Marhoon et al., 2009 showed urethral rupture (1 (1.4%)) in the TUCL group and bladder perforation (1 (1.4%)) in the PCCL group.14\n\nGroup B (TUCL versus CL)\n\nMahran et al., 2000 reported one (4%) patient who was observed for urethral rupture and extravasation during TUCL and one (4%) patient who had small intestinal injury in the CL group.16 Javanmard et al., 2018 reported six patients from the TUCL group who developed haematuria and one patient who underwent CL had urinary leakage and perivesical fluid collection.15 Al-Marhoon et al., 2009 showed one (1.4%) patient in the TUCL group who had a urethral rupture and one (1.9%) patient who had peritoneal perforation and small intestinal injury during tube drain fixation in the CL group.14\n\nGroup C (PCCL versus CL)\n\nMahran et al., 2000 reported four (15%) patients who developed early and late complications (persistent leakage of urine, acute abdomen, and stricture urethra) for PCCL and one (4%) patient who had small intestinal injury in the CL group.16 Javanmard et al., 2018 reported complications in PCCL included surgical site infection,2 urinary leakage,1 and irritative symptoms2 and one patient who underwent CL had urinary leakage and perivesical fluid collection.15 Al-Marhoon et al., 2009 reported one (1.4%) patient had bladder perforation in the PCCL group and one (1.9%) patient had peritoneal perforation and small intestinal injury during tube drain fixation in the CL group.14\n\nProcedure duration\n\nGroup A (TUCL versus PCCL)\n\nMahran et al., 2000 reported no significant differences in procedure duration between two groups. It was 46 ± 14 minutes for the TUCL or PCCL group.16 Shahat et al., 2022 reported PCCL had significantly faster procedure duration than TUCL (p=0.012). It was 34.2 ± 24.8 minutes for TUCL group and 25.3 ±18.7 minutes for PCCL group.17 Javanmard et al., 2018 reported significantly longer procedure duration in the TUCL group (36.3 ± 5.9 minutes) than the PCCL group (30.5 ± 5.2 minutes) (p=0.000).15 Mishra et al., 2000 reported faster procedure duration for the PCCL group (33.5 ± 8.4 minutes) than the TUCL group (38.2 ± 6.7 minutes).18 Al-Marhoon et al., 2009 reported that the procedure duration was comparable in both groups (46 ± 14 minutes).14\n\nGroup B (TUCL versus CL)\n\nMahran et al., 2000 reported no significant differences in procedure duration between the two groups. It was 46 ± 14 minutes and 38 ± 12 minutes in the TUCL and CL groups, respectively.16 Javanmard et al., 2018 reported that the CL group had significantly faster procedure duration (26.0 ± 6.3 minutes) than the TUCL group (36.3 ± 5.9 minutes) (p=0.000).15 Al-Marhoon et al., 2009 reported that procedure duration was comparable in both groups, 46 ± 14 and 38 ± 12 minutes for TUCL and CL, respectively.14\n\nGroup C (PCCL versus CL)\n\nMahran et al., 2000 reported comparable procedure duration in both groups. It was 46 ± 14 minutes in the PCCL group and 38 ± 12 minutes in the CL group.16 Javanmard et al., 2018 reported that the CL group (26.0 ± 6.3 minutes) had significantly faster procedure duration than the PCCL group (30.5 ± 5.2 minutes) (p=0.000).15 Al-Marhoon et al., 2009 reported that procedure duration was comparable in both groups, 46 ± 14 and 38 ± 12 minutes in the PCCL and CL groups, respectively.14\n\nLength of hospital stay\n\nGroup A (TUCL versus PCCL)\n\nMahran et al., 2000 reported that length of stay was comparable in both groups (1.6 ± 0.8 days).16 Shahat et al., 2022 reported no significant difference in terms of length of stay for both groups, 3.2 ± 1.4 and 3.2 ± 1.4 days (p=0.13) in the TUCL and PCCL groups, respectively.17 Javanmard et al., 2018 reported that the TUCL group (1.3 ± 0.6 days) had shorter length of stay than the PCCL group (2.4 ± 0.7 days) (p=0.001).15\n\nGroup B (TUCL versus CL)\n\nJavanmard et al., 2018 reported that the TUCL group (1.3 ± 0.6 days) had shorter length of stay than the CL group (3.5 ± 1 days) (p=0.001).15 Mahran et al., 2000 reported significant differences regarding length of stay. It was shorter in the TUCL group (1.6 ± 0.8 days) than the CL group (3.9 ± 1.2 days) (p<0.05).16\n\nGroup C (PCCL versus CL)\n\nJavanmard et al., 2018 reported that the PCCL group (2.4 ± 0.7 days) had a shorter length of stay than the CL group (3.5 ± 1 days) (p=0.001).15 Mahran et al., 2000 reported significant differences in terms of length of stay. It was shorter in the PCCL group (1.6 ± 0.8 days) than the CL group (3.9 ± 1.2 days) (p<0.05).16\n\nStone-free rate\n\nAll five studies reported the SFRs for all techniques. A meta-analysis for group A (TUCL versus PCCL) revealed no significant intergroup differences in SFR (OR 0.31; 95% CI: 0.05-2.00; p = 0.22; Figure 3). Meta-analysis was not deemed appropriate for other groups (TUCL versus PCCL and TUCL versus CL) because the heterogeneity test was not applicable (Figure 3).\n\nTUCL, transurethral cystolithotripsy; PCCL, percutaneous cystolithotomy.\n\nComplications\n\nComplication rates were not significantly different among all studies in group A (TUCL versus PCCL) (OR: 1.59; 95% CI: 0.81-3.12; p = 0.18) (Figure 4). Group B (TUCL versus CL) showed that the complication rate was lower among the CL group, but the intergroup differences were not significant (OR: 2.32; 95% CI: 0.90-5.99; p = 0.08) (Figure 5). For group C (PCCL versus CL), the complication rate seemed lower among the CL patients, but the difference was not significant (OR: 2.11; 95% CI: 0.90-4.95; p = 0.09) (Figure 6).\n\nTUCL, transurethral cystolithotripsy; PCCL, percutaneous cystolithotomy.\n\nTUCL, transurethral cystolithotripsy; CL, cystolithotomy.\n\nPCCL, percutaneous cystolithotomy; CL, cystolithotomy.\n\nProcedure duration\n\nFor group A (TUCL vs. PCCL), the procedure duration was reported in all studies, and a meta-analysis showed a significant difference in favour of PCCL (Mean difference: 5.08; 95% CI: 2.87-7.28; p < 0.00001) (Figure 7). Group B showed that the procedure duration of the CL group was shorter than that of the TUCL group (Mean Difference 9.83; 95% CI: 7.50-12.17; p < 0.00001) (Figure 8). Group C reported that the CL group had a significantly shorter procedure duration than the PCCL group (Mean difference 4.91; 95% CI: 2.90-6.92; p < 0.0001) (Figure 9).\n\nTUCL, transurethral cystolithotripsy; PCCL, percutaneous cystolithotomy.\n\nTUCL, transurethral cystolithotripsy; CL, cystolithotomy.\n\nPCCL, percutaneous cystolithotomy; CL, cystolithotomy.\n\nLength of hospital stays\n\nFigure 10 shows that TUCL resulted in a significantly shorter length of hospital stay than PCCL (Mean difference -0.71; 95% CI: -0.96-(-0.46); p < 0.00001). For group B, the length of hospital stay was shorter in the TUCL group than the CL group (Mean difference -2.22; 95% CI: -2.50-(-1.93); p < 0.00001) (Figure 11). Group C showed that the PCCL group had a significantly shorter hospital stay than the CL group (Mean difference: -1.35; 95% CI: -1.62-(-1.07); p < 0.00001) (Figure 12).\n\nTUCL, transurethral cystolithotripsy; PCCL, percutaneous cystolithotomy.\n\nTUCL, transurethral cystolithotripsy; CL, cystolithotomy.\n\nPCCL, percutaneous cystolithotomy; CL, cystolithotomy.\n\nAs a rule of thumb, tests for funnel plot asymmetry should be used only when there are at least 10 studies included in the meta-analysis, because when there are fewer studies the power of the tests is too low to distinguish chance from real asymmetry. Thus, in this meta-analysis we did not proceed with reporting bias assessment.\n\nThis systematic review and meta-analysis have several limitations. In general, the quality of the studies according to the GRADE score in this meta-analysis varied from low to moderate. There were some studies with serious limitations and no reporting bias assessment was reported (Table 2).\n\nNR, not reported; TUCL, transurethral cystolithotripsy; PCCL, percutaneous cystolithotomy; CL, cystolithotomy; NRS, non-randomised study; RCT, randomised controlled trials.\n\n\n\n• TUCL versus PCCL (4 NRS) (1 RCT) (437)\n\n\n\n• TUCL versus PCCL (4 NRS) (1 RCT) (437)\n\n\n\n• TUCL versus CL (3NRS) (318)\n\n\n\n• PCCL versus CL (3NRS) (318)\n\n\n\n• TUCL versus PCCL (4 NRS) (1 RCT) (437)\n\n\n\n• TUCL versus CL (3 NRS) (318)\n\n\n\n• PCCL versus CL (3 NRS) (318)\n\n\n\n• TUCL versus PCCL (2 NRS) (1 RCT) (311)\n\n\n\n• TUCL versus CL (2 NRS) (211)\n\n\n\n• PCCL versus CL (2 NRS) (211)\n\n\nDiscussion\n\nUrolithiasis in children is rare in the developed world, representing 1–5% of all cases of urinary tract stones. On the other hand, in developing countries, paediatric urolithiasis accounts for 30% of all cases of urinary tract stones, and the so-called endemic bladder stones are still common in childhood. In determining the treatment of choice for bladder stones, many factors must be considered, such as stone composition and size, general patient health, previous treatment history, and anatomic abnormalities. Surgical equipment and techniques also play an important role in therapeutic success.19,20\n\nEndoscopic techniques (TUCL and PCCL) are commonly used because of their high efficacy and low morbidity.21 By contrast, the open surgical method (CL) has been used for a long time with high SFRs and low morbidity rates, and several urologists are familiar with this technique. However, whether one is superior in terms of operative characteristics or the incidence of complications, length of stay, and procedure duration, especially in children, remains unclear and controversial. Few studies have reported these data. Therefore, we conducted the present systematic review and meta-analysis to compare the efficacy and efficiency of these techniques in the removal of bladder stones in children.22\n\nComplete stone removal is the most important outcome in evaluations of the efficacy of stone treatment. The authors chose SFR as the main outcome of this study to help identify the best way to treat bladder stones in children. Our results indicated no difference in SFR among techniques, with SFR of 85–100%.\n\nIn terms of endoscopic treatment, there was no significant difference in SFR among procedures. Nevertheless, secondary outcomes were informative. PCCL was superior to TUCL in terms of procedure duration. Removing fragmented stones from the bladder is time-consuming in TUCL because of the narrow calibre of the urethra in children, and procedure time is the determining factor for relative complications and postoperative recovery in the TUCL procedure.23,24 The risk of urethral stricture also increases due to urethral trauma during TUCL.14,25 Ener et al., assumed that the nephroscope used in PCCL has a larger lumen than the cystoscope, making it better for removing calculus fragments through its lumen, which can also shorten the procedure time.24 In another case, TUCL had a shorter length of hospital stay than PCCL. We assumed that PCCL tended to have a longer hospital stay because of the wound that had been created to secure access to the bladder to remove the stones.\n\nIn comparing the endoscopic (TUCL and PCCL) versus CL approach, the CL technique had a shorter procedure duration; however, the endoscopic (TUCL and PCCL) techniques were superior in terms of length of hospital stay. The CL has an incision almost double that of the PCCL and TUCL, which expedited the bladder stone removal. Moreover, the operation success rate was 100%, but the involved wound led to an extended length of hospital stay versus the endoscopic techniques.\n\nIn addition to SFR, complication rates are important for treatment decisions. Major postoperative complication rates were low, and the meta-analysis revealed no significant differences among the techniques. However, CL was superior, with a lower complication rate than the endoscopic approach (TUCL and PCCL). Al-Marhoon et al., showed that postoperative complications are increased with the percutaneous approach, reporting three cases of urinary leakage (5.6%) with the percutaneous approach versus one (1.9%) with the open approach.14 Salah et al., reported that complications of PCCL included paralytic ileus (9.7% patients) and abdominal distention (0.6%) due to the leakage of irrigation fluid into the abdominal cavity.25 They reported that endourological management resulted in a shorter hospital admission but that CL was safer.14,25 TUCL featured a longer procedure time than other approaches for larger or multiple stones, which might increase the risk of urethral stricture subsequent to urethral trauma in younger children due to the smaller urethral calibre.15\n\nThis systematic review and meta-analysis included broad scope population (male and female children), which is also essential and could be implementable and applicable in clinical practice for treating bladder stones in children. Our meta-analysis indicates that further research comparing treatments for bladder stones, especially in children, is required to compare endoscopic treatments (TUCL and PCCL) and CL with more RCT-based data. Stone size and age may be added to the patient characteristics, which can be another informative outcome.\n\n\nConclusions\n\nThis systematic review and meta-analysis showed that the three techniques (TUCL, PCCL, and CL) examined here had comparable SFRs. PCCL was superior to TUCL in terms of procedure duration; however, TUCL featured a shorter hospital stay than PCCL. Moreover, CL had a shorter procedure duration than either TUCL or PCCL; however, TUCL and PCCL featured shorter lengths of hospital stay than CL.",
"appendix": "Data 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 ‘Endourological versus open cystolithotomy for bladder stone management among children: A systematic review and meta-analysis’. https://doi.org/10.6084/m9.figshare.21915915. 26\n\nFigshare: SAGER guidelines checklist for ‘Endourological versus open cystolithotomy for bladder stone management among children: A systematic review and meta-analysis’. https://doi.org/10.6084/m9.figshare.21922461. 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\nYıldız A, Anıl H, Erol İ, et al.: Comparison of three different modalities for the treatment of bladder calculi by size. Urologia. 2022; 89(3): 413–417. PubMed Abstract | Publisher Full Text\n\nSchwartz BF, Stoller ML: The vesical calculus. Urol. Clin. North Am. 2000; 27(2): 333–346. Publisher Full Text\n\nTrinchieri A: Epidemiology of urolithiasis: an update. Clin. Cases Miner. Bone Metab. 2008; 5(2): 101–106. PubMed Abstract\n\nAbarchi H, Hachem A, Erraji M, et al.: Pediatric vesical lithiasis. 70 Case reports. Ann Urol (Paris). 2003; 37(3): 117–119. PubMed Abstract | Publisher Full Text\n\nMenon M:Urinary lithiasis: etiology, diagnosis, and medical management. Walsh PC, editor. Campbell’s urology. Saunder; 2002; p. 3229–305.\n\nTorricelli FC, Mazzucchi E, Danilovic A, et al.: Surgical management of bladder stones: literature review. Rev. Col. Bras. Cir. 2013; 40(3): 227–233. PubMed Abstract | Publisher Full Text\n\nPapatsoris AG, Varkarakis I, Dellis A, et al.: Bladder lithiasis: from open surgery to lithotripsy. Urol. Res. 2006; 34(3): 163–167. PubMed Abstract | Publisher Full Text\n\nDemirel F, Cakan M, Yalçinkaya F, et al.: Percutaneous suprapubic cystolithotripsy approach: for whom? Why? J. Endourol. 2006; 20(6): 429–431. PubMed Abstract | Publisher Full Text\n\nSalah MA, Holman E, Tóth C: Percutaneous suprapubic cystolithotripsy for pediatric bladder stones in a developing country. Eur. Urol. 2001; 39(4): 466–470. PubMed Abstract | Publisher Full Text\n\nEriksen MB, Frandsen TF: The impact of patient, intervention, comparison, outcome (PICO) as a search strategy tool on literature search quality: a systematic review. J. Med. Libr. Assoc. 2018; 106(4): 420–431. PubMed Abstract | Publisher Full Text\n\nHiggins JPT, Altman DG, Gotzsche P, et al.: The Cochrane Collaboration’s tool for assessing risk of bias in randomised trial. BMJ. 2011; 343: d5928. Publisher Full Text\n\nWalter SD, Yao X: Effect sizes can be calculated for studies reporting ranges for outcome variables in systematic reviews. J. Clin. Epidemiol. 2007; 60(8): 849–852. Publisher Full Text\n\nGrade working group: Grading quality of evidence and strenthg of recommendations. BMJ. 2004 Jun 19; 328(7454): 1490.\n\nAl-Marhoon MS, Sarhan OM, Awad BA, et al.: Comparison of endourological and open cystolithotomy in the management of bladder stones in children. J. Urol. 2009; 181: 2684–2688. PubMed Abstract | Publisher Full Text\n\nJavanmard B, Karkan MF, Razzaghi MR, et al.: Surgical management of vesical stones in children: a comparison between open cystolithotomy, percutaneous cystolithotomy and transurethral cystolithotripsy with holmium-YAG laser. J. Lasers Med. Sci. 2018; 9: 183–187. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMahran MR, Dawaba MS: Cystolitholapaxy versus cystolithotomy in children. J. Endourol. 2000; 14: 423–426. PubMed Abstract | Publisher Full Text\n\nShahat AA, Kamel AA, Taha TM: A randomised trial comparing transurethral to percutaneous cystolithotripsy in boys. BJU Int. 2022; 130: 254–261. PubMed Abstract | Publisher Full Text\n\nMishra DK, Bhatt S, Mukhilesh R, et al.: Mini-percutaneous cystolithotripsy (mPCCL) versus transurethral cystolithotripsy (TUC) in pre-school children: prospective comparative non-randomized outcomes over 8 years. J. Pediatr. Urol. 2020; 16(782): 782.e1–782.e6. Publisher Full Text\n\nJavali T, Nayak KA, Babu SMLP: Simultaneous antegrade and retrograde endoscopic surgery for benign prostatic hyperplasia with vesical calculi—a single-centre experience. Arab. J. Urol. 2018; 16(4): 417–421. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSarkis J, Alkassis M, Chebel JA, et al.: Bladder stone following intravesical migration of surgical clip five years after radical prostatectomy. Urol. Case Rep. 2020; 28: 101060. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRoslan M, Przudzik M, Borowik M: Endoscopic intact removal of medium-size or multiple bladder stones with the use of transvesical laparoendoscopic single-site surgery. World J. Urol. 2019; 37(2): 373–378. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBichler KH, Strohmaier WL, Korn S: Urolithiasis in childhood. Monatsschr. Kinderheilkd. 1985; 133(5): 256–266.\n\nGou L, Wang Z, Zhou Y, et al.: Comparison of nephroscopy and cystoscopy used in the treatment of bladder stones: a systematic review and meta-analysis of randomized controlled trials. BMC Surg. 2021; 21: 4. Publisher Full Text\n\nEner K, Agras K, Aldemir M, et al.: The randomized com- parison of two different endoscopic techniques in the management of large bladder stones: transurethral use of nephroscope or cystoscope?. J. Endourol. 2009; 23(7): 1151–1155. Publisher Full Text\n\nSalah MA, Holman E, Khan AM, et al.: Percutaneous cystolithotomy for pediatric endemic bladder stone: experience with 155 cases from 2 developing countries. J. Pediatr. Surg. 2005; 40: 1628–1631. Publisher Full Text\n\nFauzan R: PRISMA checklist. [Dataset]. figshare. 2023. Publisher Full Text\n\nFauzan R, Herman H, Sitompul AP, et al.: sager checklist. [Dataset]. figshare. 2023. Publisher Full Text"
}
|
[
{
"id": "162181",
"date": "14 Feb 2023",
"name": "Andika Afriansyah",
"expertise": [
"Reviewer Expertise Endourology",
"Urooncology",
"Functional Urology",
"Neurourology"
],
"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\nCongratulations on producing a well-executed systematic review. Your attention to detail and thorough analysis have undoubtedly contributed valuable insights to the existing body of knowledge in your field. The dedication to the rigorous process of conducting a systematic review is admirable, and your efforts have resulted in a comprehensive and reliable synthesis of the available evidence.\n\nHowever, there are some points that you might be revised:\n1. Figures 10, 11, and 12 did not show clearly the diamond which shows the overall effect size.\n2. I don't know how to read clearly the meaning of table 2. I suggest the authors explain in more detail what table 2 want to describe especially the component of the column (study limitations, imprecision, etc).\n3. In the discussion, I suggest author consider the results of the meta-analysis based on the lithotripsy energy that used in the study.\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",
"responses": []
},
{
"id": "220407",
"date": "25 Mar 2024",
"name": "Rabea Ahmed Gadelkareem",
"expertise": [
"Reviewer Expertise Endourology",
"urolithiasis",
"kidney transplantation"
],
"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 rationale and aim of this review are strong and clear. This systematic review was conducted using the PRISMA guidelines. It compared the techniques (TUCL, PCCL, and CL) for the treatment of bladder stones in children. The conclusion was based on sound methodology. It revealed that studies examined here showed comparable SFRs. PCCL was superior to TUCL in terms of procedure duration; however, TUCL featured a shorter hospital stay than PCCL. Moreover, CL had a shorter procedure duration than either TUCL or PCCL; however, TUCL and PCCL featured shorter lengths of hospital stay than CL. However, some concerns should be addressed through the following comments: 1) Abstract-Methods: Needs a more precise description of the methods 2) Frame of search: from 1 to 30 August 2022!! It seems not accurately described in the text and abstract. You included studies between 2009 and 2022. So, this issue is a major concern because many points in the methods are based on it. 3) Results synthesis; stone free rate, In the sentence (Meta-analysis was not deemed appropriate for other groups (TUCL versus PCCL and TUCL versus CL), there is a mistake in the groups: The group (TUCL versus PCCL) seems to be mistaken with the group (TUCL versus CL). Clarify. 4) In the Discussion section: The grades and varieties of complications and their effects on the outcomes need more discussion. For example, were the intraperitoneal and intestinal injuries potential to all procedures? Also, were the urethral complications related to TUCL and affected its outcomes? Although these items were mentioned in the details of the Results, still their discussion can be improved.\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? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
},
{
"id": "184194",
"date": "16 Sep 2024",
"name": "Muhammad Asykar Palinrungi",
"expertise": [
"Reviewer Expertise paediatric urology",
"Functional Urology"
],
"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\nCongratulation, you have successfully conducted a systematic review of this issue in detail and used a thorough analysis which has provided valuable insight to the scientific fields of pediatric urology. I have one question: after you have explained the advantages and disadvantages of each action in this systematic review, what can you suggest or recommend that you might add to the conclusion?\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/12-124
|
https://f1000research.com/articles/12-123/v1
|
02 Feb 23
|
{
"type": "Research Article",
"title": "Blood RNA and protein biomarkers are associated with vaping and dual use, and prospective health outcomes",
"authors": [
"Andrew Gregory",
"Zhonghui Xu",
"Katherine Pratte",
"Seth Berman",
"Robin Lu",
"Rahul Suryadevara",
"Robert Chase",
"Jeong H. Yun",
"Aabida Saferali",
"Craig P. Hersh",
"Edwin K. Silverman",
"Russell P. Bowler",
"Laura E. Crotty Alexander",
"Adel Boueiz",
"Peter J. Castaldi",
"Andrew Gregory",
"Zhonghui Xu",
"Katherine Pratte",
"Seth Berman",
"Robin Lu",
"Rahul Suryadevara",
"Robert Chase",
"Jeong H. Yun",
"Aabida Saferali",
"Craig P. Hersh",
"Edwin K. Silverman",
"Russell P. Bowler",
"Laura E. Crotty Alexander",
"Adel Boueiz"
],
"abstract": "Background: Electronic nicotine delivery systems (ENDS) are driving an epidemic of vaping. Identifying biomarkers of vaping and dual use (concurrent vaping and smoking) will facilitate studies of the health effects of vaping. To identify putative biomarkers of vaping and dual use, we performed association analysis in an observational cohort of 3,892 COPDGene study participants with blood transcriptomics and/or plasma proteomics data and self-reported current vaping and smoking behavior. Methods: Biomarkers of vaping and dual use were identified through differential expression analysis and related to prospective health events over six years of follow-up. To assess the predictive accuracy of multi-biomarker panels, we constructed predictive models for vaping and smoking categories and prospective health outcomes. Results: We identified three transcriptomic and three proteomic associations with vaping, and 90 transcriptomic and 100 proteomic associations to dual use. Many of these vaping or dual use biomarkers were significantly associated with prospective health outcomes, such as FEV1 decline (three transcripts and 62 proteins), overall mortality (18 transcripts and 73 proteins), respiratory mortality (two transcripts and 23 proteins), respiratory exacerbations (13 proteins) and incident cardiovascular disease (24 proteins). Multimarker models showed good performance discriminating between vaping and smoking behavior and produced informative, modestly powerful predictions of future FEV1 decline, mortality, and respiratory exacerbations. Conclusions: In summary, vaping and dual use are associated with RNA and protein blood-based biomarkers that are also associated with adverse health outcomes.",
"keywords": [
"e-cigarettes",
"vaping",
"smoking",
"biomarkers"
],
"content": "Introduction\n\nThe high prevalence of electronic cigarette use (vaping) among both adolescents1 and adult cigarette users2 is a major public health concern. Electronic cigarettes, also referred to as electronic nicotine delivery systems (ENDS), were initially marketed as a means of smoking reduction, with the hope that their effects on the health of cigarette users would be a net positive. However, vaping is associated with acute respiratory symptoms3–5 and lung injury6,7 and is likely to be associated with long-term adverse health effects. Vaping companies are targeting young people as a profitable demographic and promoting ENDS use beyond the population of established cigarette users, resulting in an ongoing epidemic of vaping in adolescents and non-cigarette user adults that is clearly detrimental to public health.8–10\n\nThe Family Smoking Prevention and Tobacco Control Act of 2009 gave the Food and Drug Administration (FDA) regulatory oversight over tobacco products which, by the FDA Deeming Regulation of 2016, includes ENDS. Thus, the FDA is responsible for reviewing the safety of all ENDS products introduced to market after February 15, 2007. To facilitate this review process, it is important to determine whether there are validated biomarkers of ENDS use and combined use of ENDS and cigarettes (dual use). While biomarkers of vaping and dual use have been reported, few if any vaping biomarkers have been assessed for their association to prospective health outcomes, and the predictive performance of multi-biomarker panels has not been assessed. In this paper, the term biomarker refers to molecular measurements tested for association to vaping or smoking exposure, which we distinguish from validated biomarkers in which a specific association has been demonstrated in multiple studies. Validated biomarkers that are also predictive of prospective health events can be considered for use as surrogate outcomes in safety and health assessments11,12 which would be a useful tool for evaluating the health effects of an increasingly diverse array of ENDS products. Thus, the goal of this study is to establish a set of candidate biomarkers for future validation and further study as potential surrogate outcomes.\n\nWe hypothesized that vaping and dual use are associated to multi-omic biomarkers, and that a subset of these biomarkers would be associated with the development of pulmonary and cardiovascular disease. We conducted high throughput transcriptomic and proteomic analyses that identified over 100 biomarkers associated with vaping and dual use in a cohort of adult current and former cigarette users in the COPDGene study. We tested these biomarkers for association with prospective spirometric changes, mortality, and incident cardiovascular disease, identifying dozens of significantly associated biomarkers. We also investigated the extent to which multimarker panels can predict vaping and smoking status and the development of prospective health outcomes.\n\n\nMethods\n\nThe COPDGene study recruited 10,198 non-Hispanic White and Black cigarette users with at least 10 pack-years of lifetime cigarette smoking history at 21 U.S. clinical centers (NCT00608764, www.copdgene.org)13 between 2007 and 2011. COPDGene obtained five-year follow-up data and is currently obtaining 10-year follow-up of available subjects to collect longitudinal data on study participants. A total of 6,756 subjects completed their five-year study visit (Visit 2) and the 10-year study visit (Visit 3) is ongoing at time of writing. Data collected includes questionnaires, spirometry, and self-reported smoking and vaping behaviors. At Visit 2, whole-blood RNA sequencing (RNA-seq), plasma protein measurements (SOMAscan version 4.0 (5.0K) assay for human plasma), and plasma cotinine were obtained from a subset of subjects. Throughout the study, subjects were also regularly contacted via the phone or Internet (web-based survey link) as part of the COPDGene Longitudinal Follow-up (LFU) program to assess interval events, including respiratory exacerbations, incident comorbidities, and mortality. Definitions of respiratory exacerbations, incident comorbidities, and mortality assessment are included in the Extended data.28 Written informed consents were obtained for all subjects, and each clinical site obtained institutional review board approval.\n\nStarting from Visit 2, vaping was determined by self-report including ever use, current use, intensity, cartridge size, brand, and flavoring. The four comparison groups for biomarker discovery (vapers, current cigarette users, former cigarette users, and dual users) were defined based on the subjects’ questionnaire responses at Visit 2. Vapers were subjects who reported using at least one e-cigarette within the prior week and had a history of smoking tobacco cigarettes, but not within the last 30 days. Current cigarette users reported current smoking with an average of at least one cigarette per day without any e-cigarette use. Dual users were vapers who also reported current smoking, and former cigarette users were defined as those who reported a history of smoking but did not meet criteria for current smoking or vaping. In most of the reported analyses, former cigarette users are used as the reference group. Differences in baseline characteristics between groups were assessed with Kruskal-Wallis and chi-square tests for continuous and categorical measurements, respectively.\n\nThe extraction protocol for total blood RNA was performed either manually or with the Qiagen QIAcube extraction robot according to the company’s standard operating procedure. RNA samples with an RNA integrity number (RIN) > 6 and a concentration of ≥ 25 μg/μl were sequenced. Library preparation was performed with the Illumina TruSeq Stranded Total RNA with Ribo-Zero Globin kit (Illumina, Inc., San Diego, CA). Samples were sequenced to an average depth of 20 million paired end reads on Ilumina HiSeq 2500 sequencers. Reads were aligned to the GRCh38 genome using the STAR (version 2.5.2b) aligner. Gene annotations and transcript GTF were downloaded from the Biomart Ensembl database (Ensembl Genes release 94, GRCh38.p12 assembly). Quality control was performed using the FastQC and RNA-SeQC programs, and samples were included for analysis if they met the following criteria: > 10 million total reads, > 80% of reads mapped to the reference genome, XIST and Y chromosome expression was consistent with reported sex, < 10% of R1 reads in the sense orientation, Pearson correlation ≥ 0.9 with samples in the same library construction batch, and concordant genotype calls between variants called from RNA sequencing reads and DNA genotyping. Sequencing read counts were obtained from the featureCounts function in the Rsubread R package (v1.32.2). Genes were filtered to remove very low expressed genes; we limited our analysis to include only those genes which had an average counts per million (CPM) value > 1 in more than 20 subjects. The trimmed mean of M values (TMM) procedure from the edgeR R package (v3.24.3) was applied to account for the differences in sequencing depth. The gene count data used for this analysis is available in GEO (accession number GSE158699). Counts were transformed to log2 counts per million (CPM) values and quantile-normalized.\n\nAt Visit 2, plasma samples were assayed for 4,979 proteins in 5,670 COPDGene participants using the SOMAscan Human Plasma 5.0K assay, a multiplex aptamer-based assay (SomaLogic, Boulder, Colorado).14 The standardization process included within-plate hybridization, median signal normalization, and plate scaling and calibration of SOMAmers to control for inter-assay variation between analytes and batch differences between plates. Inverse normal transformation was applied to all protein measurements prior to association analysis.\n\nPlasma metabolite measurements were obtained from plasma for 1,136 subjects at COPDGene Visit 2 using the Metabolon Global Metabolomics Platform (Durham, NC, USA).15 Metabolite levels were quantified as raw area counts. Plasma cotinine levels were evaluated, and missing values were assigned a level of half the lowest detected amount of cotinine. Values were log-transformed, and differences in cotinine distribution between groups were evaluated with the Wilcoxon Rank Sum test. COPDGene metabolomic data are available in the Metabolomics Workbench of the NIH Common Fund’s National Metabolomics Data Repository (Study ID ST001443).\n\nWe used the limma R package (v3.38.3)16 to test for the associations between RNA transcripts and the vaping/smoking groups, using the former cigarette user group as the reference and adjusting for age, sex, race, and library preparation batch effects. The voom function was used in the RNA-seq analysis. Regression models for protein expression used identical covariates, with the exception that library preparation batch effects were replaced with a variable for clinical center. For both differential gene expression and protein association analyses, we corrected for multiple testing with the Benjamini-Hochberg method and applied a threshold of significance of a false discovery rate (FDR) of 10%.17 For selected genes and proteins that were associated in only one contrast (vaping or dual only associations), we also conducted association analyses for the contrasts of vapers versus cigarette users, vapers versus dual users, and dual users versus cigarette users. Gene set enrichment analyses were performed using the fast gene set enrichment analysis (FGSEA) R package (v3.12).18 Further details are included in the Extended data.27\n\nBiomarkers significantly associated with vaping or dual use were tested for association to prospective health-related outcomes, namely change in FEV1 (absolute volume and percent change from baseline), prospective exacerbations, all-cause and respiratory mortality, and incident CVD. FEV1 changes were computed by subtracting Visit 2 from Visit 3 FEV1 values and dividing this difference by the number of years between both visits. FEV1 changes were calculated as both absolute and relative (as a percentage of the Visit 2 measurement) values. Data points >5 standard deviations from the mean were excluded from analysis.\n\nThe FEV1 outcomes were evaluated using multivariable linear regression models, and the time-to-event outcomes were evaluated using Cox-proportional hazards models using Visit 2 as the starting point. Analyses were adjusted for sex, race, and age at baseline (Visit 2). For time-to-event outcomes, baseline FEV1 percentage of predicted was included as a covariate. Since the sample sizes of our vaping/smoking groups were small, these association analyses were performed in all available COPDGene study subjects without stratifying by vaping or smoking exposure. The FDR was controlled at 10% using the Benjamini-Hochberg method.\n\nPredictive models using only transcript and protein biomarkers were constructed for vaping/smoking groups and prospective health outcomes. For categorical and binary outcomes, linear discriminant analysis (LDA) was used. For change in FEV1 models, elastic net models were constructed. Cross-validation was used to prevent overfitting and estimate predictive performance. Model performance was assessed by cross-validation using the Youden index (sensitivity + specificity - 1), area under the receiver operator characteristic curve (AUROC), and area under the precision recall curve (AUCPR) for binary outcomes. R2 was used to evaluate the performance of change in FEV1 models. Additional details are included in the Extended data.28\n\n\nResults\n\nA visual overview of the study and data flow is included in Supplemental Figures 1 and 2. There were 51 and 77 subjects reporting current vaping only or dual use, respectively, at the COPDGene second study visit. Differences in baseline characteristics of these groups along with the current and former cigarette user groups are reported in Table 1. The large majority of subjects in the vaping group (80%) reported vaping at least once a day. The dual user group reported lighter vaping on average, with only 42% reporting daily vaping, and their pack-years exposure to combustible tobacco was similar to the current cigarette user group. FEV1 % of predicted values were comparable for all groups. Biochemical confirmation of nicotine exposure via analysis of plasma cotinine levels in 853 subjects demonstrated elevated cotinine levels in the vaping, dual use, and current cigarette user groups relative to the former cigarette user group (Figure 1, Wilcoxon rank sum test p<0.005 for all comparisons). A subset of the former cigarette user group had elevated levels of nicotine that could be due to use of nicotine replacement therapy, secondhand exposure to tobacco smoke or e-cigarette aerosols, or unreported smoking or vaping.\n\nIn a subset of subjects, plasma metabolomics data was measured using the Metabolon Global Metabolomics Platform. Violin plots of log-transformed cotinine raw area counts are shown. Cotinine levels are significantly higher in all three groups relative to FS (Wilcoxon rank sum p < 0.005 for all three comparisons). FS = former cigarette users. CS = current cigarette users.\n\nA total of 18,303 genes were tested for differential expression analysis of vapers, dual users, and current cigarette users, using former cigarette users as the reference group. The top results from each analysis are shown in Table 2, and complete results are reported in Tables S1-S3. For vapers, three significant associations were identified at an FDR of 10% (Figure 2). Two of these genes (LINC02470 and NPHP1) were expressed at a higher level in vapers than any of the other three groups (p<0.05 for all comparisons, Table S4). The third gene, GPR15, was one of the most well-reported genes upregulated by smoking. This gene was also upregulated in vapers, but to a lesser extent than in either cigarette users or dual users (p<0.005 for all comparisons). Gene set enrichment analysis identified 16 significant MSigDB Hallmark pathways with the top three processes being related to inflammation, oxidative phosphorylation, and heme metabolism (Table 3). For all significant gene sets, enrichment was in the direction of decreased expression in vapers compared to former cigarette users. Since smoking has been shown to have mixed effects on inflammation, we compared the pattern of gene set enrichment for the Hallmark Inflammation pathway in vapers, current cigarette users, and dual users, and we observed that smoking and dual use show elements of activation and repression of this gene set; the effect of vaping was more clearly downregulation of this pathway (Supplemental Figure 3).\n\nThree RNA biomarkers were significantly associated at 10% FDR in the analysis comparing vapers to former cigarette users. NPHP1 and LINC02470 were significantly associated in the vaping but not the smoking or dual use comparison to former cigarette users. GPR15 is significantly elevated in all three groups relative to former cigarette users, but its expression is relatively lower in vapers relative to dual users and current cigarette users (p<0.005 for all comparisons).\n\nFor dual users, 90 differentially expressed genes were identified, and 17 of these genes were significant only in the dual user analysis. All 17 genes were also significantly differentially expressed when comparing dual users to current cigarette users, suggesting that these genes have a distinctive response to dual use (p<0.005 for all comparisons, see Table S5). Gene set enrichment analysis identified four significant Hallmark pathways related to heme metabolism, oxidative phosphorylation, E2F signaling, and interferon gamma response (Table 3). Complete results for the vaping, dual use, and smoking analyses including MSigDB Immunologic Signature pathways are presented in Supplemental Tables S6-S8.\n\nA total of 4,979 SOMAscan aptamers mapping to 4,720 unique proteins were tested for association to vaping and smoking groups. The top significantly associated proteins are shown in Table 2 (see Table S9 for complete results), and violin plots for selected top protein biomarkers associated with vaping or dual use are shown in Figure 3. Three protein biomarkers (EDIL3, DPYL5, and KLK13) were significantly associated with vaping status at a 10% FDR, and DPYL5 expression was found to be higher in vapers compared to each of the other groups (p<0.05 for all comparisons, Table S10). One hundred protein biomarkers were associated with dual use, with four (CXA8, Keratin 19, CSKP, and PXDC1) being significantly associated only with dual use. All four of these proteins also showed nominal association (p<0.05) in an analysis comparing dual users to current cigarette users, indicating a distinct response to dual use (Table S11).\n\nThe distribution of the top significantly associated protein biomarkers in the analysis of vapers or dual users versus former cigarette users. DPYL5 is significantly elevated in vapers relative to all other vaping/smoking groups (p<0.005). KLK13 is significantly associated with vapers, dual users, and current cigarette users when compared to former cigarette users. s-ICAM5 and Secretoglobin family member 3A member 1 were significantly associated with dual users and current cigarette users but not vapers when compared to former cigarette users.\n\nTo compare the similarity of the transcriptomic and proteomic responses to each exposure, we constructed pairwise plots of the effect sizes of all significantly associated biomarkers (Figure 4). There was a strong positive correlation between the biomarker responses to smoking and dual use (Pearson’s r = 0.76 and 0.88 for RNA and protein, respectively), whereas the vaping biomarker profile had low correlation to the profiles for both dual use and smoking (r between 0.23 and 0.44). Certain biomarkers (LINC02470 and DPYL5 protein) had particularly strong and unique associations with vaping. When we compared effect sizes between RNA and proteomic biomarkers associated with vaping and smoking, the correlation was low (r=0.11) as might be expected given various potential sources of origin for circulating blood proteins.\n\nComparison of the biomarker association profiles demonstrates that while the dual user and current cigarette user profiles are very similar, the vaping biomarker profile is more distinct. For the RNA and protein biomarker analysis of vaping/smoking groups versus former cigarette users, the effect sizes for each pair of comparisons were plotted and the Pearson correlation of effect sizes was calculated. In each pairwise comparison, only biomarkers significant in at least one of analyses were analyzed. In row A, vaping-associated RNA biomarker effects are compared to current cigarette user effects (left), dual user effects (middle), and then dual user and current cigarette user effects are compared (right). In row B, the corresponding protein biomarker effects are compared.\n\nTo determine how well RNA and protein biomarkers could classify subjects according to their vaping/smoking behavior, we used a nested cross-validation approach to provide an unbiased estimate of the classification performance achievable by multi-class prediction models using linear discriminant analysis (LDA). The performance of this model is shown in Table 4, where for each group the task was to distinguish that group from all other groups combined. The model achieved good discrimination for current cigarette users (Youden index (YI) = 0.81) and former cigarette users (YI = 0.80) and had statistically significant but less accurate performance for vapers (YI = 0.53) and dual users (YI = 0.55). More detailed metrics for each pairwise contrast (Table S12) demonstrates that the models do better in discriminating vapers from current cigarette users than former cigarette users (YI = 0.73 and 0.50, respectively), whereas for dual users, model discrimination was better for former cigarette users (YI = 0.82) than current cigarette users (YI = 0.34), providing further evidence of the similarity between dual use and current smoking biomarker profiles.\n\nTo determine whether biomarkers of vaping or dual use were associated with prospective health-related outcomes, we tested the 92 RNA transcripts and 101 protein biomarkers associated with vaping and/or dual use for association to multiple health outcomes in all COPDGene subjects. Twenty-one transcripts and 88 protein biomarkers were associated with one or more of the studied outcomes at a 10% FDR level. Of the vaping-associated biomarkers, two (KLK13 and DPYL5) were associated with loss of FEV1, and KLK13 was also associated with mortality. Boxplots for the top four vaping or dual use proteins associated with all-cause mortality are shown in Figure 5, and all significant biomarker associations are shown in Tables S13-S16.\n\nThe dual use-associated proteins Growth hormone receptor, MIC-1, and HE4 were significantly associated with overall mortality. KLK-13 was the only vaping associated biomarker that was also associated mortality. All associations were significant at a false discovery rate of 10%.\n\nWe then determined whether the effect of vaping or dual use on each protein biomarker was consistent with higher or lower risk for each adverse health outcome, and we observed that the direction of the exposure effect was overwhelmingly towards increased risk for adverse health events (Figure 6). Out of 246 total significant associations to health outcomes, 224 (91%) showed concordance between the effect of vaping or dual use and the direction of association to increased risk. Both of the vaping-associated biomarkers (KLK13 and DPYL5) showed concordant effects for higher health risk.\n\nFor protein biomarkers that were significantly associated with at least one health outcome and vaping (n=2) or dual use (n=86), we plotted the effect of the exposure (vaping or dual use) against the effect with respect to the health outcome. Since some biomarkers were significantly associated with multiple health outcomes, the total number of analyzed associations was 246. The top panel shows the relationship between exposure effect and change FEV1 (ml/yr) where each of the 107 associations was concordant for loss of FEV1. Change in FEV1 is calculated as visit 3 value - visit 2 value, meaning negative values indicate loss of lung function. The bottom panel shows the relationship between exposure effect and hazard ratio for all-cause mortality, respiratory mortality, exacerbations, or incident cardiovascular disease. 117 of 139 associations were concordant for higher health risk. Exposure effect is the beta coefficient from the dual use versus former cigarette users analysis, except for DPYL5 and KLK13 which is from the vapers versus former cigarette users analysis.\n\nTo estimate the accuracy of multi-marker panels of vaping and dual use biomarkers for predicting prospective health outcomes, we constructed predictive models for FEV1 decline, all-cause mortality, COPD exacerbations, and incident CVD using only the vaping or dual use-associated RNA and protein biomarkers. Models using the six vaping-associated biomarkers alone gave non-informative predictions, but models using the 190 dual use-associated biomarkers gave informative predictions with moderate accuracy for FEV1 decline, all-cause mortality and respiratory exacerbations (Table 5).\n\nA recently published review of vaping biomarkers listed 14 inflammatory and matrix degradation protein biomarkers that had been previously associated with vaping.19 We examined the results from these 14 biomarkers at the RNA and protein level for association to vaping or dual use, and we observed associations at nominal significance (p<0.05) for four biomarkers (IL1B, ICAM1 [both RNA and protein], IL-6, and MMP9, see Table S17).\n\n\nDiscussion\n\nIdentifying validated biomarkers of vaping and dual use is an important tool both effective regulation of ENDS. This study of established adult cigarette users identified significant associations of six and 190 blood molecular markers with vaping and dual use, respectively. Because of the comprehensive nature of the ‘omics measurements, we were able to compare overall molecular profiles of vaping, dual use, and smoking. These analyses found that the vaping profile was substantially different from current smoking, whereas dual use and smoking were similar but not identical. Biomarkers associated with vaping and dual use were also associated with multiple cardiopulmonary health outcomes, and reasonable predictive accuracy for some of these outcomes could be achieved for models using dual use biomarkers.\n\nA previous metabolomic biomarker study by Goniewicz et al. demonstrated that vaping is associated with metabolomic changes, albeit at generally lower levels compared to current cigarette users or dual users.20 A recent study of vapers versus non-cigarette users identified numerous changes in plasma biomarkers associated with inflammation, oxidative stress, and extracellular matrix degradation.19 A recent meta-analysis of biomarkers of ENDS versus cigarettes reported a more favorable biomarker profile of ENDS use, though the last author of the study has been reported to have ties to the tobacco industry.21,22 Another systematic review also reported reduced levels of some biomarkers in ENDS users relative to current cigarette users, but this is not consistent for all biomarkers (Hiler et al., 2021).23 By examining the correlation in biomarker profiles for vaping, dual use, and smoking, we observed that the vaping profile is largely distinct from both the dual use and smoking profile which are in turn highly correlated to each other. We did however observe multiple examples of shared RNA and protein biomarkers between smoking, vaping, and dual use, such as GPR15, a regulator of inflammation and T-cell trafficking. We also provided independent validation for previously reported vaping or dual use associations with IL1B, ICAM1, IL-6, and MMP9, all of which are known to influence inflammation (IL-1B can induce MMP-9 expression and activity).\n\nBoth vaping and dual use are associated with diverse effects on biological pathways related to aspects of inflammation, oxidative phosphorylation, and coagulation-related pathways. Previous studies have also shown that long non-coding RNAs (lncRNAs) are associated with vaping,24,25 and in our work we identified LINC02470 as a novel vaping biomarker. LINC02470 has previously been reported to modulate Wnt-beta catenin signaling via exosomal secretion from bladder cancer cells.26 Because Tang et al. previously demonstrated bladder urothelial hyperplasia in mice exposed daily to e-cigarette aerosols, the finding of LINC02470 in the circulation of human ENDS users is highly concerning. We also identified DPYL5 as being uniquely upregulated in vaping subjects. DPYL5 is primarily expressed in brain tissue and glial cells, though it is also expressed at detectable levels in the gastrointestinal (GI) tract. DPYL5 is potentially an important vaping biomarker, because it was also predictive of future loss of lung function. To our knowledge, this is the first report of DPYL5 as a specific and clinically relevant biomarker of vaping, a finding that requires further independent validation.\n\nMany of the biomarkers altered by vaping and dual use are also associated with risk of adverse health events such as loss of lung function, respiratory exacerbations, and mortality. For the overwhelming majority of biomarkers, the direction of effect of vaping and dual use was consistent with increased health risk. This extends numerous prior observations linking vaping to a variety of pulmonary symptoms and alterations of cardiovascular physiology,27 providing an important link to longer-term health outcomes and suggesting that some of these biomarkers may be useful in assessing health risks of specific vaping devices and e-liquid formulations. For dual use, a multi-marker panel of associated biomarkers achieved modest predictive accuracy for some important outcomes. For vapers, the biomarker profile was more subtle, and with our current sample size we did not identify a sufficient number of biomarkers to enable accurate multi-marker prediction of health outcomes.\n\nThe strengths of this study are the high-throughput approach to biomarker discovery, the characterization of associations to prospective health events, and the use of machine learning to assess the predictive performance of multimarker panels. Limitations include a modest sample size of vapers and dual users and the lack of independent replication due to lack of available cohorts with similar biomarker data and exposure characterization. Information regarding specific vaping devices and fluids was limited and reflects the challenges posed by the rapid evolution of vaping devices over the study period. Our findings cannot be assumed to generalize to newer-generation vaping devices which will require dedicated study, and our findings in adults do not necessarily apply to other important groups such as adolescents.\n\nIn conclusion, this study identified over one-hundred transcriptomic and proteomic biomarkers associated with vaping and dual use, and many of these biomarkers are also associated with prospective cardiopulmonary health outcomes. Prediction of health outcomes using multimarker panels can provide informative prediction with room for improvement, and validation in independent cohorts will increase confidence in individual biomarkers and multi-marker models. Larger-scale studies with greater power would be likely to identify additional biomarkers that could further improve predictive model performance.\n\n\nAuthor contributions\n\nDrs. Boueiz and Castaldi had full access to all the data in the study, take responsibility for the integrity of the data and the accuracy of the data analysis, had authority over manuscript preparation and the decision to submit the manuscript for publication.\n\nStudy concept and design: Gregory, Xu, Boueiz, Castaldi\n\nAcquisition, analysis, or interpretation of data: All authors\n\nDrafting of the manuscript: Gregory, Boueiz, Castaldi\n\nCritical revision of the manuscript for important intellectual content: All authors\n\nStatistical analysis: Gregory, Xu, Castaldi, Boueiz\n\nObtained funding: Boueiz, Castaldi, Silverman\n\nStudy supervision: All authors\n\nAll authors gave final approval of the version to be published.",
"appendix": "Data availability\n\nSupplemental materials are included in the medRxiv online preprint (doi: https://doi.org/10.1101/2022.09.19.22280093).\n\nNCBI dbGAP: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000179.v6.p2\n\nAll of the data used in the manuscript will be available through dgGaP as of March 1, 2023 (current study accession number: phs000179.v6.p2). Count matrices and phenotype data are also available by contacting the COPDGene Data Coordinating Center (WilsonC@njhealth.org) and completing a study proposal form (https://redcap.njhealth.org/redcap/surveys/?s=EA8NW4TP3K). Investigators can contact the study authors at peter.castaldi@channing.harvard.edu.\n\nZenodo: Blood RNA and Protein Biomarkers Are Associated with Vaping and Dual use and Prospective Health Outcomes, https://doi.org/10.5281/zenodo.7562784. 28\n\nThis project contains the following extended data:\n\n- Supplemental methods (media-1.docx)\n\n- Supplemental Tables 1-3 (media-2.xlsx)\n\n- Supplemental Tables 4-5 (media-3.xlsx)\n\n- Supplemental Tables 6-8 (media-4.xlsx)\n\n- Supplemental Table 9 (media-5.xlsx)\n\n- Supplemental Tables 10-11 (media-6.xlsx)\n\n- Supplemental Table 12 (media-7.docx)\n\n- Supplemental Tables 13-16 (media-8.xlsx)\n\n- Supplemental Table 17 (media-9.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\nGentzke AS, Wang TW, Jamal A, et al.: Tobacco Product Use Among Middle and High School Students - United States, 2020. MMWR Morb. Mortal. Wkly Rep. 2020; 69: 1881–1888. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMayer M, Reyes-Guzman C, Grana R, et al.: Demographic Characteristics, Cigarette Smoking, and e-Cigarette Use Among US Adults. JAMA Netw. Open. 2020; 3: e2020694. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLi D, Sundar IK, McIntosh S, et al.: Association of smoking and electronic cigarette use with wheezing and related respiratory symptoms in adults: cross-sectional results from the Population Assessment of Tobacco and Health (PATH) study, wave 2. Tob. Control. 2019; 29: tobaccocontrol-2018-054694. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYao T, Max W, Sung H-Y, et al.: Relationship between spending on electronic cigarettes, 30-day use, and disease symptoms among current adult cigarette smokers in the U.S. PLoS One. 2017; 12: e0187399. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSt Helen G, Eaton DL: Public Health Consequences of e-Cigarette Use. JAMA Intern. Med. 2018; 178: 984–986. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSmith ML, Gotway MB, Crotty Alexander LE, et al.: Vaping-related lung injury. Virchows Arch. 2021; 478: 81–88. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCherian SV, Kumar A, Estrada-Y-Martin RM: E-Cigarette or Vaping Product-Associated Lung Injury: A Review. Am. J. Med. 2020; 133: 657–663. Publisher Full Text\n\nHammond D, Reid JL, Rynard VL, et al.: Prevalence of vaping and smoking among adolescents in Canada, England, and the United States: repeat national cross sectional surveys. BMJ. 2019; 365: l2219. Publisher Full Text\n\nMiech R, Johnston L, O’Malley PM, et al.: Trends in Adolescent Vaping, 2017–2019. N. Engl. J. Med. 2019; 381: 1490–1491. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMiech R, Johnston L, O’Malley PM, et al.: Adolescent vaping and nicotine use in 2017-2018 - U.s. national estimates. N. Engl. J. Med. 2019; 380: 192–193. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAronson JK: Research priorities in biomarkers and surrogate end-points. Br. J. Clin. Pharmacol. 2012; 73: 900–907. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFDA-NIH Biomarker Working Group: BEST (Biomarkers, EndpointS, and Other Tools) Resource. Food and Drug Administration (US);2016.\n\nRegan EA, Hokanson JE, Murphy JR, et al.: Genetic epidemiology of COPD (COPDGene) study design. COPD. 2010; 7: 32–43. PubMed Abstract | Publisher Full Text\n\nGold L, Ayers D, Bertino J, et al.: Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS One. 2010; 5: e15004. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGillenwater LA, Kechris KJ, Pratte KA, et al.: Metabolomic Profiling Reveals Sex Specific Associations with Chronic Obstructive Pulmonary Disease and Emphysema. Metabolites. 2021; 11. Publisher Full Text\n\nRitchie ME, Phipson B, Wu D, et al.: limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015; 43: e47. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBenjamini Y, Hochberg Y: Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R. Stat. Soc. 1995; 57: 289–300.\n\nKorotkevich G, Sukhov V, Budin N, et al.: An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. biorxiv. 2021. Publisher Full Text\n\nSingh KP, Lawyer G, Muthumalage T, et al.: Systemic biomarkers in electronic cigarette users: implications for noninvasive assessment of vaping-associated pulmonary injuries. ERJ Open Res. 2019; 5: 00182–02019. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGoniewicz ML, Smith DM, Edwards KC, et al.: Comparison of Nicotine and Toxicant Exposure in Users of Electronic Cigarettes and Combustible Cigarettes. JAMA Netw. Open. 2018; 1: e185937. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAkiyama Y, Sherwood N: Systematic review of biomarker findings from clinical studies of electronic cigarettes and heated tobacco products. Toxicology Reports. 2021; 8: 282–294. Publisher Full Text\n\nNeil Sherwood: TobaccoTactics.2020. (accessed 26 Jun 2022).Reference Source\n\nHiler M, Weidner AS, Hull SC, et al.: Systemic Biomarkers of Exposure Associated with ENDS Use: A Scoping Review. Tob.Control. 2021. Nov 3;tobaccocontrol-2021-056896.\n\nTommasi S, Caliri AW, Caceres A, et al.: Deregulation of Biologically Significant Genes and Associated Molecular Pathways in the Oral Epithelium of Electronic Cigarette Users. Int. J. Mol. Sci. 2019; 20: 20. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKaur G, Singh K, Maremanda KP, et al.: Differential plasma exosomal long non-coding RNAs expression profiles and their emerging role in E-cigarette users, cigarette, waterpipe, and dual smokers. PLoS One. 2020; 15: e0243065. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHuang C-S, Ho J-Y, Chiang J-H, et al.: Exosome-Derived LINC00960 and LINC02470 Promote the Epithelial-Mesenchymal Transition and Aggressiveness of Bladder Cancer Cells. Cells. 2020; 9: 9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBozier J, Chivers EK, Chapman DG, et al.: The Evolving Landscape of e-Cigarettes: A Systematic Review of Recent Evidence. Chest. 2020; 157: 1362–1390. PubMed Abstract | Publisher Full Text\n\nGregory A, Xu Z, Pratte K, et al.: Blood RNA and Protein Biomarkers Are Associated with Vaping and Dual use and Prospective Health Outcomes.2023. Publisher Full Text"
}
|
[
{
"id": "169930",
"date": "22 May 2023",
"name": "John Holloway",
"expertise": [
"Reviewer Expertise respiratory genomics / epidemiology"
],
"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\nGregory et al. present a comprehensive analysis of data from the COPDgene cohort to identify biomarkers for vaping (electronic nicotine delivery systems, ENDS). Biomarkers were assessed using data on whole-blood RNA sequencing (RNA-seq), plasma protein measurements (SOMAscan version 4.0 (5.0K) assay for human plasma). A number of biomarkers were identified for ENDS use, some specific to vaping and some in common with other exposures (smoking and dual use) e.g GPR15.\nThe major limitations of the study are twofold, the limited sample size of the vaping only group and the comparison to the former smoking group, which to judge from the protein cotinine measurement contains some individuals who are still exposed to high levels of nicotine. In addition, vaping was compared to former smokers, not to current smokers meaning that many of the markers identified might be related to nicotine exposure rather than vaping specifically. These limitations lead to the lower discriminative ability of the classification models for vaping compared to smoking. Nonetheless, the current study is one of the largest studies of plasma / blood biomarkers for ENDS exposure (there have been other studies of urinary biomarkers).\nSpecific comments:\n\nDid the authors consider excluding individuals from the former smoking group with elevated cotinine elves? would this improve the discriminative ability of the models?\n\nOf the biomarkers (RNA and protein) that are significantly associated with vaping, which are also significantly different between vaping and current cigarette use? Which are most significantly correlated with nicotine levels (i.e. are the vape fluid markers of nicotine markers?).\n\nRegression models were adjusted for age, sex and ethnicity. However BMI, Pack Years and FEV1 are also significantly different between groups. Why not adjust for these as well, either in the main analysis or in sensitivity analyses?\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": "201270",
"date": "10 Oct 2023",
"name": "Fatema Shafie Khorassani",
"expertise": [
"Reviewer Expertise Biostatistics",
"data integration",
"survival analysis",
"tobacco use",
"cancer epidemiology."
],
"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 work to identify multi-omic biomarkers associated with vaping (use of electronic nicotine delivery systems, or ENDS) and dual use (defined as using ENDS and cigarettes), and to find associations between those biomarkers and the development of pulmonary and cardiovascular disease. The goal of the paper is to present a set of potential biomarkers for further research and validation. The data comes from the COPDGene study, a prospective cohort study of 10,198 non-Hispanic White and Black cigarette users with at least 10 pack-years of lifetime smoking history. At a five-year visit, a subset of the initial study participants received whole-blood RNA sequencing, plasma protein measurements, and plasma cotinine. Additional data was collected from surveys every 3-6 months.\nSome comments below:\nIntroduction:\nIt would be helpful to have citations added to the statements “likely to be associated with long-term adverse health effects” and “While biomarkers of vaping and dual use have been reported”.\n\nThe authors mention that validated biomarkers can be considered as surrogate outcomes. It should be clarified what they would specifically be surrogate outcomes for. For example “surrogate outcomes for mortality or cardiac disease”.\nMethods\nIt may be clearer to use the term “non-current” rather than “former” since the study population are established smokers and the definition only requires 30 days without smoking.\n\nThe sample size numbers in the text do not match the supplemental figures (e.g. SF2 says there were a total of 6,284 subjects at visit 2, while the text says there were 6,756)\n\nHow were the subjects chosen from the full study sample to receive RNA sequencing, plasma protein measurements, and plasma cotinine measurements?\n\nIt is not clear how long after the second visit the outcome measures were collected. For the FEV1 changes, it is noted that they’re calculated as a percent change between visits 3 and 2. Are all the other outcome measures collected at visit 3? Is outcome data collection still ongoing? What percentage of patients were lost to follow-up?\nResults\nIt would be good to include the length of follow-up, counts of each event, and the numbers censored for each event.\n\nFor figure 5, comparing concentrations of alive and dead does not consider censoring. It would be more helpful to use the cox model results to summarize these associations.\n\nIs smoking status continuously measured on subjects after visit 2? Can you provide any indication of how likely people were to stay in the state they were categorized as at visit 2?\nDiscussion\nTo what extent can the distinctness of the vaping subgroup from the dual/cs groups be attributed to smoking cessation?\n\nThere is, naturally, significant loss to follow-up between visits 1 and 2. It would be helpful to know how many subjects returned for their third visit, and to include some discussion of how missing data may impact 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? 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": []
}
] | 1
|
https://f1000research.com/articles/12-123
|
https://f1000research.com/articles/11-253/v1
|
01 Mar 22
|
{
"type": "Research Article",
"title": "Global research on syndemics: a meta-knowledge analysis (2001-2020)",
"authors": [
"Md Mahbub Hossain",
"Nobonita Saha",
"Tahmina Tasnim Rodela",
"Samia Tasnim",
"Tasmiah Nuzhath",
"Tamal Joyti Roy",
"James N. Burdine",
"Helal Uddin Ahmed",
"E. Lisako J. McKyer",
"Banga Kamal Basu",
"Ping Ma",
"Md Mahbub Hossain",
"Nobonita Saha",
"Tahmina Tasnim Rodela",
"Tasmiah Nuzhath",
"Tamal Joyti Roy",
"James N. Burdine",
"Helal Uddin Ahmed",
"E. Lisako J. McKyer",
"Banga Kamal Basu",
"Ping Ma"
],
"abstract": "Background: Syndemics or synergies of cooccurring epidemics are widely studied across health and social sciences in recent years. Methods: We conducted a meta-knowledge analysis of articles published between 2001 to 2020 in this growing field of academic scholarship. Results: We found a total of 830 articles authored by 3025 authors, mostly from high-income countries. Publications on syndemics are gradually increasing since 2003, with rapid development in 2013. Each article was cited more than 15 times on average, and most (n = 604) articles were original studies. Syndemics research focused on several areas, including HIV/AIDS, substance abuse, mental health, gender minority stressors, racism, violence, chronic physical and mental disorders, food insecurity, social determinants of health, and coronavirus disease 2019. Moreover, biopsychosocial interactions between multiple health problems were studied across medical, anthropological, public health, and other disciplines of science. Conclusions: The limited yet rapidly evolving literature on syndemics informs transdisciplinary interests to understand complex coexisting health challenges in the context of systematic exclusion and structural violence in vulnerable populations. The findings also suggest applications of syndemic theory to evaluate clinical and public health problems, examine the socioecological dynamics of factors influencing health and wellbeing, and use the insights to alleviate health inequities in the intersections of synergistic epidemics and persistent contextual challenges for population health.",
"keywords": [
"Syndemics",
"Multimorbidity",
"Health inequity",
"Health disparity",
"Health Promotion",
"Health Policy",
"Global Health",
"Meta-knowledge Analysis"
],
"content": "Introduction\n\nAddressing health inequities in marginalized populations requires a complex understanding of the epidemiological burden of multiple health problems and associated factors that determine the health statuses and outcomes in that context.1–3 Theoretical frameworks may help in examining different dimensions of population health, adopting intellectual inspirations from scholarly concepts that emerged in the past across scientific discipline.4,5 Amongst many contemporary theories, “syndemic(s) theory” offers critical perspectives on the relationships between diseases and biopsychosocial factors that not only explain the high burden of diseases in populations but also sustain a series of adverse health and social outcomes.6,7 Conceptually, syndemics have three fundamental components that characterize them.6,8,9 Firstly, two or more health problems cluster together that can be assessed epidemiologically or described as co-morbidity or multimorbidity. Secondly, syndemic diseases or conditions interact among themselves using biological, psychological, or social pathways. Lastly, syndemics are associated with social, structural, and contextual forces that precipitate disease clustering and progression in the first place, which may include but are not limited to poverty, segregated housing, systematic exclusion from opportunities, enslavement, colonialism, neo-colonialism, and neo-liberal economic measures that result in disproportionate distribution of wealth, lack of access to resources and services that may improve health and wellbeing, and other socioeconomic inequalities.6,8–10\n\nSince its conceptualization by Merrill Singer in the 1990s,10–12 syndemic(s) theory has become one of the eminent ideas that has influenced scholarly discourses in different disciplines, including social epidemiology and medical anthropology, investigating the dynamics of persistent health inequities in disadvantaged population groups such as homeless, racial and ethnic minorities, and people affected by chronic diseases or social problems.6,9 One of the earliest examples used in theorizing syndemics was substance abuse, violence, and HIV/AIDS (SAVA).8,10 The case of the SAVA syndemic illustrated the clustering of these three health problems where a high burden of substance abuse and violence were prevalent in people living with HIV/AIDS, predominantly in the systematically oppressed communities in the United States.10 Most of them were urban poor, people of color, and deprived of opportunities to live healthy lives in the first place. Another syndemic of HIV and Hepatitis C virus (HCV) is recognized in people who use drugs (PWUD).9,13 Nearly 2.3 million out of 36.7 million people living with HIV in 2015 were infected with HCV. The co-infection of HIV and HCV significantly increases the risks of advanced liver disease and associated adverse health outcomes compared to those with HCV infection alone.9,14,15 Moreover, HCV facilitates the pathogenesis and disease progression of HIV, thus interacting with each other in multiple pathways that may result in adverse health outcomes among the affected individuals.14 These infections are highly prevalent in PWUD, who are more likely to share syringes and engage in other high-risk health behaviors. In addition to these pathological and psychological challenges, these people share similar socioeconomic marginalization driven by structural forces that transform their life choices, health behaviors, and biopsychosocial outcomes.9,14 Rather than presenting the disease burden and their correlates only, syndemic(s) theory highlights the complicated relationships between these co-existing health problems that can be biological, psychological, or social in nature. More importantly, studying these problems in the context of their shared determinants and interactions between multiple constructs provides a broader understanding to address the problems, which is less probable if these problems are examined individually without exploring their synergistic characteristics.9,13\n\nA growing body of literature indicates that the academic and professional interests in syndemics have increased over the past three decades.6–8 A review of syndemics associated with HIV/AIDS identified 60 articles published in 2019 alone,6 which reported co-conditions such as substance abuse (n = 40; 67%), high-risk sexual behavior (n = 36; 60%), depression (n = 36; 60%), interpersonal violence (n = 35; 58%), stigma (n = 19; 32%), sexually transmitted infections (STIs) (n = 16; 27%), trauma (n = 14; 23%), and noncommunicable diseases (NCDs) (n = 6; 10%). Such inclusive nature of those syndemics literature informs the scope of interdisciplinary research using tools from diverse sources to answer common questions of interest in different contexts and populations. The increasing recognition of research on syndemics can potentially specify, describe, and explain bio-social interactive pathways advancing both science and practice. Another review identified 143 journal articles, 23 book chapters, and 29 other types of publications.9 In this review, the authors reported five thematic categories of studies that included syndemics (12%) with cooccurring diseases with bib-bio and bio-social interactions, potential syndemics (18%) where those interactions are referred but not fully articulated, socially determined heightened health burden of diseases (15%) that described social conditions associated with poor health without identifying disease clusters or interactions, harmful disease clusters (17%) that identified disease clusters and social factors without mentioning their interactions, and adverse additive co-morbidities (38%) describing diseases and social determinants through an additive approach to adverse health outcomes without examining the evidence on interactions. Furthermore, a systematic literature review assessed a potential syndemic comprising of HIV, HCV, intimate partner violence, and posttraumatic stress disorder (PTSD).16 In this review, the authors reported childhood physical and sexual abuse and intimate partner violence as social sources of trauma, which was associated with elevated unsafe health behavior leading to a higher burden of HIV infections and subsequent health outcomes. Existing literature provides an overview of diverse health problems and methodological measures adopted by different authors to study syndemics and associated conditions,6,9 which highlight both the complexity of the current evidence base and the necessity of improving our understandings of syndemics applied in different frontiers of knowledge.\n\nPrimary studies and analytical reviews offer syntheses of evidence focusing on specific research questions relevant to a field or a problem of interest, which are useful for evaluating evidence in that scenario. However, such focused approaches may not provide a comprehensive overview of the entire scientific landscape or describe how research on a domain or topic evolved over time. In this regard, meta-knowledge analyses offer quantitative assessments of research identifying the overall status and characteristics of research. Through scientometric and bibliometric measures, meta-knowledge studies identify top contributing scholars, institutions, journals, and countries that may promote further research collaborations. In addition, meta-knowledge studies aim to identify research hotspots where most studies have emphasized previously, thus inform research trends and explore research areas that are not examined extensively. Recognizing areas that require further studies is one of the many goals of knowledge development in a field or topic of interest. To the best of our knowledge, there is no meta-level study on syndemics, which informs an overview of the current status and the evolution of global knowledge on syndemics-related research. Such studies, if conducted systematically, can inform the scholars and practitioners to understand the historical development of knowledge in this field, explain the status of intellectual advancements, and guide future research and scientific advancements in this area of growing interest in health sciences research.\n\nIn the current study, we primarily aimed to analyze the characteristics and trends of the global research literature on syndemics. Secondarily, we evaluated the most prolific authors, institutions, journals, affiliating countries, and funding institutions contributing to syndemics-related research. Lastly, we mapped the major knowledge domains on syndemics highlighting the intellectual development in this field.\n\n\nMethods\n\nIn this study, we adopted meta-knowledge methods that have been used in previous research.17,18 To retrieve scientometric data on syndemics, we accessed the Web of Science (WoS) core collection that included multiple citation sources such as Science Citation Index-Expanded (SCI-Expanded), the Social Sciences Citation Index (SSCI), the Arts & Humanities Citation Index (A&HCI), and the Emerging Sources Citation Index (ESCI). The selection of WoS as the data source was informed by several advantages that it offers. Firstly, WoS provides extensive coverage of more than 20,000 journals, making it one of the most widely used databases for bibliometric studies.19 Moreover, WoS includes publications not only from biomedical sources but also social sciences and other scholarly disciplines, thus making the bibliographic collective more inclusive in nature.20,21 As syndemics are associated with a wide range of biopsychosocial issues relevant to different scientific disciplines,9,22 WoS is likely to provide a transdisciplinary overview of the research landscape in this topic.\n\nWe used “syndemic*” keyword in the topic field for searching the titles, abstracts, and keywords in the WoS database collection. The search process was structured using several eligibility criteria. First, we included citations published from January 1, 2000, to December 31, 2020. Second, we reviewed the titles and abstracts of the retrieved citations and excluded studies on topics such as “parasyndemicolpate” OR “syndemicolpate” that could have provided false positive entries. Third, we limited our search in citations published in English language, thus we excluded citations published in languages other than English. Lastly, we included all publication types such as original articles, reviews, commentaries, editorials, letters, and book chapters considering a low number of citations in the emerging field of knowledge. For all eligible citations, the complete bibliometric data on publication records, authorship, institutional affiliations, funding information, keywords, and citations data were extracted for subsequent analytic steps. No alterations were made for the primarily collected data.\n\nThe corpus of the eligible literature was used for descriptive analysis, social network analysis, and conceptual structure analysis using measures that have been used in previous knowledge mapping studies.17,19,23,24 The descriptive analyses on the key bibliometric characteristics such as total citations, publication trends, top ten cited articles, prolific authors, h-index and g-index of the authors, contributing journals, research institutions, affiliating countries of the authors were analyzed using Microsoft Excel 2021 and R software (version 4.1.2).25\n\nKnowledge mapping offers visual representations of the social connectedness among affiliating authors, institutions, and countries that reflect the research collaborations in a topic. We used a free software called the VOSviewer (version 1.6.16) that applies a natural language processing algorithm (NLP), which represents the units of analysis as a circular node within the map.26 The size of the node portrays the volume (e.g., number of publications in a dataset) and the position represents the resemblance with other nodes in the same set. As a result, closer nodes are more alike than nodes far apart from each other in the final map. The lines connecting multiple nodes represent the relationships among those nodes, whereas the thickness of those lines indicate the strength of that relationship. Finally, the color of the node indicates the cluster to which each node has been allocated to. In this way, all nodes in the map are clustered together based on their affiliation.26 To make the map, VOSviewer uses the SMACOF algorithm,27 which minimizes the function:\n\nn–the number of nodes in a given network,\n\nXi–the locations of node i within a two-dimensional space,\n\n||Xi−Xj||–the Euclidean distance between nodes i and j.\n\nVOSviewer builds clusters of nodes by maximizing the following function:\n\nci–the cluster to which node i is assigned,\n\nδ (c1, cj)–a function that equals one if ci = cj; and zero otherwise,\n\nγ–a resolution parameter that determines the level of detail of the clustering (the higher γ is, the higher the number of clusters).\n\nThis method uses a distance-based approach to construct the bibliometric maps in three steps.26,28 At the first step, it normalizes the differences between multiple nodes. At the next step, it builds a two-dimensional map where the distance between multiple nodes reflects the similarities between those nodes. Further, it combines closely related nodes into clusters sharing similar bibliometric properties allowing visual representation of the research field. Moreover, we conducted a co-occurrence analysis of keywords to evaluate the conceptual relationships between multiple topics. The frequency of co-occurrence of two or more keywords indicated the strength of their association, whereas multiple keywords appearing within a cluster highlighted the topical foci or knowledge base within the research landscape. This approach was used to map multiple clusters with an overview of research domains and a graphical evolution of those domains across years. Lastly, we developed a three-field plot connecting the current literature with cited references using KeyWords Plus in the WoS database. This was used to generate the most frequently appearing words or phrases in cited sources, depicting the intellectual linkages between the existing studies on syndemics and cited research articles. This meta-knowledge study is registered in the Open Science Framework, and the data on eligible studies can be found in the underlying data.\n\n\nResults\n\nWe found a total of 830 articles eligible for this bibliometric study, including 604 original articles, 75 reviews, and 151 other types of publications from 314 scholarly sources (Table 1). These documents were authored by 3025 individual authors, on average most articles were authored by more than three authors Most (n = 750) articles had multiple authors, whereas 80 articles were authored by a single author. The collaboration index was 4.03 suggesting more than four co-authors per article index calculated only using the multi-authored article set. Figure 1 shows the citation retrieval process.\n\nTable 2 provides an overview of the top 10 cited articles on syndemics published from 2003 to 2019, with the average citation per article per year ranging from 12.81 to 124.67. Seven of these articles focused on HIV-related syndemics, whereas the remaining articles discussed HIV in syndemic-related discourses emphasizing other health issues such as substance abuse, tuberculosis, violence, nutritional disorders, chronic diseases, and social determinants of health.\n\nFigure 2 highlights an increasing trend of scholarly publications on syndemics since 2003. Only 33 articles were published before 2010, whereas the frequency of publication increased significantly since 2013. The annual growth rate of the scholarly publications on syndemics was calculated as 10.47%.\n\nTable 3 provides an overview of the top ten contributing authors who contributed to the published manuscripts on syndemics. Among the authors, Safren S.A. had the highest number of publications (n = 26), followed by Singer M (n = 24) and Halkitis P.N. (n = 17). Moreover, Singer M. had the highest number of citations (n = 949), followed by Stall R. (n = 679) and Mendenhall E. (n = 555). Singer M. also had the highest h-index (12) and g-index (24) among the top authors.\n\nMost articles on syndemics were published in AIDS and Behavior journal (7.23%, n = 60), followed by Annals of Behavioral Medicine (3.73%, n = 31) and AIDS Care (2.89%, n = 24). Four out of the top ten journals were associated with AIDS and STI-related topics, whereas all journals were related to epidemiological, behavioral, anthropological, social, and public health sciences (Table 4).\n\nTable 5 shows the top 10 institutions that were affiliated with syndemics-related research. The majority of the studies were authored by scholars from the University of California System (11.93%, n = 99), followed by Harvard University (8.19%, n = 68), and the Johns Hopkins University (6.63%, n = 55). Figure 3 shows extensive collaborations between the key affiliating institutions with a higher publication frequency (n = 5 or above), which highlights the interconnectedness of top contributing institutions in collaborative research on syndemics.\n\nGlobal contributors at the country level show 76 countries that published at least one document on syndemics-related topics. Among those countries, the top 10 contributors are listed in Table 6. Most articles originated from the United States (74.46%, n = 618), followed by Canada (11.93%, n = 99) and UK (6.14%, n = 51). Figure 4 shows global collaborations among participating countries (with at least one publication), highlighting a high volume of syndemics research from high-income countries compared to low- and middle-income countries. Moreover, North American and other high-income countries had stronger collaborative ties on syndemics research that informs higher cumulative production of scientific research from these regions.\n\nSeveral research areas were identified within the broader umbrella of syndemics using clusters of keywords that overlapped with each other. We mapped keywords that had a frequency of 5 and above across the collective bibliography. A total of 104 top keywords were identified and clustered to generate common areas of research in multiple clusters highlighted in the same color. Figure 5 shows the distribution of keyword clusters where the greater size of a circle represents a higher number of publications on that keyword and the thickness of connecting line between circles represents the intensity of coexistence of these terms in the literature.\n\nAmongst multiple research hotspots, the first cluster highlighted in red consisted of keywords related to syndemic theory and associated concepts such as syndemic, substance use, intimate partner violence, depression, health disparities, transgender, gay, bisexual, food insecurity, and intersectionality (Figure 5). Several studies were identified that used these keywords, indicating their relevance to this research cluster. For example, Couture et al., adopted the syndemic framework to evaluate the effects of comorbid psychosocial problems on the risk of physical and sexual violence on female entertainment and sex workers (FESW) in Cambodia.29 They reported a high burden of client-perpetuated violence that was associated with housing insecurity, substance use, and psychological distress. FESW with two psychosocial conditions had twice the odds (adjusted odds ratio [AOR] = 2.08; 95% confidence interval [CI] 1.00-4.31), whereas women with 5-6 psychosocial conditions had eightfold higher odds (AOR = 8.10; 95% CI 3.4-19.31) of violence, highlighting a syndemic model of cooccurring psychosocial problems. Another study examined the prevalence and correlates of trauma in South African youth living in syndemic HIV risk.30 More than 99% of the participating youths experienced at least one potentially traumatic event (PTE), whereas a high PTE score associated with high food insecurity among adolescent men (AOR 2.63, 95% CI = 1.36-5. 09) and women (AOR = 2.57, 95% CI = 1.55-4.26, respectively). This study reported biopsychosocial pathways including depression and inconsistent condom use as pathways of syndemic of trauma and HIV in that context.\n\nThe second cluster illustrated in green includes keywords on syndemics of infectious diseases such as HIV, AIDS, tuberculosis, STIs, hepatitis c, antiretroviral therapy, adherence, comorbidity, and coinfection. For example, Dyer et al., conducted a cohort study among 301 men who have sex with men (MSM) to assess syndemic relationships.31 They reported that depression symptoms were associated with sexual compulsiveness (odds ratios [OR]: 1.88, 95% CI = 1.1, 3.3) and stress (OR: 2.67, 95% CI = 1.5, 4.7); sexual compulsiveness was associated with stress (OR: 2.04, 95% CI = 1.2, 3.5); substance misuse was associated with intimate partner violence (IPV) (OR: 2.57, 95% CI = 1.4, 4.8); stress was associated with depression symptoms (OR: 2.67, 95% CI = 1.5, 4.7), sexual compulsiveness (OR: 2.04, 95% CI = 1.2, 3.5) and IPV (OR: 2.84, 95% CI = 1.6, 4.9). Also, men who reported three or more syndemic constituents (three or more conditions) were engaged in high-risk sexual behavior compared to men who had two or fewer health conditions (OR: 3.46, 95% CI = 1.4-8.3). Moreover, a review by Meyer and colleagues identified 45 articles that emphasized SAVA syndemic and associated conditions such as HIV-associated risk-taking behaviors, mental health, utilization of health services and medication adherence, and a bidirectional relationship between violence and HIV/AIDS.32 This review highlighted the complex relationships and associated outcomes of poor decision making and high-risk behavior in the context of the SAVA syndemic.\n\nIn the third cluster highlighted in blue, several keywords were identified, including mental health, MSM, sexual compulsivity, stigma, resilience, internet, and aging. Studies in this cluster focused on health behavior and syndemic relationships in gay and bisexual men. For example, a study by Parsons and colleagues examined 1,033 HIV-negative gay and bisexual men living in the U.S. and found that more than 62% of men reported having at least one syndemic condition.33 Also, HIV-related risk behavior was associated with polydrug use, sexual compulsivity, being single, and being Latino. Moreover, the risk was highest among participants with three or more syndemic conditions. Another study from Mexico conducted by Pitpitan et al. found that MSM with a high number of syndemic conditions showed an increased prevalence of sexual risk-taking.34 Moreover, MSM who were out to more people showed a weaker association between high-risk sexual behavior and syndemic conditions suggesting outness or disclosure of same-sex preference as a resilience factor from a syndemic perspective.\n\nA fourth cluster highlighted in yellow included keywords related to psychosocial and health behavior-related keywords such as violence, substance abuse, HIV testing, homophobia, and suicide. This research cluster emphasized the growing number of studies that examined the psychosocial health of MSM and associated syndemic conditions and relationships. For example, a study by Herrick and colleagues recruited 1551 MSM and found that different life-course predictors such as internalized homophobia and victimization were significantly associated with syndemic condition as well as psychosocial health conditions including stress, depressive symptomology, substance abuse, compulsive sexual behavior, and intimate partner violence.35 Moreover, the authors used a nested negative binomial analysis and found that the overall life course significantly explained the variability in syndemic outcomes (chi(2) = 247.94; P<.001; df = 22). Another study by Ferlatte and colleagues examined the data from a survey of 8382 Canadian gay and bisexual men and found that suicidal ideation and attempts were associated with individual marginalization and psychosocial health problems such as mental disorders, substance use, STIs, and HIV risks.36 In addition, individuals with three or more psychosocial problems had higher odds of experiencing suicidal ideation [6.90 (5.47-8.70) times] and suicide attempts [16.29 (9.82-27.02)] compared to participants with no such problems. These relationships show the complex nature of syndemic relationships among people living under psychosocial stressors that impacts their health and wellbeing.\n\nThe fifth research cluster highlighted in purple color consisted of keywords including coronavirus disease 2019 (COVID-19), obesity, diabetes, chronic disease, poverty, and social determinants of health. This cluster emphasizes a research domain that includes noncommunicable diseases and contemporary health problems such as the COVID-19 pandemic. For example, Mendenhall and colleagues conducted a study in Kenya and found that adults with diabetes shared a complex social and medical framework associated with their health conditions. People with diabetes also had comorbid anxiety, depression, and infectious diseases such as HIV/AIDS, malaria, and tuberculosis.7 The authors also reported that social problems were associated with biophysical suffering, whereas women had a higher burden of psychosocial distress and somatic symptoms such as multimorbidity compared to men. People with diabetes reported not only concurrent anxiety and depression but also common infections, including malaria, tuberculosis, and HIV/AIDS. Another study from Puerto Rico found that the subaltern status negatively affected obesity rates that could be attributable to limited federal assistance for health insurance and healthier food items. Moreover, weight mismanagement and a lack of healthcare providers were amongst the psychosocial challenges that were associated with the obesity syndemic in this population. Furthermore, recent studies focused on the relevance of syndemic perspectives on coronavirus disease (COVID-19) pandemic. For example, Gutman and colleagues argued that coinfections such as malaria and other parasitic diseases with SARS-CoV-2 could result in detrimental health outcomes necessitating increased testing and disease surveillance during the COVID-19 pandemic.22 Moreover, Perez-Escamilla and colleagues discussed the persistent effects of food and nutrition insecurity associated with poor maternal and child health outcomes that can be exacerbated during the COVID-19 pandemic.37 Furthermore, long-standing health inequities and systemic racism are associated with multimorbidity, which may have syndemic relationships leading to adverse health outcomes in marginalized communities.38 In this regard, Poteat and colleagues used the syndemic framework to discuss the syndemic conditions in Black Americans who experienced psychosocial stressors such as mortgage redlining, history of enslavement, political gerrymandering, lack of access to healthcare, job discrimination, and health care provider bias.39 The authors argued that racial disparities in COVID-19 require acknowledging and addressing structural racism and determinants of these chronic disparities among the affected individuals. These articles highlight the biopsychosocial challenges and their relationships that share common determinants and affect population health, predominantly in vulnerable population groups.\n\nThree more clusters with fewer keywords appeared in the intersections of major clusters reported above. The sixth cluster identified in pink color consisted of keywords such as men who have sex with men, condom use, transgender women, and India. Moreover, keywords such as AIDS, HCV, and tuberculosis (TB) colored in brown formed the seventh research cluster on syndemics. Lastly, scattered nodes of keywords colored in orange included HIV infection, South Africa, pregnancy, qualitative, sexual minority, network analysis, and mental illness. These clusters highlight diverse topics that overlap with other clusters and highlight the interconnectedness of the keywords as well as research topics that are common across research domains.\n\nResearch domains within the scientific field of syndemics evolved over the years, which is highlighted in Figure 6. Since most articles were published in recent years, keywords used until 2015 highlight the scholarly themes of earlier publications on syndemics. These keywords are marked in purple, which included HIV/AIDS, substance abuse, prevention, syndemic theory, coinfection, social determinants, social inequality, internet, mortality, sexually transmitted diseases, and health policy. Moreover, keywords colored in bluish-purple show a transition of those topics being used in publications around 2016, which include syndemics, tuberculosis, obesity, harm reduction, health disparities, poverty, and aging. Furthermore, keywords used across publications during 2017-18 are presented in green color, where most keywords such as syndemic, men who have sex with men, gay and bisexual men, diabetes, domestic violence, food insecurity, global health, public health, drug use, intimate partner violence, HIV risk, testing, and prevention were identified. Lastly, keywords in yellow represent topics used in articles published around and after 2019. These recent topics included COVID-19, pandemic, social determinants of health, noncommunicable diseases, network analysis, latent class analysis, pre-exposure prophylaxis, and climate change.\n\nAn assessment of the cited references provided another perspective on how the current research publications cited and used previous scholarly items. Figure 7 represents the cited sources on the left, the most widely used keywords from the titles of cited publications in the middle, the top contributing authors on the right. Common keywords from cited sources inform the most relevant topics used from previous research, which included psychosocial health problems, gay, united states, substance use, risk, united states, prevalence, depression, health, women, and syndemics. Across these cited sources, Singer et al. authored five articles published from 1994 to 2017.7,8,10,12,40 One of earliest articles that was widely cited across syndemics literature was the article describing the development and psychometric assessment of the Center for Epidemiological Studies-Depression (CES-D) scale by Radolf, published in 1977.38 Furthermore, top published authors such as Singer and Stall have been contributing to syndemics research across most topics that are frequently cited across current publications.\n\n\nDiscussion\n\nThis study evaluated the global scientific landscape of syndemics research using bibliometric measures. The findings of this study suggest a slow yet gradual increase in syndemics-related publications, which has accelerated since 2013. In recent years, syndemic conditions are increasingly examined in both primary and review articles that draw intellectual inspirations from biopsychosocial literature, highlighting a transdisciplinary trend in syndemics research. Moreover, a higher proportion of original articles rather than reviews and other publication types indicates a rising body of empirical research on syndemic(s) theory and associated concepts. Furthermore, syndemics-related publications were published in general and specialty journals emphasizing the intersection of coexisting diseases, their shared determinants, and complex relationships between biosocial constructs as commonly seen in social medicine and allied fields of knowledge.\n\nMost of the syndemics-related publications were affiliated with authors and institutions from high-income countries, and the U.S. had the highest contributions. In addition, heavy collaborations among authors and institutions in high-income countries indicate active research across major research entities. While some of the low- and middle-income countries (LMICs) such as Brazil, Mexico, China, South Africa, and India are engaged in syndemics research, their individual and collective contributions appeared to be limited, which informs a critical research gap in LMICs. This is consistent with previous research that reported a low scholarly output from LMICs in different areas of health sciences.41–44 In the case of syndemics research, the historical and persistent gaps in research capacities in LMICs are likely to be compounded by the fact that syndemics have been primarily conceptualized and extensively studied by scholars and institutions in high-income countries. It is necessary to increase the research capacities in LMICs with a focus on syndemics, as those countries experience a high burden of infectious and noncommunicable diseases and poor social determinants of health. As the key concepts of syndemic(s) theory suggest,6,7,10 studying syndemics in such underprivileged contexts can potentially offer unique and diverse scientific perspectives on the biopsychosocial formation of health and illness in respective populations. It may enrich the current knowledge base on syndemics and inform the future transformations of medical and social care as well as disease prevention globally.\n\nSyndemics research focused on diverse topics, among which HIV-related syndemics were extensively studied across the literature. As evident in research hotspots, HIV/AIDS and associated health behaviors and outcomes were common in more than one cluster of keywords. This frequent appearance of HIV/AIDS in the syndemics research landscape can be attributable to several factors. First, HIV/AIDS-related conditions were amongst the earliest syndemics that were conceptualized and examined in the history of the syndemic theory. For this reason, many articles focusing on non-HIV syndemics also referred to the case of previous HIV syndemics such as SAVA.9,10 Secondly, syndemics literature from the US and other developed countries present studies and cases of multiple health problems and their synergies within a syndemic framework,6,9 where the study populations were urban poor from inner-city neighborhoods. As we learn from social epidemiological and anthropological studies,9,33 biosocial challenges associated with HIV/AIDS were highly prevalent in these population groups. Therefore, the academic discourses on the social reality of health and wellbeing in these marginalized people would remain incomplete without studying HIV/AIDS and related issues. Lastly, literature from the global context, particularly from Sub-Saharan countries, highlighted the burden of HIV/AIDS in the context of the continued burden of infectious and chronic diseases in those contexts.6,9 For this reason, we can find studies that provide national and regional assessments of HIV/AIDS-related syndemics from those countries, which also compared their findings with what was known from similar studies conducted in developed nations. As many scholars described HIV/AIDS as a pandemic rather than just a disease outbreak,45,46 global studies comparing and connecting the concepts and associated evidence revealed the worldwide relevance of HIV/AIDS in syndemics research.\n\nIn addition to HIV/AIDS, syndemics literature also discussed infectious diseases such as tuberculosis and COVID-19. While tuberculosis research was often studied as a comorbid condition in people living with HIV/AIDS,6,9 recent literature examined the relevance of comorbid diseases that are relevant to susceptibility to COVID-19 and subsequent health outcomes.39,47–49 Given the growing burden of biopsychosocial challenges associated with COVID-19,38,50–55 it is necessary to investigate bio-bio and bio-social interactions between coexisting health problems in COVID-19 patients and survivors. Such research may reveal the true burden of disease clustering, biopsychosocial relationships, shared determinants, and health outcomes in the context of this pandemic. Despite a growing body of evidence that is mostly epidemiological and predominantly cross-sectional in nature, transdisciplinary and longitudinal investigations would be necessary to understand syndemic aspects of this pandemic. Furthermore, COVID-19 has demonstrated the vulnerability of people with noncommunicable diseases who are more likely to have adverse outcomes.38,39,49 Limited literature exists on syndemics of non-HIV chronic diseases,9 which necessitates a more comprehensive yet inclusive study of communicable and noncommunicable diseases from a syndemic perspective.\n\nSocial determinants of health constituted a significant proportion of syndemics research. This is consistent with the fundamental idea of syndemic conditions that have common social factors and bio-social interactions.9,10,12 However, there were distinct patterns in research on social factors that influenced health status, disease development, and subsequent outcomes in study populations. As evident in research hotspots, sexual and gender minorities such as men who have sex with men, bisexuals, and transgender people were frequently studied in the syndemics literature. Although many of those studies examined health problems and associated factors in the context of HIV/AIDS,6 studies have also presented their psychosocial vulnerability due to minority stressors such as social stigma and other determinants of health in the affected individuals. The added value of those studies may include, but are not limited to, a broader understanding of how gender roles and norms may have biosocial interactions with pre-existing health conditions, contribute to the progression of diseases, and impact their health and wellbeing at the individual and population level. Such research findings must be translated to clinical and social decision-making addressing the stressors that affect health outcomes in gender minorities. Moreover, future syndemics research may need to extend the scope and depth of conceptual and empirical investigations on other psychosocial stressors such as racism, poverty, lack of education, unemployment, inadequate access to health and social care, xenophobia, and other means of marginalization. In recent years, public interests in those issues reflect not only their relevance to the social oppression experienced by minorities but also inform a critical need to examine the biopsychosocial dynamics of such stressors to understand how they may determine health and social outcomes in respective populations.\n\nThe current literature emphasizes diseases and their interactions among individuals in the social context. However, socioecological perspectives may inform the need for research in several under-investigated areas that may provide a more accurate understanding of how syndemics work in individuals and populations.56,57 For example, the role of caregivers and family members is critical for the psychosocial wellbeing of the affected individuals.44,58,59 Moreover, caring for someone with one or more chronic diseases is reported to be associated with adverse health and social outcomes among family caregivers.60,61 Since they share the same or similar social and contextual factors relevant to the respective syndemics, future research should investigate the roles of and impacts on informal caregivers alongside primarily affected individuals in syndemic scenarios. Furthermore, syndemic conditions, as well as their determinants and consequences, may not have equal impacts on people of different age groups. Disease dynamics and associated social forces are likely to be different in children, adolescents, young adults, and older adults with varying sociodemographic characteristics.9,62,63 Future research should examine syndemics in different population groups, associated biopsychosocial relationships, and multiple outcomes.\n\nFrom a health services perspective, syndemics may impose unique challenges to the affected individuals requiring personalized care that may address multiple health concerns at a time. The recent technological advancements have facilitated the digitalization of health services with a focus on personalized or precision health.64–66 Syndemics research in the digital age should explore avenues of integrating interventions that target intersections of coexisting diseases and associated factors in specific contexts. Such integrative technological measures may inform spatial and temporal challenges through real-time measurements,67,68 and enable the practitioners to mitigate the burden of multimorbidity using evidence-based digital and traditionally delivered interventions.\n\nGiven the complex nature of syndemics, implementation research on coexisting diseases, common determinants, cumulative impacts, and shared sociocultural aspects should be conducted, and the findings should be incorporated in public health and social welfare policymaking. Despite a growing need for translating the current evidence to transform clinical and social care for syndemics, it is necessary to acknowledge that the current literature does not emphasize implementation dimensions of complex health and social problems. Researchers and decision-makers should recognize this gap as the persistence of comorbid disease would be critical for common healthcare operations such as patient-provider interactions and the delivery of health services. Institutional measures, including sensitizing the stakeholders and establishing evidence translation systems for practitioners, should be prioritized for minimizing knowledge-to-practice gaps in this regard.\n\nSyndemics research highlights global health disparities by emphasizing the roles of context-specific forces and determinants of health.9,13 Therefore, local and global health systems should be examined from a syndemic perspective, which may enable health system strengthening that results in a better understanding of concurrent syndemics, future population health challenges, and how to respond to the same in a systematic way. Such insights on syndemics would also necessitate the active participation of global health organizations and member countries to use their collective resources to combat global health crises such as infectious disease outbreaks, food insecurity, climate migration, and health inequities that continue to affect populations. In these processes, the role of political commitment and collaborations will be of paramount importance.\n\nFrom a health promotion perspective, it is critical to engage communities who are vulnerable to syndemics to increase their awareness on social determinants of cooccurring diseases.69,70 The public should be informed through targeted and mass media interventions regarding common challenges and preventive measures. However, empowering community-based organizations to assess their risks and address the same using local resources would be far more impactful. Such efforts may require technical assistance and external support, which should be organized through public health institutions. As syndemics researchers argue that context-specific factors and biopsychosocial interactions make syndemics unique to individuals and populations,9,40,48 participatory research and action plans may create opportunities to exchange knowledge and develop context-appropriate interventions for syndemics.\n\nSyndemics research highlights an intersection of academic contributions from multiple scholarly disciplines, including medical anthropology, social epidemiology, health policy, health promotion, clinical sciences, and social sciences.6,30,57,69 The combined use of multiple quantitative and qualitative methods has complemented the investigations of complex syndemic problems in current literature, which couldn’t have been understood using any single-best method.6,9,16 Arguably, syndemics necessitate transdisciplinary approaches to integrate multiple research methodologies to answer complex research questions. Such integrative measures may help the scholars to apprehend the ontology and phenomenology of syndemics from shared epistemological perspectives.\n\nGlobal research on syndemics informs the deteriorating effects of cooccurring health problems in populations living under chronic social stressors.8,10,31,56 Understanding these complex scenarios may offer insights on humanitarian challenges that are infrequently studied and discussed in contemporary health and social policy discourses. Notably, the production of health in a population reflects its commitment to improve people’s wellbeing and maximize public welfare through regulating factors that may be harmful to individual and social health. Such initiatives may also include mandates for better access to health services irrespective of social, economic, cultural, geographic, and other differences across individuals and communities. However, many high-income countries such as the United States are far behind in ensuring equitable access to health.71 Previous research on political determinants of health informs critical challenges such as systematic racism, implicit bias, environmental injustice, and other structural factors that share the policy responses to public health problems.71–74 From an ethical perspective, it is a shared responsibility of healthcare providers, researchers, and organizations to advocate for using science for bringing social justice through meaningful changes in the socio-political determinants of syndemics and health disparities in marginalized populations.\n\nThere are several limitations of this meta-knowledge study, which are necessary to understand the scope and findings of this study. Also, the limitations of this study would inform future research addressing the theoretical, methodological, and empirical shortcomings of the current findings. One such limitation is the choice of the database; although WoS is one of the most inclusive sources of bibliographic data, it may not contain all articles published on syndemics. Therefore, this study could not include potential studies that may exist elsewhere. Although this limitation is very common across knowledge mapping studies,17,19,23 we encourage methodologists and other scholars to continue intellectual discourses on how the global knowledge community can find opportunities to harmonize citations data across databases. This is extremely challenging as journals are not universally indexed, and databases do not contain bibliographic data on all key variables of interest. This challenge necessitates an integration of technological advancements and cooperation between database authorities to facilitate a uniform distribution of scholarly resources globally. Another challenge was the framing of syndemics in the published literature. As found in the previous synthesis of empirical research,9 many scholars do not examine all criteria of syndemics in their studies. For example, the coexistence of multiple health problems without specifying the bib-bio or bio-social relationships is often studied within the syndemic framework. Also, it is possible to describe all criteria of syndemic without using the framework, which is perhaps a major challenge leading to a limited observation of literature on complex health problems. We recommend wide scholarly communication of syndemic theory and adoption of relevant keywords and explanations whenever possible. This may eliminate the existing knowledge biases and improve future mapping of the global knowledge landscape. Lastly, despite using contemporary knowledge mapping approaches, this study may not inform population-level estimates or determinants of syndemics. As we discussed earlier, the field of syndemics research is evolving, and this study highlighted key research areas within this growing field of knowledge. We recommend further primary studies and evidence synthesis on disease clusters that have synergistic effects, interactions, and shared sociocultural factors that may inform specific insights on context-specific syndemics.\n\n\nConclusions\n\nIn this meta-knowledge study on global research on syndemics, we found a limited yet growing body of scientific literature on syndemics and associated population health problems. Most studies on syndemics were published from high-income countries, and they included diverse topics ranging from STIs to various social determinants of health. Further research is needed to understand the dynamics of multiple coexisting infectious and noncommunicable diseases across global populations with a focus on cumulative disease burden, biopsychosocial relationships, and common structural forces that are associated with health and wellbeing. The findings of this study highlight the scope of syndemics to inform advanced research, health policymaking, and practices, not only through focusing on a single disease but also addressing health inequities in the intersections of multiple health problems through inclusive, context-specific, socioculturally appropriate, and evidence-based approaches.\n\n\nData availability\n\nOpen Science Framework: A meta-analysis of global research on syndemics (2001-2020). https://doi.org/10.17605/OSF.IO/8N9R6.\n\nThis project contains the following file:\n\n- DataFile-Authors-DOI-Titles.xlsx\n\n- Flowchart of the citations retrieval process (1).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\nCompeting interests\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThe authors declared that no grants were involved in supporting this work.",
"appendix": "Acknowledgements\n\nThe previous version of the manuscript is available on medRxiv (https://doi.org/10.1101/2021.05.19.21257413).\n\n\nReferences\n\nBraveman PA, Kumanyika S, Fielding J, et al.: Health disparities and health equity: the issue is justice. Am J Public Health. 2011; 101(S1): S149–S155. PubMed Abstract | Publisher Full Text\n\nGee GC, Ford CL: Structural racism and health inequities: Old issues, New Directions1. Du Bois Rev Soc Sci Res Race. 2011; 8(1): 115–132. PubMed Abstract | Publisher Full Text\n\nQuinn SC, Kumar S: Health inequalities and infectious disease epidemics: a challenge for global health security. Biosecurity bioterrorism biodefense Strateg Pract Sci. 2014; 12(5): 263–273.\n\nDover DC, Belon AP: The health equity measurement framework: a comprehensive model to measure social inequities in health. 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}
|
[
{
"id": "125796",
"date": "11 Mar 2022",
"name": "Nicola Bulled",
"expertise": [
"Reviewer Expertise I am a syndemics researcher having published numerous syndemics papers with Merrill Singer",
"including the heavily cited Lancet piece noted in this manuscript as the 6th most cited syndemics article. I have worked on syndemics for close to 15 years. My primary focus area is infectious disease and syndemic theory development",
"including the evidencing of the theory."
],
"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, “Global research on syndemics: a meta-knowledge analysis (2001-2020)” for consideration in F1000 Research, offers a detailed meta-knowledge analysis of published syndemics literature from 2001-2020. Having conducted a review of syndemics literature myself, I agree with the approach taken by the authors regarding search engine, and generally agree with the analysis offered by the data generated. I do, however, feel the authors need to offer a more critical assessment of the analysis regarding what it reveals about the application of the theory, drawing on current conversations.\nA couple of points of clarification are needed regarding how the data is analyzed. What is the relevance of bibliographic elements with reference to how the work is related? It is unclear to me how these elements are included or not in a network analysis of similarities. Incorporate the dates of the other reviews conducted. The reviews mentioned included fewer publications because their dates and in some cases topics were significantly narrower. Also include additional reviews that have not been mentioned, including that by Tsai and Burns 2015.\nI encourage the authors to highlight the limitations of the approach at the outset of the methods rather than in a limitations section at the end. One of the primary limitations is that the authors do not identify what of the literature calling itself “syndemics” is actually a syndemic analysis. In one of the prior reviews of syndemic literature conducted (mentioned in this manuscript), only 12% of the literature reviewed actually met a syndemics definition. If that is the case in your analysis, then close to 90% of the literature included in this analysis is likely not syndemics at all. This needs to be considered as a limitation at the outset of the study. Or at least, the reader needs to be made aware of this problem. The discussion of the prior review did not lay this out clearly enough.\nThis is my primary concern for this study. While the results are very interesting, I feel that the story the results tell are not presented in the context of current syndemic theory conversations. The authors fail to include any of the work of A. Tsai, who has strongly critiqued syndemic theory as lacking evidence. A special issue of Social Science and Medicine published between 2019-2022 includes different work attempting to evidence syndemics. Many of these publications do not. What has been recognized is that the method to assess a syndemic arrangement introduced by R. Stall in 2005 actually is a summative score, with more “syndemic” factors present resulting in worse outcomes. This does not indicate a syndemic arrangement with synergy occurring between the factors. Stall himself has agreed that his analytical approach was wrong. The data presented in this study indicates the significant impact this work of Stall has had in directing syndemic literature, completely changing the trajectory of the theory and the approaches to assessing the theory. Stall is one of the top 10 authors and, as shown in Figure 7, has significantly impacted other key authors in the field. Many of the examples offered on pages 12-13 fall into this erroneous application of syndemics. While this may be where syndemics literature is at present, the authors should indicate the problem. Scholars appear to be using “syndemics” as a fashionable new term to describe co-morbidities, with some acknowledging social elements, but many not offering much at all, and few considering evaluating synergistic rather than summative relationships.\nThe assessment of institutions also does not offer a great deal. I don’t understand the network dynamic shown, how are these relationships determined? The statistics of frequency per institution need to be proportional to the number of scholars present in the institution or at least offer some indication of size. In this light, UCONN might be producing significantly more than other institutions, which would make sense given as that is where Merrill Singer is based. The authors offer no assessment of why these arrangements are the way they are. In which case, it isn’t clear what the value of the data is. Similarly, the authors do not interrogate the bibliographic data presented. While it is interesting to consider number of authors, number of documents per author, and number of keywords. What does this really tell us? If the network is generated on these similarities, I don’t see the value of the network.\nOne final point of note, in the top 10 articles listed, the Lancet piece on global obesity syndemic is second. This proved a highly contentious article in the field of syndemics researchers as it posited that a global syndemic could exist. For syndemics scholars that recognize the influence of social factors, this was not possible. An obesity epidemic in India is not socially the same as an obesity epidemic in the US or South Africa or Australia. What this study did, much like Stall’s, was set syndemics theory on another course of inaccurate application.\nThe authors need to:\nInclude the work of Tsai and the conversations he has provoked regarding the direction of syndemics' work.\n\nInterrogate the data presented in reference to Tsai’s work, where has syndemic theory gone, and is this problematic.\n\nDon’t use examples of syndemics literature that isn’t presenting a syndemics arrangement, unless the aim is to indicate how it isn’t a syndemic arrangement (references such as: 22, 29, 30, 31, 32, 33, 34, 35, 36, 37). Anything that indicates that more factors results in worse outcomes is using an additive/summative approach and not assessing for synergy between factors.\n\nFix the typo “bib-bio”, it comes up twice.\n\nOffer a richer analysis of the data presented, including discussing the relevance of bibliographic elements, presenting institutional publication records relative to institutional size, and assessing how different frameworks of understanding syndemic theory and evaluating syndemics influenced 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? 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? Partly",
"responses": [
{
"c_id": "9261",
"date": "02 Feb 2023",
"name": "Samia Tasnim",
"role": "Author Response",
"response": "Comment: The article, “Global research on syndemics: a meta-knowledge analysis (2001-2020)” for consideration in F1000 research, offers a detailed meta-knowledge analysis of published syndemics literature from 2001-2020. Having conducted a review of syndemics literature myself, I agree with the approach taken by the authors regarding search engines and generally agree with the analysis offered by the data generated. I do, however, feel the authors need to offer a more critical assessment of the analysis regarding what it reveals about the application of the theory, drawing on current conversations. Response: We appreciate the valuable comments of the respected reviewer. The goal of a scientometric study is to examine the meta-knowledge development in a given topic in terms of research growth and trends1-3. It is used for unraveling and mapping the cumulative scientific knowledge in well-established fields by objective analysis of large volumes of unstructured data. It aims to uncover emerging trends in the field by highlighting the article and journal performances, collaboration patterns, research constituents, along with the intellectual structure of a specific domain. In this current study, we evaluated the scientific development of syndemics and related health and social issues. This approach is significantly different than what can be done in a systematic review or a critical review. However, the scope of critical evaluation of the research topics in light of the previous research and academic discourses remain relevant. In this revised version, we revisited those areas and provided updated information and explanations that may address the shared concerns. Reflection of our critical assessment can be found in the discussion section. Comment: A couple of points of clarification are needed regarding how the data is analyzed. What is the relevance of bibliographic elements with reference to how the work is related? It is unclear to me how these elements are included or not in a network analysis of similarities. Incorporate the dates of the other reviews conducted. The reviews mentioned included fewer publications because their dates and in some cases topics were significantly narrower. Also include additional reviews that have not been mentioned, including that by Tsai and Burns 2015 Response: As mentioned in the methods section, we have included all the articles meeting the inclusion criteria indexed in Web of Science until 6/26/2022. The article by Tsai et al., might have been missed due to mismatched indexing. We have also mentioned in our limitation that due to lack of universal indexing of scientific journals there is a possibility of missing articles not indexed in this major database. We have also reviewed the analyzed works and relevant literature as suggested. We found that some of the studies indexed outside of WoS were not included in the current study. However, adding them to the dataset from non-homogenous bibliographic sources would create further discrepancies on bibliometric indicators. Therefore, we confined our work within the scope of WoS collection and discussed this elaborately both in the methods and discussion sections of our manuscript. The rest of the network analyzes were revisited and they are consistent with the WoS collection on syndemics, which we believe cover the majority of, if not all, scientific publications on this topic. Comment: I encourage the authors to highlight the limitations of the approach at the outset of the methods rather than in a limitations section at the end. One of the primary limitations is that the authors do not identify what of the literature calling itself “syndemics” is actually a syndemic analysis. In one of the prior reviews of syndemic literature conducted (mentioned in this manuscript), only 12% of the literature reviewed actually met a syndemics definition. If that is the case in your analysis, then close to 90% of the literature included in this analysis is likely not syndemics at all. This needs to be considered as a limitation at the outset of the study. Or at least, the reader needs to be made aware of this problem. The discussion of the prior review did not lay this out clearly enough Response: Thank you for mentioning this critical problem. We acknowledge this issue and we have revised the methods and limitations accordingly to make the readers aware of this problem. “Due to discrepancy in the framing of syndemics in the published literature, the coexistence of multiple health problems without specifying the underlying bio-bio or bio-social relationships is often studied within the syndemic framework.9 Thus studies titled syndemics can be included in the analysis despite the differences in the scope of their work. This issue has been elaborated in the limitations section.” Comment: This is my primary concern for this study. While the results are very interesting, I feel that the story the results tell are not presented in the context of current syndemic theory conversations. The authors fail to include any of the work of A. Tsai, who has strongly critiqued syndemic theory as lacking evidence. A special issue of Social Science and Medicine published between 2019-2022 includes different work attempting to evidence syndemics. Many of these publications do not. What has been recognized is that the method to assess a syndemic arrangement introduced by R. Stall in 2005 actually is a summative score, with more “syndemic” factors present resulting in worse outcomes. This does not indicate a syndemic arrangement with synergy occurring between the factors. Stall himself has agreed that his analytical approach was wrong. The data presented in this study indicates the significant impact this work of Stall has had in directing syndemic literature, completely changing the trajectory of the theory and the approaches to assessing the theory. Stall is one of the top 10 authors and, as shown in Figure 7, has significantly impacted other key authors in the field. Many of the examples offered on pages 12-13 fall into this erroneous application of syndemics.While this may be where syndemics literature is at present, the authors should indicate the problem. Scholars appear to be using “syndemics”as a fashionable new term to describe co-morbidities, with some acknowledging social elements, but many not offering much at all, and few considering evaluating synergistic rather than summative relationships. Response: We revisited our analyses and also retrieved the data again to cross-check if there was any discrepancies. We included all articles in Web of Science until 6/26/2022 and realized that a major proportion of Tsai’s work was published in 2021-22, whereas our primary analyses included studies up to 2020. By that time, Tsai had 7 publications on syndemics, whereas the last author mentioned in our list had 9 publications. This is the reason why we couldn’t mention Tsai from an objective viewpoint. Perhaps this is also the reason why our paper may not inform anything regarding articles that were published beyond the scope of our dataset. As we explained in the methods section of our revised submission, we included any work related to syndemics irrespective of the definitions or frameworks used by the respective authors. We welcome the discussion on the references related to Stall and colleagues. We have presented arguments from both sides in the discussion to inform the readers. We have also mentioned the differences in the opinions and objectively reflected its impact on research synthesis in the discussion section of this revised submission. “It is also crucial to highlight the existing debate within the field of syndemics is the framing and the statistical approaches used to establish relationships between the diseases and outcomes. Considering the complex multilevel involvement of syndemics Tsai et al and colleagues believe that most empirical studies purporting to validate the theory lack in statistical robustness. Tsai identified that most studies in the field of syndemics demonstrate a statistically significant association between psychosocial problems and health outcomes using simple linear models, very few studies assess the how these psychosocial problems interact to magnify the outcomes as they only use summative approach for measuring the effect. Additionally, the summative approach is only successful to measure the changes when the effect sizes are small. Authors suggested to use the summative model using the count variable approach to conduct a latent factor analysis for confirming that a single parameter model is adequate. They emphasized on sharpening the theory’s prediction approaches by incorporating advanced systems level approaches. Stall argued in favor of the summative approach saying that majority of the existing data in this field comes from self-reported data from cross-sectional studies. Applying more rigorous data analysis method would require redesigning studies such as long-term cohorts to collect data to establish the theory. However, considering the current nature of the funding, implementing such resource intensive cohort study is not feasible. Due to the physical and psychological burden of these diseases (especially HIV) on highly vulnerable marginalized communities such as young gay black men or transgender women, the current approach is acceptable as it can demonstrate the dangerous existence of these co-morbidities highlighting the needs for prevention efforts from practitioners and policy makers.” Comment: The assessment of institutions also does not offer a great deal. I don’t understand the network dynamic shown, how are these relationships determined? The statistics of frequency per institution need to be proportional to the number of scholars present in the institution or at least offer some indication of size. In this light, UCONN might be producing significantly more than other institutions, which would make sense given as that is where Merrill Singer is based. The authors offer no assessment of why these arrangements are the way they are. In which case, it isn’t clear what the value of the data is. Similarly, the authors do not interrogate the bibliographic data presented. While it is interesting to consider number of authors, number of documents per author, and number of keywords. What does this really tell us? If the network is generated on these similarities, I don’t see the value of the network. Response: As mentioned in the method section of the paper we conducted descriptive analysis of key bibliometric characteristics, institutions conducting research are commonly considered as a key characteristics in the bibliometric analysis as it can provide ideas about distribution of resources and potential areas for collaboration between institutions across the globe 4-6. However, it was not possible to further the analysis at individual researcher level as this information was not included in the bibliometric data retrieved from the database. Moreover, there is a possibility for the researchers to change their work affiliation or hold more than one affiliation, thus analysis based on publications as proportional to the number of scholars will vary but publications from institutions will remain relatively constant. Our approach is consistent with previous bibliometric studies that offered aggregated outcomes for authors and institutions 7,8. Lastly, the value of the network, particularly those illustrating clusters of research nodes, are useful to visualize research hotspots and themes. As noted in earlier works 9,10 those insights not only inform current research trends, but also provide critical insights on research gaps in a scientific area. Both in our results and discussion, we discussed those hotspots and potential gaps in syndemic literature, which can be considered as the added contributions of this study. References: Abdalla SM, Solomon H, Trinquart L, Galea S. What is considered as global health scholarship? A meta-knowledge analysis of global health journals and definitions. BMJ global health. 2020 Oct 1;5(10):e002884. Wallin JA. Bibliometric methods: pitfalls and possibilities. Basic & clinical pharmacology & toxicology. 2005 Nov;97(5):261-75. Chen C, Song M. Visualizing a field of research: A methodology of systematic scientometric reviews. PloS one. 2019 Oct 31;14(10):e0223994. Sweileh, W. M. (2022). Bibliometric analysis of scientific research publications on COVID-19 vaccine hesitancy (2020–2021). Sweileh, W. M. (2020). Bibliometric analysis of global scientific literature on vaccine hesitancy in peer-reviewed journals (1990–2019). BMC public health, 20(1), 1-15. Song, P., & Wang, X. (2020). A bibliometric analysis of worldwide educational artificial intelligence research development in recent twenty years. Asia Pacific Education Review, 21(3), 473-486. Mooghali A, Alijani R, Karami N, Khasseh AA. Scientometric analysis of the scientometric literature. International Journal of Information Science and Management (IJISM). 2012 Jul 18;9(1):19-31. Ramy A, Floody J, Ragab MA, Arisha A. A scientometric analysis of Knowledge Management Research and Practice literature: 2003–2015. Knowledge Management Research & Practice. 2018 Jan 2;16(1):66-77. Chen C, Dubin R, Kim MC. Emerging trends and new developments in regenerative medicine: a scientometric update (2000–2014). Expert opinion on biological therapy. 2014 Sep 1;14(9):1295-317. Zhao X. A scientometric review of global BIM research: Analysis and visualization. Automation in Construction. 2017 Aug 1;80:37-47."
}
]
},
{
"id": "125794",
"date": "29 Mar 2022",
"name": "Ashley V. Hill",
"expertise": [
"Reviewer Expertise I am a reproductive epidemiologist and have published research examining social determinants of sexually transmitted infections",
"some which apply a syndemic framework."
],
"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 of the present article provided a robust review of the literature examining “Syndemics” in multiple areas of emphasis and with various health indicators and outcomes. This article attempts to provide an overview of syndemic named literature published in the past 20 years and highlights both the researchers, institutions, and countries within which this work is being conducted.\nAn understanding of the scope of syndemic work being conducted globally is helpful, however, the article lacks any examination of the statistical approaches used across the articles included and overlooks the relatively robust discourse in the literature on criticisms of commonly used analytical approaches to syndemic research. As mentioned by the previous reviewer, the article would be significantly strengthened by a discussion of Tsai and colleagues’ recommendations for analytical approaches and a true discussion of the types of additive or interactive evaluations in the studies listed.\nTsai, A. C., & Burns, B. F. (2015). Syndemics of psychosocial problems and HIV risk: A systematic review of empirical tests of the disease interaction concept. Social Science & Medicine, 139, 26-35.1 Stall, R., Coulter, R. W., Friedman, M. R., & Plankey, M. W. (2015). Commentary on “Syndemics of psychosocial problems and HIV risk: A systematic review of empirical tests of the disease interaction concept” by A. Tsai and B. Burns.2 Tsai, A. C., & Venkataramani, A. S. (2016). Syndemics and health disparities: a methodological note. AIDS and Behavior, 20(2), 423-430.3 Tsai, A. C. (2018). Syndemics: a theory in search of data or data in search of a theory?. Social Science & Medicine, 206, 117-122.4 Mendenhall, E., Newfield, T., & Tsai, A. C. (2021). Syndemic theory, methods, and data. Social science & medicine (1982).5\n\nThe inclusion of academic institutions, authors, and countries in the assessment is lacking recommendations. What are the authors hoping readers do with this information? How does it facilitate or foster collaboration? How would the authors recommend better support of syndemic research in low- and middle-income countries? At present, this information does not add additional value to the 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? 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": "9262",
"date": "02 Feb 2023",
"name": "Samia Tasnim",
"role": "Author Response",
"response": "Comment: The authors of the present article provided a robust review of the literature examining “Syndemics” in multiple areas of emphasis and with various health indicators and outcomes. This article attempts to provide an overview of syndemic named literature published in the past 20 years and highlights both the researchers, institutions, and countries within which this work is being conducted. An understanding of the scope of syndemic work being conducted globally is helpful, however, the article lacks any examination of the statistical approaches used across the articles included and overlooks the relatively robust discourse in the literature on criticisms of commonly used analytical approaches to syndemic research. As mentioned by the previous reviewer, the article would be significantly strengthened by a discussion of Tsai and colleagues’ recommendations for analytical approaches and a true discussion of the types of additive or interactive evaluations in the studies listed. Tsai, A. C., & Burns, B. F. (2015). Syndemics of psychosocial problems and HIV risk: A systematic review of empirical tests of the disease interaction concept. Social Science & Medicine, 139, 26-35.1 Stall, R., Coulter, R. W., Friedman, M. R., & Plankey, M. W. (2015). Commentary on “Syndemics of psychosocial problems and HIV risk: A systematic review of empirical tests of the disease interaction concept” by A. Tsai and B. Burns.2 Tsai, A. C., & Venkataramani, A. S. (2016). Syndemics and health disparities: a methodological note. AIDS and Behavior, 20(2), 423-430.3 Tsai, A. C. (2018). Syndemics: a theory in search of data or data in search of a theory?. Social Science & Medicine, 206, 117-122.4 Mendenhall, E., Newfield, T., & Tsai, A. C. (2021). Syndemic theory, methods, and data. Social science & medicine (1982).5 Response: The goal of a scientometric study is to examine the meta-knowledge development in a given topic in terms of research growth and trends and in this study we evaluated the scientific development of syndemics and related health and social issues. We have reviewed the methodology of the studies identified including the statistical approaches. Critical evaluation of the approaches was not possible as it was out of the scope of the present study. “It is also crucial to highlight the existing debate within the field of syndemics is the framing and the statistical approaches used to establish relationships between the diseases and outcomes. Considering the complex multilevel involvement of syndemics Tsai et al and colleagues believe that most empirical studies purporting to validate the theory lack in statistical robustness. Tsai identified that most studies in the field of syndemics demonstrate a statistically significant association between psychosocial problems and health outcomes using simple linear models, very few studies assess the how these psychosocial problems interact to magnify the outcomes as they only use summative approach for measuring the effect. Additionally, the summative approach is only successful to measure the changes when the effect sizes are small. Authors suggested to use the summative model using the count variable approach to conduct a latent factor analysis for confirming that a single parameter model is adequate. They emphasized on sharpening the theory’s prediction approaches by incorporating advanced systems level approaches. Stall argued in favor of the summative approach saying that majority of the existing data in this field comes from self-reported data from cross-sectional studies. Applying more rigorous data analysis method would require long-term cohort studies designed to establish the theory. However, considering the current nature of the fundings, implementing such resource intensive cohort study is not feasible. Due to the physical and psychological burden of these diseases (especially HIV) on highly vulnerable marginalized communities such as young gay black men or transgender women, the current approach is acceptable as it can demonstrate the dangerous existence of these co-morbidities highlighting the needs for prevention efforts from practitioners and policy makers.” Comment: The inclusion of academic institutions, authors, and countries in the assessment is lacking recommendations. What are the authors hoping readers do with this information? How does it facilitate or foster collaboration? How would the authors recommend better support of syndemic research in low- and middle-income countries? At present, this information does not add additional value to the study. Response: Thank you for your insightful comment regarding the recommendation about research institutions, authors, and countries. We have added additional recommendations based on our findings in the discussion in the revised manuscript. “It is critical to foster collaborative efforts among researchers across the globe to expand the ongoing research in thef1000 field of syndemics by including diverse perspectives. The present study has highlighted which institutions, mainly from high-income countries, have expertise in syndemics research. An ideal next step would be to focus on developing long-term collaboration by resource sharing and capacity building with scholars from LMICs to amplify their work. International public health organizations can establish global strategic planning groups that help fund collaborative work to address syndemics across nations. These groups could also concentrate on implementing multilevel strategies involving researchers, policymakers, health workers, and other key stakeholders to achieve a sustainable solution.”"
}
]
}
] | 1
|
https://f1000research.com/articles/11-253
|
https://f1000research.com/articles/10-1234/v1
|
03 Dec 21
|
{
"type": "Research Article",
"title": "Antioxidant effect of ethanolic extract of Pleurotus Ostreatus on 4-hydroxy-2-nonenal (HNE) and glutathione (GSH) level in lung rats exposed to cigarette smoke",
"authors": [
"Santun Bhekti Rahimah",
"Arto Yuwono Soeroto",
"Diah Dhianawaty Djunaedi",
"Tatang Bisri",
"Arto Yuwono Soeroto",
"Diah Dhianawaty Djunaedi",
"Tatang Bisri"
],
"abstract": "Background: Cigarette smoke can trigger oxidative stress. An alternative to overcome the harmful effects of cigarette smoke is through antioxidants. White oyster mushrooms (Pleurotus Ostreatus) are a source of exogenous antioxidants because many contain active compounds for potential antioxidants such as phenol and flavonoid compounds. The purpose of this study was to analyze the effect of ethanolic extract of Pleurotus ostreatus on 4-hydroxy-2-nonenal (HNE) and glutathione (GSH), as well as to analyze their correlation in the lung of Wistar male rats exposed to cigarette smoke. Methods: The study was a preclinical experiment conducted on 24 rats divided into four groups. The treatment was carried out for 42 days and antioxidant effects were assessed through levels of HNE and GSH in rat lungs. Groups were divided as follows: I- normal control, II- negative control, III and IV exposed to cigarette smoke for 60 minutes/day. Group III (treatment group) was treated with ethanolic extract of Pleurotus ostreatus at 250 mg/kg BW rat/day, and group IV (comparison group) was treated with N-acetyl cysteine 600 mg /day. Data analysis used was one-way ANOVA and Kruskal Wallis test, and Spearmen rank correlation coefficient test. Results: The results showed that the group receiving ethanolic extract of Pleurotus ostreatus had HNE levels of (44,18 ± 2,09 pg/mL) and GSH (0,04 ± 0,00 pg/mL) protein. This extract significantly increased GSH levels and inhibited the increase of HNE levels. Results of GSH (p≤0.01) showed significant results using one-way ANOVA. Conclusions: The ethanolic extract of P. ostreatus can prevent lipid peroxidation and decrease endogenous antioxidant levels in lung cells exposed to cigarette smoke. Ethanolic extract of Pleurotus ostreatus has good antioxidant potential.",
"keywords": [
"Antioxidants",
"cigarette smoke",
"ethanol extract",
"lung rats",
"Pleurotus ostreatus"
],
"content": "Introduction\n\nCigarette smoke is a mixture of more than 4,700 chemical components (nicotine, tar, benzene, carbon monoxide, etc.), reactive oxygen species (ROS), and a large source of free radicals that are divided into the gas phase and tar phase.1–3 Free radicals can cause oxidative stress, and cause damage to the important biomolecular (lipid, sugar, protein, DNA), membrane dysfunction, protein modifications, DNA damage, and enzyme inactivation. The effects of cigarette smoke on the body are influenced by many variables, including the dose and type of tobacco used, the route of administration, duration or duration of exposure, and other factors that may be present during stimulation. Inactive smokers and passive smokers, cigarette smoke causes a rapid dissolution of toxins in the mouth or respiratory epithelium and systematically.2,4–7 Acute and chronic exposure of cigarette smoke can result in tissue damage that can increase lipid peroxidation products and degradation products of extracellular matrix proteins, such as malondialdehyde (MDA), 8-isoprostane, hydrogen peroxide, and 4-Hydroxy-2-nonenal (HNE).2,8,9\n\nHNE is one of the cytotoxic lipid peroxidation end-product lipids from ω6 polyunsaturated fatty acids. Linoleic acid and arachidonic acid are potential precursors of HNE. 4-Hydroxy-2-nonenal can react with proteins and form HNE-adduct proteins with histidine, cysteine, and lysine. This complex can change the function of these proteins.6,8 Cigarette smoke can increase lipid peroxidation and HNE formation, which then activates mitogen-activated protein kinase (MAPK) and the release of TGFβ1 and induction of γGCS. This eventually causes inflammation because there is a redox imbalance.6,8\n\nOxidative stress can be inhibited by the body's defense system through antioxidants which can eliminate free radicals and minimize damage. Various enzymatic and non-enzymatic systems play a role in this process.10,11 Antioxidants can be defined as chemical molecules containing monohydroxy/polyhydroxy phenols and work by inhibiting lipid peroxidation.12–14 The appropriate antioxidants, both endogenous and exogenous antioxidants are important in the overall defense mechanism.9,15 Glutathione (GSH) is the primary antioxidant because it produces in the body and is important for the first defense mechanism to free radicals. It is also a secondary antioxidant with N-acetylcysteine (NAC) and flavonoids that act as radical scavenging to prevent the chain reaction of free radicals, play a role in various transcription factors, and detoxications. Cigarette smoke can make ineffectively of endogenous antioxidants and the body needs to supply exogenous antioxidants to maintenance the defense.9,15,16 Several studies have shown that smokers have lower levels of vitamins E, C, β carotene, and GSH in plasma compared to nonsmokers.2,10,17 Glutathione is abundant in the body and are found in Epithelial lining fluid (ELF) in high concentrations and serve to protect various oxidants that enter inhalation. GSH concentrations in ELF 10–100x higher than the levels in plasma. Exposure to chronic cigarette smoke can reduce GSH levels in ELF, plasma, and lungs after the GSH adaptive response period is exceeded.18–20\n\nPrevious studies have shown that supplementation with vitamins C and E is expected to reduce the harmful effects of cigarettes. The effectiveness of most antioxidants is generally seen in proportion to the number of hydroxyl (OH) groups present in the aromatic ring so that natural substances appear to have better antioxidant activity than synthetic antioxidants.10,16,21,22 One exogenous antioxidant that has been found in foods that have strong antioxidant effects is a white oyster mushroom (Pleurotus ostreatus)7,12,23\n\nP. ostreatus are nutritious, high in fiber, and contain many vitamins and minerals.10,24–26 This oyster mushroom has strong antioxidant activity due to secondary metabolite compounds contained in it. Components in white oyster mushrooms that are believed to have antioxidant effects include vitamin C, beta-carotene, selenium, ergothioneine, and phenolic components for the primary component. Phenolic antioxidant activity is mainly due to its ability as a hydrogen donor reducing agent and oxygen quencher singlet and has a potential metal chelation effect.7,12,27 Phenolic antioxidant derivatives will also induce GSH enzyme synthesis in human alveolar epithelial cells.12,21,24 P. ostreatus as a whole when compared with winter and shitake mushrooms have antioxidant activity, reducing power, scavenging abilities, and higher total phenol content.7,10,23,28 Previous studies have shown that P. ostreatus extract has a protective effect on the liver, kidneys, and brain.7,29 Other studies have shown that ethanol extract of white oyster mushrooms has the effect of preventing an increase in MDA11 levels and a decrease in lung density in rats induced by cigarette smoke.16,24,28,30 In this study, we assess the antioxidant effect of P. ostreatus, their influence in preventing a decrease in GSH levels and preventing an increase in HNE levels, and their correlation in Wistar rat lung cells that are exposed to cigarette smoke.\n\n\nMethods\n\nThe laboratory experimental study was conducted in vivo using Wistar strain male rats. The study design used was a randomized block design. This study is reported in line with the Animal Research: Reporting of in vivo Experiments (ARRIVE) guidelines.49\n\nThis study uses male Wistar strain rats that were selected based on the inclusion criteria and exclusion criteria that have been set. Inclusion criteria were animals of 8-12 weeks of age and a weight of 200-250 grams at the beginning of the treatment. Exclusion criteria were rats that showed behavioral changes during the adaptation period and had weight loss >10% during the adaptation period. Some animals were dropouts if they died during the research treatment period.\n\nRats were randomly selected for each group and the number of samples was determined based on the Power Analysis formula, using G * Power 3.1.9.2 software. The sample size required for this study is a minimum of 20 experimental animals and considering the possibility of dropout (DO), the total number of experimental animals in this study will be 24.31\n\nThe variables used in this study consisted of three groups of variables, namely: independent variables (ethanol extract of white oyster mushrooms, exposure to cigarette smoke); dependent variables (HNE level, GSH level); and controlled variables (rat strain, sex, weight, age, food and drink).\n\nThe equipment used in this study were: a smoking pump/tobacco smoke discharger (designed for this research, more information below), HNE Elisa Kit Assay (Abbexa) 83, Reduced Glutathione (GSH) Assay Kit (Colorimetric) (K464-100) 84, tissue homogenizer, multichannel micropipette reservoirs; Multiscan GO Reader (Thermo Scientific 1510).\n\nA tobacco smoke discharger (Figure 1) is a device that functions as a means of sucking cigarette smoke and flowing it into the test room (smoking room) with a certain flow speed. This tool utilizes electric power which is then converted into mechanical energy so as to produce a pressure difference sufficient for the suction and flow of cigarette smoke. The use of this tool is for research purposes because this tool helps to simulate a test room containing cigarette smoke with a certain intensity and its impact on test animals is investigated. The advantage of using this tool is the achievement of steady and measurable smoke flow stability so as to produce valid research data.\n\nDetermination of white oyster mushrooms was carried out at the Sekolah Tinggi Ilmu Hayati (STIH) Institut Teknologi Bandung (ITB), aimed at ensuring macroscopic identification of white oyster mushrooms based on size, shape, color, surface characteristics, and texture of natural materials.\n\nPlant material was derived from fresh white oyster mushrooms taken from Panandaan oyster mushroom cultivation, Jambudipa Village, Cisarua District, West Bandung Regency. Fresh mushrooms were washed, drained, thinly torn with a thickness of 1-2 cm, then put in an oven with temperature of 50oC for 5-6 days. The dried mushroom was mashed and then put into the macerator and macerated by ethanol 96% in a ratio of 1:10. This mixture was macerated for 24 hours with occasional stirring and then filtered. Maceration was repeated 3 times. The aqueous extract was then concentrated using a rotary evaporator and heated in a water bath.32 The concentrated extract is in the form of a paste.\n\nBased on empirical data and previous research on white oyster mushrooms, this study used a dose of 250 mg/kg BW.7,10 The comparison group was given the drug N-acetyl-cysteine (NAC) which is a precursor of GSH and acts as a free radical scavenger. The dose of NAC used in chronic obstructive pulmonary disease (COPD) cases is 600 mg once a day.33 The dose was converted to the Paget & Barnes (1964) conversion table for rats.\n\nA tobacco smoke discharger can smoke 2 cigarettes in an average time of 6 minutes 30 seconds and the time needed to refill cigarettes and restart combustion is about 30 seconds. In this study, each group received exposure to cigarette smoke for 60 minutes/day or the equivalent with eight cigarettes/group/day with a time lag of about 5 minutes for burning two cigarettes. The cigarettes given were clove cigarettes with a tar content of 38 mg.\n\nMeasurement of HNE levels of protein adducts was taken using 4-HNE ELISA Assay Kit as per manufacturer’s instructions, a competitive enzyme-linked immunosorbent assay technology developed for quantitative rapid examination. Samples were taken from rat lung tissue, washed with phosphate buffer then homogenized and centrifuged at 1,000 rpm for 20 minutes at 4 ° C. The supernatant from the centrifugation result was then used for 4-HNE examination, compared with standard of 4-HNE.34\n\nMeasurement of glutathione (GSH) levels in lung cells was done using BioVision’s Reduced Glutathione Kit as per manufacturer’s instructions. Samples were taken from tissue homogenates from lung cells. This tool uses the principle of colorimetric reaction, by measuring the quantification of GSH levels from the absorbance of chromophore reduction formed at a wavelength of 450 nm. This tool can detect GSH at a minimum level of 50 pmol/well GSH in a 100 μL reaction. In this study samples were taken from rat lung tissue and homogenized by centrifuged at 10,000 rpm for 20 minutes at 4° C. The centrifugation supernatant is used for glutathione examination.35\n\nRats were adapted to a laboratory atmosphere for 7 days. During the adaptation period, the experimental animals were kept in comfortable cages, one group/cage, with a large enough cage size (60x45x35 cm) so that the animals could move actively, with sufficient lighting in the room where the rat cage is stored, and low humidity. The animals in this study were given the type of food and food calories that were adjusted to their needs. Drinking water was provided in the cage and given ad libitum. The rats were randomized with a completely randomized design (CRD) into 4 groups each consisting of 6 rats and given different treatments: Group I: Negative control group (rats were given standard food and drink for 42 days, were not exposed to cigarette smoke and did not get ethanolic extract of P. ostreatus ), Group II: positive control group (rats given cigarette smoke exposure for 60 minutes/day for 42 days using a smoking pump in the smoking chamber. Cigarettes were kretek brand. Without the administration of ethanolic extract of Pleurotus ostreatus, only given carrier fluid 3 cc/rat/day). Group III: treatment group (rats were given cigarette smoke exposure for 60 minutes/day in 42 days and were given ethanolic extract of Pleurotus ostreatus dose 250 mg/kg BW orally), group IV: comparison group rats were given cigarette smoke exposure for 60 minutes/day in 42 days and given N-acetyl-cistein (NAC) dose 10.8 mg/day orally. On the 43rd day, rats were taken for lung tissue to be examined for levels of HNE and glutathione in rat lung tissue.\n\nThe rats were previously anesthetized using ketamine and the rat lung tissue was surgically removed. The rat was supine, then the ventral part of the thoracic cavity was opened using surgical instruments and the lungs were removed using a scalpel. After that, the rats were euthanized by deep anesthesia or increasing the anesthetic dose until the animals died. The carcasses of the rats were exterminated using incinerator.\n\nDuring the research, experts or laboratory assistants supervised the experimental animal research process from the adaptation process of the experimental animals to execution. Sampling and analysis of the results are carried out by the research team.\n\nData analysis with Shapiro-Wilk for normal data and Bartlett's test for equal variances was done. After that Kruskal Wallis test was used for HNE and the analysis of variance (ANOVA) for GSH, followed by post hoc Bonferroni test. A 95% confidence level (P < 0.05) was considered significant. A Spearman’s rank test was also done to test the correlation between the GSH and HNE parameters. SPPS v 20.0 was used to analyze data of 4-HNE and GSH, and Stata MP 16 was used for testing the correlation among the two variables.\n\nThis research applies the ethical principles of research in general: Respect, Benefit, and Justice and the principle of using experimental animals, namely 3R: replacement, reduction, and refinement. This research got ethical approval from The Health research ethics committee of Faculty medicine of Padjadjaran University No: 210/UN6.C10/PN/2017, in accordance with \"Principles of Laboratory Animal Care\" (NIH publication no. 85-23, revised 1985). All efforts were made to ameliorate harm to the animals by following appropriate procedures for animal experiments.\n\nThe experimental study was conducted at the Faculty of Pharmacy, Universitas Islam Bandung, and Aretha Medika Main Biomolecular Research Center from January 2018 to January 2019.\n\n\nResults\n\nOn macroscopic examination of the lungs, it was seen that the rat lung tissue was pink and did not show any significant color differences in each group. With a smooth lung surface, there were no lumps or nodules visible or palpable.\n\nTable 1 shows that the group with the highest average HNE value was group 2 with HNE levels of 47.70 ± 5.35 pg/mol, while the group with the lowest HNE was group 1 with HNE 40 values, 40 ± 1.93 pg/mol.49 HNE levels in group 3 and group 4 were higher than group 1, but lower than group 2. Group 3 had a lower HNE value than group 4.\n\nGroup 1: normal control group (normal feed, without treatment); Group 2: negative control group (normal feed, cigarette smoke 60 minutes/day); Group 3: treatment group (normal feed, ethanol extract of Pleurotus ostreatus 250 mg/kg BW, exposure to cigarette smoke 60 minutes/day); Group 4: comparison group (normal feed, NAC, cigarette smoke exposure 60 minutes/day); SD: standard deviation; 4-HNE: 4-hydroxy-2-nonenal; GSH: glutathione.\n\nTable 2 shows the K-Wallis test outcome of HNE data with a value of P=0.03 which means that there is a significant difference in the mean HNE between the test groups. In this study, it may be concluded that cigarette smoke caused a significant increase in HNE levels compared to normal controls and ethanolic extract of Pleurotus ostreatus signicantly reduced the level.\n\n4-HNE: 4-hydroxy-2-nonenal; GSH: glutathione; P (F) *: significant <0.05; P (Bartlett) *: significant> 0.05; P (K-Wallis) *: significant <0.05; P (correlation) *: significant <0.05; rs (correlation coefficient): significant> 0.00.\n\nThe ANOVA test P-value for GSH is 0.00 (p≤ 0.05). There is a significant difference in the mean GSH between groups, with Bartlett's P-value greater than 0.05 so that the post-hoc Bonferroni test can be used seeing the difference in mean GSH between groups. Significant mean differences were found in almost all groups, except for differences between groups 3 and 4 (Table 3).\n\nIn this study, cigarette smoke was shown to significantly reduce GSH compared to normal controls, and ethanol extract of white oyster mushroom significantly increased GSH levels in the lung of rats exposed to cigarette smoke. The effect of the ethanolic extract of Pleurotus ostreatus in experimental animals was as good as the effect of NAC. The GSH and HNE parameters were then tested for correlation using Spearman’s rank analysis. The results show the value of P = 0.78 and rs = 0.06 so it can be concluded that there is no correlation between GSH and HNE.\n\n\nDiscussion\n\nIn this study, exposure to kretek cigarette smoke in rats for six weeks was expected to cause significant oxidative stress in rats.4,36 Free radicals in cigarette smoke can cause membrane damage through lipid peroxidation, which will cause a cascade of further oxidative damage, increase cell membrane rigidity, osmotic fragility, decrease the life span of erythrocytes, and disrupt lipid fluidity.7\n\nLipid peroxidation will produce secondary metabolites from peroxidation products such as malondialdehyde (MDA) and HNE.7,8 Secondary product levels of lipid peroxidation are thought to have a correlation with the degree of obstrucibility of the respiratory tract in COPD patients.37 Membrane damage or lipid peroxidase also can cause changes in phospholipase to arachidonic acid which can further increase HNE and induce the release of inflammatory mediators such as prostaglanding and leukotrienes. This can cause the respiratory tract to become more vulnerable to inflammation and develop cell proliferation changes and cause airway obstruction.37,38\n\n4-Hydroxy nonenal is a specific metabolite which is very toxic, reactive and has high diffusion ability. It also has an important role as a signaling molecule for cell differentiation, proliferation, regulation of the cell cycle and regulation and expression of various stress-response genes. The concentration of HNE in cells can be used for the determination of signaling for apoptosis, differentiation, or proliferation.8,39 In this study the high HNE in rats exposed to cigarette smoke indicates that lipid membrane damage has occurred and poses a risk for further damage and can initiate a heavier process. Increased 4-HNE adducts have a good correlation with pulmonary function measurement through FEV1. This reinforces the suspicion that 4-HNE has an important role in the pathogenesis of COPD.40,41\n\nThe ethanolic extract of P. ostreatus at a dose of 250 mg/kg body weight in this study showed a preventive ability or could inhibit the increase in HNE levels in rats exposed to cigarette smoke exposure, so it can be concluded that this extract can inhibit pulmonary lipid peroxidation due to free radicals from cigarette smoke.\n\nThe mechanism of P. ostreatus ethanol extract in inhibiting the increase in HNE can be caused by several mechanisms, mainly because the hydroxyl group in the ethanol extract of white oyster mushroom can function as an excellent hydrogen donor so as to prevent membrane damage due to free radicals. Another possibility is to increase the synthesis of endogenous antioxidants such as glutathione, so that further damage from oxidative stress can be prevented.\n\nThese results are reinforced by in vitro data in previous studies, which showed the potential antioxidant activity of ethanolic extracts of white oyster mushrooms. In vitro, the ethanolic extract of white oyster mushroom with a concentration of 10 mg/mL has an effectiveness of 56.20% in inhibiting lipid peroxidation (LPO) activity, while ascorbic acid as a standard can inhibit 67.15%. The 50% inhibitory concentration for lipid peroxidation activity for extracts and ascorbic acid was 8 and 6 mg/mL.7,28 The water-soluble P. ostreatus polysaccharide extract on Caco-2 cells showed inhibition of lipid peroxidation with MDA markers with fluctuating results for three days, the first day showed a decrease in MDA, but the third day the effect of the inhibition disappeared. This is thought to be correlated with GSH levels whose results are the opposite of MDA levels, on the same day.42\n\nIn vitro test of ethanol extract P. ostreatus has a potent reducing power and this effect increases with increasing extract concentration. The reduction ability at 10 mg/mL is 1.367, which is better than BHT (1,192).23 In previous studies, ethanol extract of P. ostreatus in vivo was proven to be able to prevent increased levels of malondiadehyde (MDA) in the liver, kidney and brain in mice given CCl4 as hepatotoxic.23 The above studies confirm the hypothesis that ethanol extract of P. ostreatus can prevent lipid peroxidation.\n\nAntioxidant agents can inhibit the process of lipid peroxidation.11 One of the most abundant endogenous antioxidant in the body is GSH.21,36 In this study rats exposed to cigarette smoke showed a significant reduction in GSH compared to normal rat. The imbalance of oxidants and antioxidants in the body will cause oxidative stress.43,44\n\nGSH levels in the body depend on a balance between the synthesis process and the metabolic process of GSH which causes GSH to be inactive. Synthesis of de novo GSH is influenced by yGLCL and GLS and is influenced by GPx and glutathione reductase (GR) in the process of reducing GSH to GSSG. The highest GSH synthesis is in the liver, which is the place of primary synthesis, so that if there is a decrease in other organs there should also be a fairly extreme decrease before the liver. Oxidative stress that occurs in cells will cause GSH to reduce H2O2 and change into the reduced form of GSSG that accumulates in cells or can also form sulfhydryl form proteins that form a mixed disulfide or released from the cell. So far the GSH:GSSH ratio is one of the best indicators for assessing oxidative stress conditions in cells.18,45,46 The body's defense system or endogenous antioxidants are not fully able to fight free radicals in the body, so exogenous antioxidant supplements are needed.10\n\nExogenous antioxidants can be synthetic antioxidants or antioxidants derived from natural ingredients such as medicinal plants. The most commonly used synthetic antioxidants are butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate and tert-butylhydroquinone. However, the use of BHA and BHT is very limited because it is suspected to be carcinogenic and cause liver damage. So now it is still very necessary to develop antioxidants that are sourced from natural sources.7 P. ostreatus are medicinal plants that have high antioxidant potential and, in this study, increased GSH levels in male rats exposed to cigarette smoke. The effect given is significant, and the result is the same as the effect arising from the administration of GSH precursors, namely NAC.\n\nThe mechanism by which ethanol extract of P. ostreatus enhances the synthesis of GSH is suspected to be through several mechanisms as follows: 1) increasing the expression of enzymes yGLCL and GLS which play an important role in the synthesis of glutathione in the body; 2) increasing cysteine residues in the body, which is one of the glutathione amino acids, this mechanism is almost the same as the mechanism of action of NAC; 3) P. ostreatus contain selenium which is considered as one of the precursors of glutathione with a mechanism that cannot be clearly explained.7,24,26,45 All three of the above mechanisms as a whole cause ethanol extracts of P. ostreatus to increase levels of glutathione in the body.\n\nIn this study the antioxidant ability of ethanolic extracts of P. ostreatus compared was with N-acetylcysteine (NAC). N-acetylcysteine is also an antioxidant that contains thiol which is also a precursor of GSH. N-acetylcysteine increases GSH synthesis and maintains a balance of GSH levels in cells. This antioxidant can prevent liver damage due to high doses of paracetamol in humans and prevent liver damage and GSH depletion in mice. NAC antioxidants are widely used in COPD cases. The thiol group in NAC can reduce free radicals and has functioned as a chelating agent which is very useful in the case of heavy metal poisoning. N-acetyl cysteine can also penetrate cell membranes, so that its level are high intracellular.34,47\n\nIn this study, the potency of the ethanolic extract of P. ostreatus at a dose of 250 mg/kg BW in preventing the decrease in GSH levels in rats exposed to cigarette smoke was as good as the potency of NAC.\n\nPrevious studies have shown that intraperitoneal administration of P. ostreatus extract at a dose of 200 mg/kg body weight in old rats can increase levels of enzymatic antioxidants such as CAT, SOD, Gpx, GST and GR in liver, kidney and brain organs.7 In other studies, the administration of ethanolic extracts of P. ostreatus with the same dosage and administration method has been found to inhibit lipid peroxidation and increase enzymatic antioxidants such as CAT, SOD, Gpx, GST. The ethanolic extract also can increase non-enzymatic antioxidants (GSH, vitamins C and E) in CCl4-induced rat liver, kidney and brain tissue.7,23\n\nThe antioxidant potential of P. ostreatus is supported by the content of secondary metabolites contained therein. The results of phytochemical tests previously showed that white oyster mushrooms contain many alkaloids, steroids, flavonoids, tannins, saponins and phenolic components. Previous research also showed that P. ostreatus can contain about 100 different bioactive components. This fungal cell wall contains many non-starch polysaccharides, where β-glucans are the most attractive components, and contain phenolic components such as protocatechuic acid, gallic acid, homogentisic acid, rutin, mirisetin, chrysin, naringin, tocopherol like α-tocopherol, γ-tocopherol, ascorbic acid and β-carotenoids.12,30\n\nOther research also states that the ethanol extract of P. ostreatus contains many polyphenols or phenolic components in which there are many flavonoids such as routine, also contain β-carotenoids, vitamin A and C, and selenium. In this study, the results of testing of compound markers using HPLC showed that the ethanol extract of P. ostreatus used in the study contained rutin (flavonoids) and cinnamic acid (phenolic acid).12,47\n\nThe ethanolic extract of P. ostreatus in vitro has antioxidant power that can trap hydroxyl radicals and superoxide, inhibit lipid peroxidation, reduce ferric ions, chelating ferrous ions and quenching 2,3-diazabicyclo[2,2,2]oct-2-ene (ene DBO). This extract also shows good antioxidant activity in vivo by reducing lipid peroxidation and increasing enzymatic and non-enzymatic antioxidant activity.24,28\n\nOther studies mention that water soluble crude polysaccharide from P. ostreatus shows the superior ability of free radical scavenging and NOS, due to the alleged role of the P. ostreatus β-glucan antioxidant potential. This means that P. ostreatus can be a herb that can be developed into a good natural antioxidant.48 Some of the above studies are strongly related to the mechanism of aging, whereas studies to see the effect of ethanol extracts of white oyster mushrooms on endogenous antioxidant levels in rat models with COPD have not been examined. This is why this research can pave the way to develop the use of natural antioxidants in COPD cases. Provision of antioxidants and anti-inflammatory drugs alone in COPD patients can be used based on several conditions that need to be considered. Currently exogenous antioxidants are often used in COPD patients among mucolytic antioxidants such as erdostein, carbocystein and NAC.34,46\n\nCigarette smoke is known to reduce levels of total glutathione (GSH + GSSG) in the respiratory tract. Glutathione is widely known to be present in ELFs and airway epithelium. Glutathione plays an important role in cellular redox balance and is considered to be the most important antioxidant against inhalable reactive components. The mechanism underlying the total glutathione depletion is presumably because there is a part of the cigarette smoke phase which will react irreversibly with GSH to form a non-reduced GSH derivative (GSX), thereby causing GSH depletion. Under normal conditions, intracellular GSH will generally be stored in a reduced form, but the imbalance between GSH and oxidized gluthatione (GSSG) will change under conditions of oxidative stress, and the ratio between GSH and GSSG will illustrate how intracellular cells condition. In vitro and in vivo studies state that under oxidative stress conditions the free sulfhydryl (-SH) group of GSH will become oxidized, and exposure to the cigarette smoke phase in vitro and in vivo will generally reduce GSH but the amount of GSSG does not increase significantly. Another study concluded that cigarette smoke does not cause GSH oxidation to GSSG, but rather causes a reaction so that it forms glutathione-aldehyde derivates or non-reduced GSH derivatives (GSX), which in turn will reduce total GSH. This will cause chronic antioxidant deficiency. Chronic smokers will continue to be exposed to free radicals and with the decrease in GSH the negative effects of these free radicals will be even higher. This condition causes GSH synthesis which is essential for cell defense and lung protection. Depletion of GSH Intracellular depletion will significantly trigger oxidative stress and stimulate signal transduction pathways, cell proliferation, apoptosis and inflammation.41\n\n4-Hydroxy nonenal is a toxic molecule and can further increase the level of ROS in cells through the mechanism of mitochondrial dysfunction 4-Hydroxy-2-nonenal, because mitochondria are organelles that are susceptible to HNE. This condition will further increase the inflammatory response that will occur.8 One of the mechanisms for detoxifying HNE from cells is by forming conjugations with GSH (glutathione-4-hydroxynonenal/GSHNE) to then be taken out of the cell. This conjugation process is catalyzed by glutathione-S-transferases (GSTs), which play an important role in regulating HNE levels in cells. There are two groups of proteins involved in transporting foreign species from within cells: namely ATP-binding cassette (ABC) transporters and non-ABC transporters. ABC transporters, including P-glycoprotein (Pgp) and multidrug resistance-associated protein (e.g., MRP1). Various xenobiotics and natural metabolites such as GSHNE will be transported past MRP1. Non-ABC transporters involved in transporting toxins, some drugs and antineoplastic agents and various glutathione conjugations are Ral-binding protein 1 (RalBP1), also known as RLIP76. This protein is abundant in various body tissues and is bound to cell membranes.39\n\nThis reinforces the hypothesis that GSH will affect HNE levels in the network, because high GSH will cause HNE to decrease because it forms GSHNE. The data in this study also show that the levels of GSH and HNE for each group are contradictory, if the GSH rises then the HNE will decrease, but the statistical analysis states that the data obtained is not significant enough to reinforce that there is a correlation between GSH levels and HNE levels in the lung of rats exposed to cigarette smoke. Insignificant results between GSH and HNE correlations can also be due to the limited number of samples, so the results cannot be applied to the population.\n\nOne important factor that can break the cascade of cigarette smoke inflammatory processes early is antioxidants. Glutathione is an endogenous antioxidant found in many cells including lung cells and ELF. During the synthesis and use of glutathione in a balanced body, no further damage is expected, but high consumption of glutathione can cause levels to decrease in the body. In this condition exogenous antioxidant supplements are needed which can help the work of endogenous antioxidants such as GSH. P. ostreatus are expected to optimize the body's endogenous antioxidants. Ethanol extract of P. ostreatus is expected to increase the synthesis of GSH in the body and help the body's defense of antioxidants through the mechanism of hydrogen donors from its hydroxyl groups. This plant can be developed into a potential source of antioxidants as well as a potential anti-inflammatory.\n\n\nConclusions\n\nEthanol extract of P. ostreatus inhibits the increase in levels of HNE and increases level of GSH in the lungs of male Wistar strain rats exposed to cigarette smoke exposure. There is no correlation between GSH levels and HNE in male Wistar strain rats exposed to cigarette smoke.\n\n\nData availability\n\nFigshare: 4-HNE And GSH Lung rats exposed to cigarrete smoke.\n\nhttps://doi.org/10.6084/m9.figshare.16550964.49\n\nThis project contains the following underlying data:\n\n- Report of Data Analysis of GSH level at lung rats that exsposed cigarrete smoke.xls\n\n- Report of Data Analysis of 4-HNE level at the lung rat that exsposed cigarrete smoke.xls\n\nFigshare: ARRIVE guidelines for ‘Antioxidant effect of ethanolic extract of Pleurotus Ostreatus on 4-hydroxy-2-nonenal (HNE) and glutathione (GSH) level in lung rats exposed to cigarette smoke’. https://doi.org/10.6084/m9.figshare.16550964.49\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
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}
|
[
{
"id": "119854",
"date": "14 Jan 2022",
"name": "Ali Akbar Nekooeian",
"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 manuscript has examined the effects of ethanolic extract of Pleurotus Ostreatus on 4-hydroxy-2-nonenal (HNE) and glutathione (GSH) levels in lung rats exposed to cigarette smoke. Although the manuscript has an interesting message for the readers, however, it is not appropriately written and is in need of revision.\n\nMaterials and methods The components of this section are usually written based on chronology. This needs to be followed in this manuscript. What test was used after Kruskal Wallis for multiple comparisons? The data presentation form has not been mentioned in the statistical analysis section.\nResults Tables 2 and 3 are outputs of statistical software used to analyze the data. They have to be deleted. Presenting correlation coefficient and P values in the text does the job.\nDiscussion The discussion is too long. The manuscript does have results on two items. This indicates a short discussion. The discussion should include part of the changes in HNE and GSH by smoke and the effects of the extract on these variables. In the present form, the discussion is somehow chaotic and needs to be 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? 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": "9278",
"date": "15 May 2023",
"name": "Santun Bhekti Rahimah",
"role": "Author Response",
"response": "Thank you for the review of the article of ethanolic extract of Pleurotus Ostreatus on 4-hydroxy-2-nonenal (HNE) and glutathione (GSH) levels in lung rats exposed to cigarette smoke. I will tried make the revision for the article based on your feedback. Materials and methods; The components of this section will be written based on chronology, and make it clear for the analysis test that used This needs to be followed in this manuscript. At this article, we used Kruskal Wallis test for HNE and ANOVA for GSH. Because HNE analysis using nonparametric test the data did not followed by post hoc Bonferroni test. The test for correlation between GSH and HNE using A Spearman’s rank test. Results Tables 2 and 3 will be deleted and presenting correlation coefficient and P values will be menin the text does the job. Discussion We tried to make a short discussion for the article and include part of the changes in HNE and GSH by smoke and the effects of the extract on these variables."
}
]
},
{
"id": "123370",
"date": "15 Feb 2022",
"name": "Arumugam Vijaya Anand",
"expertise": [
"Reviewer Expertise Phytotherapeutics",
"Clinical Biochemistry",
"Medical 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\nThe authors have put effort to evaluate the “Antioxidant effect of ethanolic extract of Pleurotus Ostreatus on 4-hydroxy-2-nonenal (HNE) and glutathione (GSH) level in lung rats exposed to cigarette smoke”. The authors describe the research undertaken with this in an organized manner, emphasizing the results obtained by them. The article needs modification for better cohesion of information to achieve the goal and the minor shortcomings which need to be considered. Hence, the paper can be accepted after MINOR REVISIONS are carried out:\nThere are some grammatical, alignment and typographical errors are noted in the manuscript and it should be thoroughly checked and corrected throughout the manuscript. For example, the words “and systematically” maybe as “systematically”; “to maintenance the” as “to maintain the”; “are found” as “is found”; “ELF 10-100x” as “ELF are 10-100x”; “with temperature” as “with a temperature”; “this study” as “this study,”; “incinerator” as “an incinerator”; “signicantly” as “significantly”; “increasedGSH” as “increased GSH”; “prostaglanding” as “prostaglandins”; “but the third” as “but on the third”; “malondiadehyde” as “malondialdehyde”; “normal rat.” as “normal rats”; “level are” as “level is”; “vitaminAand” as “vitamin A and”; “water soluble” as “water-soluble”; “Currently” as “Currently,”; “andHNElevels” as “and HNE levels”; “condition exogenous” as “condition, exogenous”; “increases level” as “increases the level”.\n\nCheck the abbreviations throughout the manuscript and introduce the abbreviation when the full word appears the first time in the text and then use only the abbreviation (For example, malondialdehyde (MDA), TGFβ1, γGCS, glutathione (GSH), etc.,). And it should be in both abstract as well as in the remaining part of the manuscript. Make a word abbreviated in the article that is repeated at least three times in the text, not all words need to be abbreviated.\n\nThe full form of the species should be given when the first time appears and followed by only the first letter of the genus in both the abstract and the remaining part of the manuscript (For example, Pleurotus ostreatus when the first time appears and followed by P. ostreatus). And the name should be italic all over the manuscript and the species name should start with lower case (small letter).\n\nWhen referring to SPSS versions beginning from 19, authors should cite ‘IBM SPSS Statistics for Windows, version 20 (IBM Corp., Armonk, N.Y., USA)'. Similarly should be for Stata MP 16 also.\n\nThe authors should properly mention the subscript and superscript (For example, in “CCl4”, 4 should be subscripted) and it should be checked throughout the manuscript, wherever applicable.\n\nThe authors may justify how the dose is optimized for the present investigation either in the materials and methods or any part of the results or discussion (either based on available literature or previous study). If from the others study should be supported with reference.\n\nThe conclusion seems simple, hence, it is highly recommended to include weaknesses or limitations of the study and potential future research goals.\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": "9279",
"date": "15 May 2023",
"name": "Santun Bhekti Rahimah",
"role": "Author Response",
"response": "Thank you for the feedback, we will tried to make a revision for the article: We will check again the grammatical, alignment and typographical errors that find in the manuscript and corrected. The abbreviations throughout the manuscript will be check again and revise based on your suggestion. For the species will be completed name for the first time appears and followed by only the first letter of the genus in both the abstract and the remaining part of the manuscript (For example, and the name will be italic all over the manuscript. The citations will be added for referring to SPSS and stata. We will check again the subscript and superscript throughout the manuscript, wherever applicable. The article will added some information about how the dose is optimized for the present investigation. We will added about weaknesses or limitations of the study."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1234
|
https://f1000research.com/articles/11-467/v1
|
27 Apr 22
|
{
"type": "Research Article",
"title": "Factors affecting access to health services by older adults in an urban community in Thailand: a cross-sectional study",
"authors": [
"Areeya Jirathananuwat"
],
"abstract": "Background: The impending rapid change in Thailand’s older population has many important implications for health policy, especially older adults’ health problems, which are major cause of them accessing health services. This study aimed to study factors affecting access to health services for older adults in urban communities in Thailand, as well as performing a situational survey of health service utilization. Methods: This cross-sectional study included 886 older adults from four types of urban communities (slum, city, suburban, and community building). Data were collected using an interview questionnaire. Information about health service variables were extracted and followed the five dimensions of accessibility by Penchansky & Thomas: availability, accessibility, accommodation, affordability and acceptability. Data were analyzed using percentage mean and standard deviation (SD). Analysis of factors affecting access to health service was performed using Logistic regression. Results: The utilization of health services was high among five dimensions. They were composed of availability (mean 4.2, SD.=0.59), accessibility (mean 4.1, SD.=0.69), accommodation (mean 3.9, SD.=0.67), affordability (mean 4.2, SD.= 0.62), and acceptability (mean 4.1, SD.=0.62). A summary of all dimensions revealed a mean of 4.1 (SD.= 0.52). Factors affecting older adults access to health services were using health insurance rights for health care service, and concern about the necessity of health care. Conclusions: Encouraging older adults to change their health insurance rights to the nearest hospital and promoting the provision of holistic health information, which will support older adults in accessing more health services to improve their health outcomes.",
"keywords": [
"Access to health service",
"Elderly",
"Urban areas"
],
"content": "Introduction\n\nAn older adult is defined by the United Nations as a person who is over 60 years of age. In 2017, the world had a population of 7.550 million people. Approximately 12.7% were older adults, meaning that our world has become an ‘aging society’. In 2017, older adults made up 17.1% of Thailand’s population,1,2 and this expected to increase to 25.2% by 20303 and 30% by 2035.2 This changing population has a direct impact on public health policy and countries due older adults having different physical, mental, emotional, and social health issues to other demographics. The most common issues are related to economic, social and health issues, especially chronic health issues that require dependency from other people.\n\nDue to chronic illnesses of older adults, health policies need to ensure that health services cover patient treatment and prevention of health issues, as well as providing a well-prepared health service system.4 The World Health Organization5 has suggested three concepts (factors of health, participation and security factors) to ensure that people will be covered by health services regardless of income, ethnicity gender and age. Their access to health services depends on financial factors, sufficient service and the organization of the health service. In 2002, Thailand’s government has implemented medical insurance rights6 with the goal of giving people access to health care services. However, medical insurance rights do not ensure that Thai people will have access to health services completely. Other related factors must be considered, such as socioeconomic factors, distance from habitation to service facilities, travel expenses, and presence of reliable caretakers.7\n\nIn 2013, Thailand’s urban population was 53.6% of the total population, with an increasing trend. Previous research has shown that people in the urban areas have limited access to health services.8 Good health service system management is significant to older adults in allowing them to access the service thoroughly. Therefore, the Ministry of Public Health’s primary objective is to ensure that people have access to health services when they need them. Previous studies in Thailand have shown that older adults have access to health services using health insurance rights through the Government (44%), the Universal Coverage Scheme (24%), or the Social Security Scheme (3%). It was also reported that use of health services was different dependent on the health insurance rights used and geographical region.9 Access to health services can be assessed by five dimensions: availability, accessibility, accommodation, affordability, and acceptability.10 However, an individual's access to and use of health services is considered to be a function of three characteristics as defined by Aday & Anderson11: a) Predisposing Factors; b) Enabling Factors; and c) Need Factors. This study aimed to study the factors affecting access to health services for older adults in urban communities, as well as to perform a situation survey of health service utilization.\n\n\nMethods\n\nThis cross-sectional study was conducted among older adults from four types of urban communities (slum, city, suburban, and community building). A purposive sampling method was used to select communities. A stratified random sampling technique was used to ensure proportional numbers of sample from slum, city, suburban, and community building urban types. Given a type I error of 0.05 and 80% power, the sample size was estimated to be 1,086.\n\nParticipants in this study were older adults who responded to the survey from September to December 2018. The inclusion criteria were a) aged >60 years; b) agree to participate in research. Those unwilling to participate or did not provide consent were excluded. Convenience sampling was used to select the participants. The setting was in Bangkok, Thailand. The numbers of participants from communities of slum, city, suburban, and community building who lived in communities were 430, 432, 108, and 116 respectively. In order to contact the participants, local community leaders and community health volunteers publicly announced the project and recruited participants in the community. Data collection took place in the community’s common space.\n\nData were collected using an interview questionnaire – questions were read to the participants by the researcher, and the participants responded verbally. The questionnaire was based on the five dimension of accessibility developed by Penchansky & Thomas10 (availability; accessibility; accommodation; affordability; and acceptability) and the three factors affecting access to health services, defined by Aday & Anderson11; Predisposing Factors, Enabling Factors, and Need Factors. Predisposing Factors mean the socio-cultural characteristics of individuals that exist prior to their illness, such as age, gender, religion, education. Enabling Factors mean the logistical aspects of obtaining care, such as monthly income, medical rights, transport to hospital, distance and time to hospital. Need Factors mean the most immediate cause of health service use, from functional and health problems that generate the need for health care services, such as self-perceived health.\n\nThe questionnaire was composed of three sections. Section 1 surveys general demographic information of the participants. Section 2 ‘Access to health service’ consisted of 11 items including items relating to Enabling Factors and Needs Factors. Section 3 ‘Opinion on healthcare service utilization’ contained 16 items: availability (4 items), accessibility (2 items), accommodation (4 items), affordability (3 items), and acceptability (3 items). A five-point Likert scale (1=strongly disagree, 2=disagree, 3=moderately, 4=agree, and 5= strongly agree) assess the 16 items. Interpretation of opinion on healthcare service utilization score in each item was as follows: 1.00 – 2.33 indicating low level access to healthcare service, 2.34 – 3.67 indicating moderate level access to healthcare service, and 3.68 – 5.00 indicating high level access to healthcare service.\n\nA pilot test was performed with 30 older adults who had the same characteristics as the participants, which were aged>60 years and willing to answer. The reliability of the questionnaire was tested using Cronbach’s alpha, with results of 0.9. As a result of the pilot study, the questionnaires had no change in the wording.\n\nA copy of the questionnaire both in Thai and English can be found in the Extended data.\n\nData were analyzed by using SPSS Statistics for Windows, Version 28.0 (IBM SPSS Statistics for Windows, Version 28.0. Armonk, NY: IBM Corp). Descriptive data were using percentage mean and standard deviation (SD). Analysis of factors affecting access to health service was performed using Logistic regression.\n\nThis study used the STROBE cross-sectional checklist when writing the report.12\n\nThis study was one of 12 projects in a set of ageing research projects approved by the Institutional Review Board of the Faculty of Medicine Vajira Hospital, Navamindradhiraj University (IRB No.067/60). Information about the study was explained to the participants (objectives, data collection steps, timing, and benefits of the study). After explanation, written informed consent was obtained from all participants. Upon completing the interview, each participant received 300-baht cash incentive for their participation.\n\n\nResults\n\nA total of 886 older adults were included in this study. Of these 70.8% were women, the average age was between 60 and 69.9 years, and most (42.3%) participants were married and lived together. In total, 58% of participants had finished primary education and most (63.8%) were currently unemployed. Almost half of participants (45.5%) had an income less than 5,000 baht.; 58% of participants stated that their income was sufficient to cover monthly bills. Most participants came from the urban communities.\n\nIn addition, 56.5% of participants reported accessing health services in the past year for an illness or health problems that required medical treatment and most of them reported that their condition was minor. More than half of respondents reported accessing health services was necessary to them with awareness that their health conditions were minimal. Most (>60%) of participants went to health facilities by themselves, and 83.6% used health services with direct health insurance. Public health facilities were the preferred health services visited.\n\nIn terms of expenses, participants reported that transportation fares were mostly below 100 baht, while 79.5% had no fees relating to medical expenses and miscellaneous fees. Most of the transport services to public health facilities were taxis, motorcycle-taxis, tricycles and vans. A total of 45% of participants visited hospitals two or three times per month. In terms of distance, most participants reported less than 5 kilometers from home to public health services, with a travel time of less than 30 minutes most reported. Most of the medical insurances were Universal Coverage Scheme. Participant demographics are shown in Table 1.\n\nParticipants reported that access to health services was high among all five dimensions: availability (mean 4.2, SD.=0.59), accessibility (mean 4.1, SD.=0.69), accommodation (mean 3.9, SD.=0.67), affordability (mean 4.2, SD.=0.62), and acceptability (mean 4.1, SD.=0.62). A summary of all dimensions revealed a mean of 4.1 (SD.=0.52). The findings are shown in Table 2.\n\nIn analyzing data on various factors, it was found that there is only data for Enabling Factors and Needs Factors that affect access to health services (Table 3). In terms of Enabling Factors, using health insurance rights for health care service has a great impact on access to health services; those who use the rights directly at health facilities have more than 1.9 times accessibility compared with those that use rights indirectly (p-value=0.006, 95%CI=1.214–3.094). For the Needs Factors, people who are concerned and aware about their health condition tend to access health services more than those who are not (about 1.5 times odds ratio) (p-value=0.043, 95%CI=1.013–2.340).\n\nIn addition, more than 80% of those who use rights directly with health facilities have received services from public health facilities, followed by private hospitals and health centers/clinics (Table 4).\n\n\nDiscussion\n\nThis study is a part of the Health Promotion Project under the Principle for the Elderly in the Urban Area of Bangkok Metropolitan, which is influenced by a well-known national practice guideline, the Philosophy of Sufficiency Economy, initiated by King Rama IX-Bhumibol Adulyadej. Previous studies have shown that the utilization of health services by older adults in urban areas does adhere to the five dimensions as described by Penchansky & Thomas.10 Firstly, based on previous data there is a high level of access to health service units at all levels from public to private sector, which are located across the country, and especially in the Bangkok Metropolis. In the Thailand’s capital city, there are a total of 4,687 health service units, and only 141 units are able to admit patients in the facility overnight. Approximately 56% of the units are in the public sector and 44% are in the private sector.13 This result is consistent with previous studies14,15 which explored the factors that affect access to health services of older adults in Bangkok. However, a previous study has revealed that availability of health service at national level is relatively insufficient.16 Secondly, for the accessibility dimension, high level access has been shown by a previous study,14 but this result is inconsistent with some studies.15,16 Obstacles in accessing health services have been reported as difficulties to travel to health facilities.17 However, in our study, most participants (60.4%) stated that the distance from home to health facilities was less than 5 kilometers, and it takes 76.2% of participants less than 30 minutes to travel to health facilities. This short distance enables participants to access health services easily, which are mostly public hospitals. Therefore, the participants are able to access and utilize the service conveniently.\n\nThirdly, for the accommodation dimension, data from our study indicates a high level of service access. A previous study17 revealed that the main problem in this dimension is the long duration between making an appointment and seeing general doctors or specialists. A study by Rahman et al.18 found that the long waiting time for doctors affected the satisfaction of patients. In addition, it was found that personal factors of patients, such as experience of previous medical care or expectation, affected satisfaction as well.19 Participants in our study had high satisfaction with appointment of doctors, as they easily made appointments. Therefore, the level of accommodation for our study is at a high level access. Fourthly, for the affordability dimension, our study revealed that there is a high level of access to services. The ability to pay a medical expense is one problem in accessing health services.20 The constitution of the Kingdom of Thailand B.E. 255021 states that “Everyone has equal rights in utilization of the public health service without medical expenses and able to received public health services thoroughly and efficiently”. Accordingly, the established health insurance rights for Thai people gives everyone the opportunity to access health services equally as prices are standardized by the state.22 Our study indicated that participants were satisfied with the rights and expenses at a high level because most of them used Universal Coverage Scheme rights, which has no payment. Therefore, the ability to access the service in the affordability dimension is at a high level. Fifthly, for the acceptability dimension, our study showed a high level service. A previous study23 found that for this dimension service characteristics, such as attitude and expectations of service recipients, can hinder the acceptance of service quality. The concept of satisfaction of service quality is significant as patients as customers should be satisfied by the service and facility, particularly when they frequently use the health services.\n\nThis study found two factors affecting health service accessibility: a) visiting health service unit they registered at, and b) the need for the service. The former factor is aligned with Enabling Factor, the latter is aligned with Need Factor. For health insurance right factor, this study statistically found that participants that visited a health service unit that they were registered at were 1.9 times more likely to access to health service, compared to those who are not registered at the unit(95%Cl=1.214–3.094). In total 83.7% of public hospital patients visited hospitals they were registered at, which is four-times more than those who visited health service units they are not registered. This was consistent with a previous study15 that found that the relationship between accessibility to health services and utilization of health services was statistically significant (p<0.05). For this reason, if patients use their rights directly the health care service is free of charge for them, or only causes minimal payment. Besides, one of factors why people access public hospitals is no medical expenses.24 It’s been shown that 61.6% of older adults used Universal Coverage Scheme rights, which effects accessibility to health services.25 In addition, use of treatment services increase with the use of health insurance rights, especially in outpatients.26,27 The lack of ability to pay for medical expenses has been shown to be an issue with utilization of health services of older adults.20\n\nFor the second factor, necessity of health care, our study revealed that participants who perceived that they needed to be treated in a hospital increases access to health facilities by 1.5 times compared to those that consider it unnecessary to be treated in a hospital (95%Cl=1.013–2.340). The necessity was making people be aware of the importance in medical treatment. However, it has been observed that using health insurance rights with no payment leads to a more accessible health services. These health services are mostly free of charge, especially for those who registered their health insurance rights at the hospital. Even though patients do not have to pay for the health services, free services are not what they actually want; usually they visit health service units due to their illness and awareness on health conditions and not just because these are free. This finding is supported by previous research24 that studied the needs for access to health services from the perspective of patients and doctors. It indicated that most patients came to access services at the outpatient department; 71.8% of them thought that it was necessary to access to health services and only 0.6% thought it was unnecessary. Nonetheless the viewpoint on treatment between patients and doctors could be different; perspective is important because different perspectives lead to different decisions about necessity in treatment. A previous study28 revealed the patients assumed that they knew about their health and were able to decide whether they needed treatment. Lack of knowledge of health may lead them to not taking care of themself or lead them going to hospital. While doctors are likely to suggest them to initially get diagnosed by general practitioners at health service units.\n\nFindings from our study suggested that the government should give the opportunity to get health insurance rights, so individuals can access health facilities nearest their habitation. Similarly the government should facilitate the ability to move health insurance rights to the health facility nearest their habitation. Due to the fact that receiving health services from health service units where patients do not have their health insurance causes extra payment for them. Instead, rights could be based on the use of identification card, as there are some older adults who do not have real address in urban communities as they may be renting a house etc. Medical facilities near the habitation will make it easier way to visit, with no payment, meaning that older adults could have access to more services. Both the public and private sectors should help raise awareness of basic health care, including health literacy to increase awareness of necessity for treatment. Indeed, a previous study indicated there is a correlation between health literacy and the quality of healthcare interactions.29 Enhancing an understanding of the concept of health literacy will eventually increase patient participation in health care standard and quality in the country holistically.30\n\nThere are a few limitations in our study, primarily the number of participants did not reach the set target due to accessibility to participants in urban communities. Also, participants were able to be contacted only via community leaders or public health volunteers for data collecting. A target number of 1,086 participants was missed by 18% - a final number of 886 participants were included in the study.\n\n\nConclusion\n\nAmong older adults in urban Bangkok, factors affecting access to health services were using health insurance rights for health care service, and concern about the necessity of health care. Encouraging older adults to change their health insurance rights to their nearest hospital and promoting the provision of public health information, will support older adults in accessing more health services to improve their health outcomes.\n\n\nData availability\n\nUnderlying data cannot be shared as the ethical committee that approved the study stated that only aggregated data could be shared openly. In addition, this study is part of a set of research projects about ageing, which all use the same underlying dataset; sharing the dataset must be permitted by all researchers of the ageing projects.\n\nResearchers interested in accessing the data will need to submit an official letter of request for the data to Navamindradhiraj University and will be asked to confirm that they will not violate the ethical standards of the ethical committee and protect the anonymity of the participants. Researchers can contact the corresponding author, who can facilitate this process.\n\nOpen Science Framework: Factors affecting access to health services by older adults in an urban community in Thailand: a cross-sectional study, https://doi.org/10.17605/OSF.IO/MTNPC.31\n\nThis project contains the following extended data:\n\n- Copy of the questionnaire in Thai with an English translation\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\nThe author would like to thank Mr. Krittanan Pensirisomboon who helped with the English, and all the individuals who responded to the survey.\n\n\nReferences\n\nFoundation of Thai Gerontology Research and Development Institute: Situation of the Thai elderly 2016. Bangkok: Octoberprint Co. Ltd; 2018.\n\nFoundation of Thai Gerontology Research and Development Institute: Situation of the Thai elderly 2016. Bangkok Amarin Printing & Publishing Public Co., Ltd; 2017.\n\nFoundation of Thai Gerontology Research and Development Institute: Situation of the Thai elderly 2016. Bangkok: TQP Co., Ltd; 2010;\n\nWattanasirichaigoon S: Universal Health Coverage of Thai Elderly. Where should we go?. Health Systems Research Institute; 2014. Reference Source\n\nWorld Health Organization: Active ageing: a policy framework. Geneva: WHO; 2002.\n\nTangcharoensathien V, Prakongsai P, Limwattananon S, et al.: From Targeting to Universality: Lessons from the Health System in Thailand. Townsend P, editor. Building Decent Societies. London: Palgrave Macmillan; 2009.\n\nPonmanee P: Trainning development program for health volunteers in disability patient of Nongkham district, Bangkok Metropolis. Bangkok: Thammasat University; 2007.\n\nMinistry of Public Health: National Health Development Plan Vol 12 (B.E. 2560-2564). Bangkok: Ministry of Public Health; 2016.\n\nSakunpanit T: Performance of Health Care for Elderly and Impact on Public Health Care Financing during 2011-2022. Thai Health Promotion Foundation; 2011.\n\nPenchansky R, Thomas JW: The concept of access: definition and relationship to consumer satisfaction. Med. Care. 1981; 19: 127–140. Publisher Full Text\n\nAday LA, Andersen R: Access to Medical Care. Michigan: Health Administration Press; 1975.\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. J. Clin. Epidemiol. 2008 Apr; 61(4): 344–349. Publisher Full Text\n\nOffice of the Permanent Secretary Ministry of Public Health Basic Data of Health Service Area, Bangkok 2013. Bangkok: Aksorn Graphic and Design Publishing Limited Partnership; 2014.\n\nNirarat K, Kidsom A, editors. Factors affecting access to health services for elderly in Bangkok. The 14th KU-KPS Conference. 2017 Dec, 7-8 2017.\n\nChaisawat P, Pawananan P, Na Nongkai S, et al.: Utilization of Elderly Health Services, Tambon Viharn Khao, Amphor Tha-Chang, Singburi. VAJIRA NURSING JOURNAL. 2016; 18(2): 42–50.\n\nPoompoung O: Access to health services for the elderly in Chiang Mai Municipality. Chiang Mai University; 2008.\n\nGaans D, Dent E: Issues of accessibility to health services by older Australians: a review. Public Health Rev. 2018; 39(20): 1–16.\n\nRahman MM, Shahidullah M, Shahiduzzaman M, et al.: Quality of health care from patient perspectives. Bangladesh Med. Res. Counc. Bull. 2002; 28(3): 87–96. PubMed Abstract\n\nBleich SN, Ozaltin E, Murray CK: How does satisfaction with the health-care system relate to patient experience?. Bull. World Health Organ. 2009; 87(4): 271–278. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThorpe JM, Thorpe CT, Kennelty KA, et al.: Patterns of perceived barriers to medical care in older adults: a laten class analysis. BMC Health Serv. Res. 2011; 11(181): 1–12.\n\nGovernment gazette: National Health Act, B.E. 2550. Vol 124 Part 16a, dated 19th March B.E. 2550.\n\nHealth Education Devision: Department of Health Service Support. Health Education Standard of Hospital Center/General Hospital. Nontaburi: Health Education Devision; 2012.\n\nPeters DH, Garg A, Bloom G, et al.: Poverty and Access to Health Care in Developing Countries. Ann. N. Y. Acad. Sci. 2008; 1136(1): 161–171. Publisher Full Text\n\nSaengow U, Wattanapisit A, Asksonthong R: Necessity of Hospital Visit: Comparing Patient and Doctor Perspectives. Nakhonsrithammaraj: Health Systems Research Institute; 2017.\n\nDeVoe JE, Tillotson CJ, Lesko SE, et al.: The Case for Synergy Between a Usual Source of Care and Health Insurance Coverage. J. Gen. Intern. Med. 2011; 26(9): 1059–1066. PubMed Abstract | Publisher Full Text\n\nGhislandi S, Manachotphong W, Perego VM: The impact of Universal Health Coverage on health care consumption and risky behaviours: evidence from Thailand. Health Econ. Policy Law. 2015; 10(3): 251–266. PubMed Abstract | Publisher Full Text\n\nGhislamdi S, Muttarak R: Fair choices in universal health coverage in Thailand. Lancet. 2016; 388(10050): 1155–1156. PubMed Abstract | Publisher Full Text\n\nWagner PJ, Warren PR, Mosely G: Patient and Physician Perceptions of Dimensions of Necessity of Medical Utilization. Qual. Rep. 2010; 15(2): 301–307.\n\nNutbeam D: Health literacy as a public health goal: a challenge for contemporary health education and communication strategies into the 21st century. Health Promot. Int. 2000; 15(3): 259–267. Publisher Full Text\n\nProtheroe J: Health literacy: a necessity for increasing participation in health care. Br. J. Gen. Pract. 2009; 59: 721–723. PubMed Abstract | Publisher Full Text\n\nJirathananuwat A: Factors affecting access to health services by older adults in an urban community in Thailand: a cross-sectional study.2022, March 30. Publisher Full Text"
}
|
[
{
"id": "136381",
"date": "29 Nov 2022",
"name": "Krit Pongpirul",
"expertise": [
"Reviewer Expertise Health Services",
"Health Systems"
],
"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 very much for the opportunity to review this work. This cross-sectional survey was conducted in one purposively selected urban community in Thailand. Although the survey result was relatively old (Sep-Dec 2018), the findings could still be useful. I have several comments and suggestions for improving this work for your consideration.\nPlease specify which community was purposively selected, along with its demographic and other characteristics, along with that of other general/urban/rural communities in Thailand. This would enhance the external generalizability of this study.\nThe author attempted to apply a stratified random sampling approach to ensure the representativeness of 4 'groups' of older adults in one urban community. To minimize confusing word choices, consider using 'neighborhoods' to represent the subgroups and use the term 'community' only if necessary. That is, the chosen urban community in this study comprises four different neighborhoods (slum, city, suburban, and condominium). Following this advice, the sampling technique should be changed from stratified to clustered.\nEthical considerations: I suggest changing the phrase \"cash incentive\" to 'modest amount of financial compensation'.\nResults: 886 (instead of the calculated 1,086) were included in this study. Please calculate the percentage and provide an appropriate term. I'm not sure if this should be a 'response rate' or a 'successfully reached rate' or other terms.\nTable 1 - \"Sufficiency of income\": Provide rationale and/or reference for this measure.\nAccess to health services should be comparatively presented across the five domains (Table 2). For example, why was the Accommodation relatively lower than the other dimensions?\nAlso, it would be more interesting to compare the findings across the four neighborhoods.\nThe terms \"medical rights\" or \"health insurance rights\" might be confusing; consider replacing them with 'health insurance status' or more relevant terms.\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? Partly",
"responses": [
{
"c_id": "9284",
"date": "01 Feb 2023",
"name": "Areeya Jirathananuwat",
"role": "Author Response",
"response": "Dear Prof Krit Pongpirul, Thank you very much for reviewing my paper. Your guidance is very helpful in my study. I have revised the paper based on your suggestions. Best Regards, Areeya"
}
]
},
{
"id": "155676",
"date": "01 Dec 2022",
"name": "Chaisiri Angkurawaranon",
"expertise": [
"Reviewer Expertise Primary care and epidmiology"
],
"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 paper. There are some comments and suggestions.\nIn the Introduction, I am a bit surprised at the low access to health services given that Thailand has universal coverage - can the authors expand just a bit more as to why it is such a low number?\n\nIn the Introduction, the authors mention the five dimensions of access to health services, then three individual characteristics (by Aday & Anderson). So I'm not really sure which framework the authors will use or if they are using both, how they can connect and intersect.\n\nI think the authors should also clearly state the gap in the literature that they are trying to address. Are the authors trying to compare different communities?\n\nAs the main objective (gap) is not clearly stated, the data analysis is also a bit underdeveloped. As the authors are presenting their access to care score as categorical data (low, moderate or high), it may not be appropriate to use only mean and sd. What is the binary outcome for the logistic regression? What were the potential confounders?\n\nWould Table 1 and Table 2 be more informative if the authors could also add columns detailing each type of community?\n\nFor Table 3, the outcome in the logistic model has not been clearly defined. What did the models adjust for?\n\nTable 4, I'm not really sure what 'use health right non-directly' means.\n\nThe section of the Discussion should be a summary of your main finding to answer the question. As the question was not clearly defined in the Introduction (please see comment 3), this section may need to be revised accordingly to discuss the key findings (based on the objectives identified) within the context of the literature, including a more in-depth discussion about access to health services within Thailand (for example, why the estimate differed from previous studies mentioned in the Introduction). A discussion or limitation about the generalisability of the results may also be required.\n\nFrom reading the Discussion, it seems like the authors want to estimate access to care for Bangkok but the authors may want to consider the variation in access to care based on the types of community.\n\nIn the Conclusion, the authors focus their conclusion on changing the patient's insurance rights to their nearest hospital but from my reading (based on the results and tables), most of the patients are already using their insurance right at a nearby facility so I'm not sure about this 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? 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? Partly",
"responses": [
{
"c_id": "9285",
"date": "01 Feb 2023",
"name": "Areeya Jirathananuwat",
"role": "Author Response",
"response": "Dear Prof Chaisiri Angkurawaranon, First of all, thank you for your comments and suggestions that allowed me to greatly improve the quality of the manuscript. I agree with all your comments, and I corrected it in the new version. Additionally from my analysis of the data again, I did not find the association of types of community and access to health service. In the conclusion, the results also showed as version 1. Thank you once again for your valuable time Best regards, Areeya"
}
]
}
] | 1
|
https://f1000research.com/articles/11-467
|
https://f1000research.com/articles/10-1233/v1
|
03 Dec 21
|
{
"type": "Research Article",
"title": "Active compound test: ethanolic extract of White Oyster Mushroom (Pleurotus ostreatus) Using HPLC and LC-MS",
"authors": [
"Santun Bhekti Rahimah",
"Agung Firmansyah",
"Winni Maharani",
"Yuke Andriane",
"Dicky Santosa",
"Nurul Romadhona",
"Agung Firmansyah",
"Winni Maharani",
"Yuke Andriane",
"Dicky Santosa",
"Nurul Romadhona"
],
"abstract": "Background: The use of herbs as traditional medicine in Indonesia is increasing, with more than 40% of Indonesia's population utilizing them. White oyster mushroom (Pleurotus Ostreatus) is a fungus that has various therapeutic effects including antioxidant, anti-inflammatory, anti-bacterial, anti-cholesterol, and anti-cancer properties. This mushroom contains many active substances in its secondary metabolites which have pharmacological effects. The purpose of this study was to identify the active compounds in the ethanolic extract of white oyster mushroom that will form the extract profile and become the basis for drug development. Methods: The active compound test used High-Performance Liquid Chromatography (HPLC) and Liquid Chromatography with Mass Spectrometer (LC-MS). Ethanolic extract of white oyster mushroom was processed by 70% alcohol maceration, evaporation, and thickening. Results: The results of the HPLC test showed that the ethanolic extract of white oyster mushroom contained cinnamic acid and rutin, while the LC-MS test showed the presence of p-coumaric acid, Ascorbic acid, Linoleic acid, 9-Eicosene (E), Niacinamide, Veritric acid, Syringic acid, Ergosterol. Conclusions: The active compounds that were detected in the ethanolic extract of white oyster mushroom showed that the extract had the potential for antioxidant and anti-inflammatory activity.",
"keywords": [
"White oyster mushroom",
"ethanolic extract",
"HPLC",
"LC-MS",
"active compounds."
],
"content": "Introduction\n\nWhite oyster mushroom (Pleurotus ostreatus) is a very popular food source, belonging to the Basidiomycetes class of fungi.1,2 This mushroom has a very high nutritional value and various secondary metabolites that have potential for pharmacological effects.1,3 Two of the most important pharmacological effects of mushrooms are the antioxidant and anti-inflammatory effects. White oyster mushroom is also widely used in the prevention of several chronic diseases such as hypertension, hypercholesterolemia, and carcinoma. Various previous studies have proven that white oyster mushrooms have strong antioxidant abilities both in vivo and in vitro.4,5\n\nMany metabolites in white oyster mushrooms act as anti-inflammatories such as beta-glucan (β-glucan) or polysaccharides, phenolic components, flavonoids, terpenoids, lectins, steroids, glycoproteins and ergothioneine (ET). White oyster mushrooms, which are believed to have antioxidant effects, include vitamin C, beta-carotene, selenium, ergothioneine, and phenolic components. Phenolic components are the main components that affect its antioxidant activity.6–8 Previous studies have shown the antioxidant effect of ethanolic extract of white oyster mushroom which can prevent the increase in MDA and decrease in lung surface density (S/V).5\n\nOyster mushrooms (of which white oyster is one type) overall when compared to winter and shitake mushrooms have antioxidant activity, reducing power, scavenging abilities, and higher total phenol content. They also have good hydroxyl and superoxide radical scavenging, and the potential to inhibit lipid peroxidase activity with an IC 50 value that is almost the same as vitamin C, which is 6-8 mg/ml.6,9\n\nThe anti-inflammatory mechanism of white oyster mushrooms varies and has not been fully elucidated, but several studies have demonstrated its anti-inflammatory potential.10–13 Oyster mushroom concentrates in vitro studies can suppress the production of TNF-α and nitric oxide (NO) in macrophages RAW 26412 induced by lipopolysaccharides (LPS) with interferon-γ (IFN-γ). Other cytokines that are inhibited are interleukin-6 (IL-6), interleukin-12 (IL-12), and prostaglandin E2 (PGE2) through downregulation of cyclooxygenase-2 (COX-2) and expression of inducible nitric oxide synthase (iNOS)). in vitro activity of White oyster mushrooms can inhibit the activation of NF-kB through the inhibition of phosphorylation of the inhibitory protein kB (IkBα).1,7,12\n\nThe use of white oyster mushrooms as a natural antioxidant and anti-inflammatory is also very beneficial for the wider community because of its widespread availability, easy and short cultivation, and affordability. The use of herbs in medicine is expected to provide lesser side effects than the use of synthetic or chemical materials.1,2\n\nFor white oyster mushroom ethanol extract to become a standardized herbal or phytopharmaca, it is necessary to carry out several tests to strengthen the scientific data regarding the effect of ethanolic extract of white oyster mushroom. The first stage that must be carried out is the phytochemical and standard compound tests, and the compound profile analysis. The results of the phytochemical analysis in preliminary research stated that ethanolic extract of white oyster mushroom contains alkaloids, steroids, tannins, saponins, flavonoids, and phenolic compounds. Based on this data, we studied the marker compounds and analyzed the profile of ethanolic extract of white oyster mushroom, to strengthen scientific data regarding the effects of white oyster mushrooms and facilitate their development into standardized herbs.\n\n\nMethods\n\nThis research is an in vitro experimental test with the subject being the ethanolic extract of White Oyster Mushroom. Only fresh white oyster mushrooms were included. 70% ethanol maceration and phytochemical tests (alkaloids, steroids, flavonoids, quinones, saponins, and tannins) were carried out on these. The materials used in this study were: White Oyster Mushroom Extract from oyster mushroom farmers in Cisarua Village, Kec. Cisarua, 70% Ethanol, Standard Compounds for High-Performance Liquid Chromatography (HPLC): Rutin, Myricetin, Cinnamic Acid, Coumaric Acid, and Liquid Chromatography with Mass Spectrometer (LC-MS) Reagents. The tools needed are the tools for preparation and administration of ethanolic extract of white oyster mushroom, analytical balance, HPLC, and LC-MS. Each test was performed twice.\n\nFresh white oyster mushrooms (50 kg) DrieD taken from oyster mushroom cultivation in Kec. Cisarua were sliced and then put in an oven at 50° Celsius with a thickness of 1-2 cm, for two to three days. After drying, the simplicia was pureed using a grinding tool.14\n\nDried mushroom was macerated with 70% ethanol for 24 hours. Then the alcohol was filtered using filter paper. The remaining solution is called aqueous extract. The maceration was repeated five times. The dilute extract was then concentrated using a rotary evaporator until no more solvent dripped into the condenser of the rotary evaporator and concentrated again with a water bath.14\n\nBased on the literature, it was found that the active substances found in white oyster mushrooms are included in the form of phenolic acids also flavonoids. The phenolic acid derivatives that were studied in this study are cinnamic acid and p-coumaric acid, while the flavonoid compounds to measured were myricetin, rutin, saponins, tannins, and steroids/triterpenoids.9\n\nThe marker compounds thought to be present in white oyster mushrooms were tested using High Performance Liquid Chromathography (HPLC) by showing quantitative analysis.15,16 The standard compounds tested in this study were rutin, myricetin, quercetin, cinnamic acid, and coumaric acid.\n\nHigh-performance liquid chromatography (HPLC) uses the principles of chromatography to measure samples. In chromatography, analysis is done by separating molecules based on differences in structure or composition. The separation occurs when the sample moves through the stationary phase (can be solid or liquid) because it is carried away by the mobile phase (can be liquid or gas). The results were obtained, comparing the standard chromatogram with the sample chromatogram, by identifying the retention time (RT).17\n\nThe results of the measurement of the active substance in the ethanolic extract of white oyster mushroom were then compared with the results of the measurement of standard compounds, by comparing the retention time of the compounds in the ethanolic extract of white oyster mushrooms with standard compounds that have been tested first.\n\nConcentrations in extracts are often very low, requiring very high selectivity and sensitivity. Detection of components with a non-targeted approach is often needed to ensure that other active substances are present in the extract and can be developed into more specific herbal medicines.\n\nMass spectrophotometry (MS) is an analytical method used to identify the compounds based on their molecular weight. In MS organic compound molecules are bombarded with electron beams so that the compound is ionized.18 Liquid Chromatography-Mass Spectrometry (LC/MS-MS) is an analytical technique that combines the capabilities of liquid chromatography with mass spectrometry. Liquid chromatography separates the components of the herb extract and then charged ions are detected by a mass spectrometer. LC-MS data can provide information about the molecular weight, structure, identity and quantity of certain sample components. Compounds are separated based on interactions with the chemical layer of the particles (stationary phase) and solvent elution through the mobile phase. The detector then calculates the induced charge or current generated when the ions hit or pass through the surface, scan the mass and calculate the ions as mass to charge ratio (m/z). There are four mass spectrometry processes, namely ionization, acceleration, deflection, and detection.18,19 The results of the LC/MS-MS data analysis yield a chromatogram in the form of a peak height groove, and the molecular weight of the compounds contained in the extract can be determined so that their number can be elucidated.\n\nThe research took place at Unisba Pharmacy Research Laboratory and was assisted by Aretha Medika Utama Biomolecular and Biomedical Research Center. Measurement of marker compounds with HPLC was carried out in two laboratories, namely the laboratory of the Faculty of Chemistry, Universitas Pendidikan Indonesia using HPLC (Hitachi D7000) for cinnamic acid and coumaric acid compounds and at the Poltekkes Malang Laboratory using UHPLC (ACCELLA type 1250) for rutin compounds, myricetin, and quercetin. The LC-MS test was carried out at the Areta Laboratory in collaboration with the Lab. Instrumental Analytical Chemistry, Department of Chemical Engineering, State Polytechnic of Malang.\n\nThis study received ethical approval from Medical research ethics committee of Universitas Islam Bandung Nomor: 111/KEPK-Unisba/XI/2020\n\n\nResults\n\nThe ethanolic extract of white oyster mushroom was made from 5 kg of wet simplicia of oyster mushrooms, of which only the umbrella part was then taken, so that it was reduced to 3 kg. After drying, the shrinkage was to 0.14 kg. Maceration was carried out with 70% ethanol in a ratio of 1:5 and maceration was carried out for 3 days with a daily change of 0.14 kg of ethanol: 0.7 L (1:5). The total extract obtained was 36.3111 grams in the form of a brown paste.\n\nThe compounds to be tested in the ethanol extract of white oyster mushrooms by HPLC are five compounds, namely rutin, myricetin, quercetin, cinnamic acid, and coumaric acid. The standard compounds were validated first and then the compounds in the ethanol extract of white oyster mushroom were measured. The validation results show that the standard of cinnamic acid and p-coumaric acid has been validated and shows retention times of 18.91 for cinnamic acid and 2.21 for p-coumaric acid.\n\nTable 1 shows that the ethanolic extract of white oyster mushroom appears to contain cinnamic acid with a concentration of 0.073% with a retention time of 18.81 minutes. This result can be seen from the retention time which is similar to the retention time of cinnamic acid, however, for cinnamic acid and p-coumaric acid, the molecular weight of the compounds analyzed is not observed.\n\nThe test results for rutin standards with initial concentrations of 0.125, 0.250, 0.500 and 1,000 g/mL and resulted in a linear regression curve as shown in Figure 1. The routine standard test showed good validation.\n\nFigure 1 shows the linear regression equation y = 35434x + 104.69 with R2 = 0.996. The increase in concentration shows a strong correlation with the area. This shows that an increase in the concentration of rutin will show an increase in the level of the substance detected on the curve.\n\nTable 2 shows the results of rutin compound measurements in the ethanolic extract of white oyster mushrooms. Ethanolic extract of white oyster mushroom samples were measured three times to get more accurate results. Based on the results of HPLC analysis, the three samples of ethanolic extract of white oyster mushroom were predicted to contain rutin, with different results. The ethanolic extract of white oyster mushroom was predicted to have a Rutin compound with a concentration of 168.45 g/g sample.\n\nCalculations for standard quercetin with initial concentrations of 0.125, 0.250, 0.500, and 1,000 g/mL resulted in a linear regression curve as shown in Figure 2. The quercetin standard test showed good validation.\n\nFigure 2 shows the linear regression equation y = 30337x + 65.711 with R2 = 0.9976. Increased concentration shows a strong correlation with area.\n\nTable 3 shows the measurement results of quercetin compounds in the ethanolic extract of white oyster mushrooms. Based on the results of HPLC analysis, ethanolic extract of white Oyster Mushroom was not detected to have quercetin compounds.\n\nThe test results for the myricetin standard showed calculations with initial concentrations of 0.5, 1.00, 2.00, and 4.00 g/mL and produced a linear regression curve as shown in Figure 3. The myricetin standard test showed good validation.\n\nFigure 3 shows the linear regression equation y = 1634.3x + 166.77 with R2 = 0.9986. The increase in concentration shows a strong correlation with the area.\n\nTable 4 shows the measurement results of myricetin compounds in the ethanolic extract of white oyster mushrooms. Based on the results of HPLC analysis, the ethanolic extract of white Oyster Mushroom was not detected to have myricetin compound.\n\nThe use of MS/MS Triple Q (quadrupole) TSQ QUANTUM ACCESS mass spectrometer with ESI (Electrospray Ionization) ionization source is controlled by TSQ Tune software which is operated with a positive charge. ESI-MS ionization conditions on direct infusion, sample flow rate of 5 l/min with MS equipment conditions are as follows: spray voltage of 3 kV; Evaporation temperature 50°C; Capillary temperature, 270°C; nitrogen as a sheath gas pressure of 5 psi.\n\nTable 5 shows that the sample of ethanolic extract of white oyster mushroom contains p-coumaric acid, Ascorbic acid, Linoleic acid, 9-Eicosene (E), Niacinamide, Veritric acid, Syringic acid, and Ergosterol.\n\n\nDiscussion\n\nThe therapeutic effects or medicinal properties of medicinal plants and fungi come from the active substances contained within them. The active substances, which are generally inert, are closely related to substances that give color and taste or affect the structure of the medicinal plant or fungi. The specificity and purification of this active substance are very important to produce a specific pharmacological effect. Standardized active substances will produce good quality herbal medicine preparations and herbal medicine standards will become more secure. The active substances contained depends on the species of the plant or fungi, the procedure of harvesting, and the manufacturing and handling of medicinal plant/fungi preparations.20,21 Ethanolic extract of white oyster mushroom has become one of the medicinal preparations that is currently being developed.\n\nThe quality of herbal preparations such as ethanolic extract of white oyster mushroom is strongly influenced by the drying process, the choice of solvent used and the ratio of solvent to be dissolved. Ethanol is a universal solvent that is widely used in the manufacture of extracts because it can dissolve polar and non-polar substances. Ethanol can dissolve active substances such as tannins, phenols, saponins, proanthocyanins, reducing sugars, flavonoids, terpenoids, and glycosides. Steroids are more commonly found in water and methanol solvents.14\n\nPhytochemical tests carried out on this white oyster mushroom extract in previous studies showed that the active substances contained in this extract were alkaloids, steroids, triterpenoids, saponins, quinones, tannins, and phenolic components.9\n\nAlkaloids can also be found in ether, methanol, or water, but cannot be found in hexane. Alkaloids are active metabolites that have antimicrobial effects by inhibiting DNA topoisomerase. The flavonoid concentration will be reversed in 70% ethanol compared to pure ethanol because it increases the polarity. Flavonoid compounds are polyphenolic components that are widely found in plants and have various biological activities including antimutagenic and anticancer.1,13 Phenols are found in the ethanolic extract of white oyster mushrooms and are the main compounds related to the antioxidant effect of white oyster mushrooms. Its antioxidant ability is closely related to its hydroxyl content. Phenolics can act as reducing agents for hydrogen donors and singlet oxygen quenchers and have potential metal chelation effects.8,13,22\n\nThe phenolic components in Pleurotus ostreatus contain various types, including vanillic acid, myricetin, naringin, homogentisic acid, 5-O-caffeoylquinic acid, chrysin, rutin, gentisic acid, gallic acid, protocatechuic, caffeic acid, tannic acid, syringic acid, cinnamic acid, and p-coumaric acid. Antioxidant properties found in mushrooms are generally in the form of phenolic acids and flavonoids, followed by tocopherols, ascorbic acid, and carotenoids.2,9\n\nThe different mechanisms of the various active substances contained in herbal preparations can strengthen the biological effects caused by the herbal preparations. Based on the results of phytochemicals, two groups of compounds that are thought to play a major role in providing biological or pharmacological effects in the ethanol extract of white oyster mushrooms are phenolic compounds and flavonoids. Phenols and flavonoids are both polyphenolics. Various studies have proven their antioxidant effects and their ability to be free radical scavengers, especially against lipid peroxyl compounds, superoxide anions, and hydroxyl radicals. Polyphenols and flavonoids have been shown to have good abilities as antioxidants.8,23\n\nPhenolic acid refers to the term phenol component which contains one functional carboxyl acid group and is a polyphenol metabolite. Phenolic acids have two different carbon groups, namely hydroxycinnamic acid which forms simple esters with glucose or hydroxy carboxylic acids. Phenolic components in plants and fungi have different molecular structures and are characterized by the presence of a hydroxylated aromatic ring. Hydroxycinnamic consists of cinnamic acid, ferulic acid, sinapic acid, and caffeic acid, while hydroxycarboxylic acids include benzoic acid, gallic acid, vanillic acid, and salicylic acid.\n\nFlavonoids such as phenolic acid are also part of polyphenolic compounds which are very low in toxicity and are widely distributed in plants. Flavonoids are also known to have very varied structural and biological properties.\n\nDietary sources of flavonoids can be found in the form of flavonols, flavones, isoflavones, and flavanones. Included in the flavones class are apigenin, luteolin, and chrysin, which include flavanones such as quercetin, kaempferol, and galangin. Examples of flavonone groups are naringenin, hesperetin, while isoflavones include genistein, daidzein.12,22,24,25\n\nQuercetin, a flavonol found in many diets, is a potent antioxidant because it has a structure suitable for free radical scavenging. Currently, phenolics, and flavonoids are considered to be strong antioxidants whose effectiveness is a better than Vitamin C, E and carotenoids. Flavones and catechins are considered the most effective flavonoids against ROS. Quercetin, kaempferol, morin, myricetin, and rutin, are also known to act as antioxidants, and have anti-inflammatory, anti-allergic, antiviral, and anticancer effects. The decrease in phenolic and flavonoid activity depends on the number of free hydroxyl groups in their chemical structure and this can be strengthened by steric hindrance.26,27\n\nThe results from HPLC showed that from the previous phytochemical results, only a few substances were detected in the white oyster mushroom extract, namely rutin, and cinnamic acid, while for coumaric acid, myricetin and quercetin had not shown significant results. The next test for the active substances in this extract was followed by LCMs and p-coumaric acid, Ascorbic acid, Linoleic acid, 9-Eicosene (E), Niaciamide, Veritric acid, Syringic acid, and Ergosterol. In LC-MS, coumaric acid was detected in the extract but cinnamic acid was not detected, while the others were not detected in HPLC because they were not examined. HPLC requires an examination standard while LCMS does not require an active substance standard as a comparison.\n\nThe advantage of LC-MS is that it can analyze a wider range of components, such as thermally labile compounds, those with high polarity or high molecular mass, and even proteins. The elution component of the chromatographic column is then transmitted to the mass spectrometer through a special interface. The principle is the separation of analytes based on their polarity, the apparatus consists of a column (as the stationary phase) and a certain solution as the mobile phase and high pressure is used to push the mobile phase. The analyte mixture will separate based on its polarity and the speed to get to the detector (retention time) will be different, this will be observed in a spectrum where the peaks are separated.15,18,19,28 When compared to the results of the previous phytochemical tests and the results of HPLC and LCMS, some of them showed relevant data, but some of them showed different data. This may be influenced by several factors, including the quality of the extract, the procedure carried out, and the study of the structure of each active substance. The results of the three tests can be the basis for better understanding of the profile of the ethanol extract of white oyster mushroom.\n\n\nConclusions\n\nAnalysis of the active substance based on the HPLC test showed that the ethanol extract of white oyster mushroom contained the active compounds rutin and cinnamic acid, while the LC-MS test showed that the ethanol extract of the white oyster mushroom contained the active compounds p-coumaric acid, ascorbic acid, linoleic acid, 9-eicosene, niaciamide, veritric acid, syringic acid, and ergosterol.\n\n\nData availability\n\nBhekti Rahimah, Santun (2021): UHPLC and LC-MS (ESI-MS) Test For Ethanolic Extract of White Oyster Mushroom.docx. Figshare. https://doi.org/10.6084/m9.figshare.16550910.v4.29\n\nThis project contains the following underlying data:\n\n• Data file 1. LC-MS (ESI-MS) Test of Ethanolic Extract of White Oyster Mushroom\n\n• Data file 2. UHPLC Test For Ethanolic Extract of White Oyster Mushroom\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\nAuthors’ contributions\n\nSantun Bhekti Rahimah: supervision, conceptualization, investigation, writing- review and editing.\n\nAgung Firmansyah: Resources, writing-review and editing.\n\nWinni Maharani: Investigation, writing original draft, writing-review and editing.\n\nYuke Andriane: Methodology, conceptualization, writing original draft, writing-review and editing.\n\nDicky Santosa: Investigation, writing-review and editing.\n\nNurul Romadhona: Validation, project administration, data curation, writing-review and editing.",
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African J Biotechnol. 2007; 6(15): 1732–1739.\n\nNn A: A Review on the Extraction Methods Use in Medicinal Plants, Principle, Strength and Limitation. Med Aromat Plants. 2015; 04(03): 3–8.\n\nDong MW, Zhang K: Ultra-high-pressure liquid chromatography (UHPLC) in method development. TrAC - Trends Anal Chem. 2014; 63: 21–30. Publisher Full Text\n\nSeal T: Quantitative HPLC analysis of phenolic acids, flavonoids and ascorbic acid in four different solvent extracts of two wild edible leaves, Sonchus arvensis and Oenanthe linearis of North-Eastern region in India. J Appl Pharm Sci. 2016; 6(2): 157–166. Publisher Full Text\n\nZhang Y, Dai L, Kong X, et al.: Characterization and in vitro antioxidant activities of polysaccharides from Pleurotus ostreatus. Int. J. Biol. Macromol. 2012; 51(3): 259–265. PubMed Abstract | Publisher Full Text\n\nSeptaningsih DA, Darusman LK, Afendi FM, et al.: Liquid Chromatography Mass Spectrometry (LC-MS) Fingerprint Combined with Chemometrics for Identification of Metabolites Content and Biological Activities of Curcuma aeruginosa.2018; 18(1): 43–52.\n\nLai K, Cheng Y, Tsai T: Integrated LC-MS/MS Analytical Systems and Physical Inspection for the Analysis of a Botanical Herbal Preparation.2015; 10641–10656.\n\nAnalytical KA: Evaluation of Herbal Drugs.2005. PubMed Abstract\n\nLegal Status of Traditional Medicine and Complementary/Alternative Medicine: A Worldwide Review.\n\nEl Guiche R , Tahrouch S, Amri O, et al.: Antioxidant Activity and Total Phenolic and Flavonoid Contents of 30 Medicinal and Aromatic Plants Located in the South of Morocco.2015; (3): 7–11.\n\nYıldız S, Yılmaz A, Can Z, et al.: Total Phenolic, Flavonoid, Tannin Contents and Antioxidant Properties of Pleurotus Ostreatus and Pleurotus Citrinopileatus Cultivated on Various Sawdust. Gida/J. Food. 2017; 42(3): 315–323. Publisher Full Text\n\nSchneider W, Breitenseher M, Engel A, et al.: The value of core decompression in treatment of femur head necrosis. Orthopade. 2000; 29(5): 420–429. PubMed Abstract | Publisher Full Text Reference Source\n\nAlispahić A, Šapčanin A, Salihović M, et al.: Phenolic content and antioxidant activity of mushroom extracts from Bosnian market. Bull Chem Technol Bosnia Herzegovina. 2015; 44: 5–8.\n\nNimmi OS, George P: Evaluation of the antioxidant potential of a newly developed polyherbal formulation for antiobesity. Int. J. Pharm. Pharm. Sci. 2012; 4(SUPPL.3): 505–510.\n\nLin D, Xiao M, Zhao J, et al.: An Overview of Plant Phenolic Compounds and Their Importance in Human Nutrition and Management of Type 2 Diabetes. (Figure 2).\n\nWidowati W, Fauziah N, Herdiman H, et al.: Antioxidant and anti aging assays of Oryza sativa extracts, vanillin and coumaric acid. J. Nat. Remedies. 2016; 16(3): 88–99. Publisher Full Text\n\nBhekti Rahimah S: UHPLC and LC-MS (ESI-MS) Test For Ethanolic Extract of White Oyster Mushroom [Data set].2021. Publisher Full Text"
}
|
[
{
"id": "129815",
"date": "19 Apr 2022",
"name": "Yi Li",
"expertise": [
"Reviewer Expertise molecular 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\nWhite oyster mushrooms were previously shown to prevent several chronic diseases due to their anti-oxidation and anti-inflammatory effects. This plant thus presents the potential to be developed as an herbal medicine with pharmacological effects. It is important to identify the active compounds in the white oyster mushroom through quantitative studies to guide the development of a standardized process for this herb. Several phenolic compounds and flavonoids were believed to be responsible for the antioxidant and anti-inflammatory effects. However, additional evidence is required to verify and quantify the presence of these compounds in the white oyster mushroom, which is the goal of this study.\nIn this article, the authors measured and analyzed the active substances contained in the ethanol extracts of dried white oyster mushrooms. HPLC and LC-MS methods were used, which are the standard and appropriate methods for such a study. The experimental results regarding the measured concentrations of various metabolites are clearly presented in the tables. The calibration curves of the corresponding compounds measured with HPLC were also reported in the figures to validate the method. LC-MS is used to analyze a wider range of compounds as it does not require the use of compound standards as comparisons. Through the analysis, the authors concluded that only a few active substances are detected in the extracts of white oyster mushrooms, such as coumaric acid, myricetin, and quercetin, while many other compounds though to be effective are not found. The results included in this study can be used to support future developments of herbal medicine that may use white oyster mushrooms as an active ingredient. I approve the publication of this study but have a few suggestions to improve the organization and readability of this article.\nAdditional details in the Methods section would help other researchers to repeat the experiments. For example, what specific instrument models and process parameters were used in the grinding of the dried mushrooms and in the rotary evaporator and water bath processes?\n\nIncluding the sample preparation steps and specific parameters used in HPLC and LC-MS methods may be more useful than introducing the mechanisms and applications of these methods in the Methods section.\n\nMuch of the paragraphs 2-10 in the Discussion section can be shortened and moved to the Introduction as the discussion should focus on explaining the significance of the results and should be more concise.\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": "102108",
"date": "26 May 2022",
"name": "Wahyu Widowati",
"expertise": [
"Reviewer Expertise Medicine",
"biochemistry",
"biotechnology."
],
"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\nPlease reference the recent journal publications. Mostly citations should not be older than 10 years.\nPlease mention the active compound was identified in the conclusion section of the abstract.\nPlease add more information about HPLC and LC-MS methods in the introduction such as principle and advantage of the methods.\nWhat is the criteria for fresh white oyster mushrooms used for extraction? Please add the brand and number catalog of the compound that was used as marker in HPLC in methods section.\nWhy are you using both cinnamic acid and p-coumaric acid as the phenolic acid derivative compound markers? And using both myricetin and rutin as the flavonoid derivative compound markers? Why not choose one? Please explain in the methods section.\nPlease be careful for writing the symbol for all sections e.g. μg/g or g/g in Table 2.\nPlease explain more clearly about results in Table 2, 3, and 4.\nPlease see annotated text manuscript for further comments here:https://f1000researchdata.s3.amazonaws.com/linked/421365.Reviewed-santun_bhekti_rahimah_20220511.pdf\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? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "9224",
"date": "15 May 2023",
"name": "Santun Bhekti Rahimah",
"role": "Author Response",
"response": "Thank you, for the feedback, based on your input, I will try to change and make it clear some parts that are not clear and try to identify some of the unfixed information in the journal: I will check and update my article references I will mention the active compounds identified in the abstract The principle and advantages of the methods HPLC and LC-MS will be added at the introduction Criteria for the fresh white oyster mushroom will be added At the methods, I will explain the reason that choosing markers for identified Table 2 will be checked again Tables 2,3 and 4 will be explained more clearly"
}
]
}
] | 1
|
https://f1000research.com/articles/10-1233
|
https://f1000research.com/articles/12-120/v1
|
01 Feb 23
|
{
"type": "Research Article",
"title": "Rehabilitation: collective construction of a concept in a focus group",
"authors": [
"Tony Ely de Oliveira Cunha",
"Soraia Dornelles Schoeller",
"Maria Manuela Ferreira Pereira da Silva Martins",
"Deisimeri Francisca Alves",
"Caroline Porcelis Vargas",
"Milena Amorim Zuchetto",
"Cristine Moraes Roos",
"Thiara Silveira de Freitas",
"Isabel Cristina Correia",
"Indiana Acordi",
"Lisiane Capanema Silva Bonatelli",
"Sônia Maria Polidório Pereira",
"Sandra Urbano dos Santos",
"Soraia Dornelles Schoeller",
"Maria Manuela Ferreira Pereira da Silva Martins",
"Deisimeri Francisca Alves",
"Caroline Porcelis Vargas",
"Milena Amorim Zuchetto",
"Cristine Moraes Roos",
"Thiara Silveira de Freitas",
"Isabel Cristina Correia",
"Indiana Acordi",
"Lisiane Capanema Silva Bonatelli",
"Sônia Maria Polidório Pereira",
"Sandra Urbano dos Santos"
],
"abstract": "Background: Human dimensions are transversal to the concepts of health rehabilitation, since they motivate care actions. The aim of this study was to understand rehabilitation from the collective discernment of a multidisciplinary group. Methods: This was participatory research that used a qualitative approach combined with brainstorming and conceptual mapping techniques, in a focus group of a team of researchers from the Laboratory of Research, Teaching, Extension and Technology in Health, Nursing and Rehabilitation of a Federal University in Brazil, with data publication authorised by the participants. Participants were 92% women and 8% men aged between 25 and 62 and who were members of the research group. The thematic analysis occurred from the semantics of words and associated connectors. Results: Actions in structured levels were found in the collective understanding of rehabilitation, which enabled the formation of a theoretical care design. The first level presented love, hope, respect, empathy, understanding, esteem, and self-determination. The second level included the pillars of the (re)habilitation process: praxis, intersubjectivity, and comfortable living as a product. The third level showed the dimensions of the person as a whole: spirituality, (re)signification of the meanings of life, functionality of biophysical structures, and biopsychosocial (re)construction — the environment where the dynamic constitution of identity is internalised. The fourth level was the environment where actors move and transform (becoming), where diversity is manifested and the uniqueness of the person is acknowledged. Conclusions: Rehabilitation is a (co)constructed process based on human attributes that facilitate or may not facilitate transformation. It implies rebuilding of the process of living, with the diversity of each person. Its actions are based on love, solidarity, and respect for mutual rights. The concept of rehabilitation can support the operationalisation of research and interdisciplinary care in a multidisciplinary team.",
"keywords": [
"Rehabilitation",
"Reconstruction",
"Functionality",
"Person-Centred Assistance."
],
"content": "Introduction\n\nThe concept of rehabilitation inspires a debate on human dimensions at the centre of health, which focuses on the centrality of the person as an active being, protagonist of choices and decisions around their own lives. However, this debate is still dichotomous, deviating from rehabilitation care to reach human wholeness in the process of reconstruction.\n\nA partial understanding of rehabilitation produces disconnections at different levels of care, which can range from interaction between professionals to the purpose of care, whose most common primary intention is the mobility of the dysfunctional organ/system, selecting it as the only object of care and distances itself from human wholeness.\n\nThinking about health in a fragmented way favours the perpetuation of an instrumentality that limits the reach of human dimensions. Rehabilitation implies identifying the necessary connections between dysfunctional aspects and meeting the global needs of the person, which demands complex care, engaged collaborative teams, and technologies. This requires interdisciplinary research and planning that includes the person, the family, and the support network, meeting rehabilitation demands.1,2\n\nRehabilitation requires person-centred assistance and a more comprehensive design, with actions aimed at rebuilding the quality of life and functional independence of the individual, minimising subsequent disabilities.3,4 On the other hand, ideas that reinforce fragments, especially ones that privilege unilateral specialised practices, may not reach the global purpose of human wholeness.\n\nThe definition of the appropriate terms that guide rehabilitation processes and their parameters of harmony, balance, connections, and disconnections between the constitutive, biopsychosocial and spiritual elements are controversial. They are not separated, except for didactic and/or research purposes, as advocated in evidence-based science.5 There are some questions regarding the meaning of the term. Definitions used to support rehabilitation specialties are claimed to be relevant to that specialty, but can hinder the actions aimed at individuals in the rehabilitation process.6 However, this is a relevant argument for the integration of health rehabilitation actions and interprofessional practices. The idea of interdisciplinary knowledge to understand a design facilitates rehabilitation actions by meeting professional expectations related to a connection around the universe of needs associated with person-centred care, which presupposes multidisciplinary teamwork and decision-making.\n\nIn this universe, it is proposed as an objective to understand the rehabilitation of the person in the conception of a multidisciplinary group, for a collective conceptualization.\n\nDue to high-quality evidence on the strength of emerging needs in the process of rehabilitation, the World Health Organization (WHO) recommends that health systems around the world should have a multidisciplinary workforce to ensure the complete and wholesome care of the individual.7\n\nSpecific skills are necessary in collaborative work to contemplate the complexity of care requiring deep knowledge about the different dimensions of the person. Rehabilitation should be based on the assessment of global needs, which requires integrated training and a concept of the whole person. These questions are essential to guide deliberation in intervention teams about rehabilitation.\n\n\nMethods\n\nThis research used a qualitative approach combined with brainstorming and conceptual mapping techniques, with a focus group method for data collection. Data were collected by the researcher at meetings of the Laboratory of Research, Teaching, Extension, and Technology on Health, Nursing, and Rehabilitation — (RE)HABILITAR, of the Federal University of Santa Catarina, Brazil, with the objective of analysing the collective understanding of (re)habilitation. The focus group discussion meeting was conducted in Portuguese and the analysis translated for this manuscript.\n\nThe perceptions on the proposed topic emerged from brainstorming techniques, with the elaboration of a conceptual map in focus group workshops. The data were registered in a diary29 that was later interpreted by thematic analysis and resulted in the collective conception.\n\nThe methodological course was based on the related literature: 1) Brainstorming promoted the collection of ideas and perceptions through insights about the topic and enabled cognitive associations and interpretations by the group with the help of a mediator. Its principles and rules reinforce the group’s ideas as complementary8; 2) The concept map developed by Novak9 from the Learning Theory by David Ausubel10 aimed at expressing the representation of the existing associations that formed the cognitive propositions, such as the connectives between one or more constructs of semantic units. The proposition was to explain the formation and association of meanings at the participants’ cognitive level11 and; 3) As a non-directive technique, the focus group provided semi-structured discussion practice to obtain information about cognitive meanings, enabling an in-depth discussion of ideas.12\n\nThe study included 13 researchers from several regions of Brazil, from multidisciplinary areas related to health sciences, such as nursing, physiotherapy, pedagogy, psychology, and social work, and members of the teaching and research laboratory. The participants were selected and invited because they were specialists in the area, and they were all researchers from the rehabilitation laboratory. 92% of participants were of female sex and 8% were of male sex, and they were aged between 25–62 years. Of these, 15.38% were at the postdoctoral level, 7.7% at the doctoral level, 30.77% had a master’s degree, 30.77% were graduates, and 15.38% were at the undergraduate level. Notably, 84.62% were professionals in addition to participating in the research group. The authors of this manuscript represent 76.93% of the workshop participants. The other participants were specialists in the field, have experience in rehabilitation studies and/or practices. There is no relevance in relation to the sex and/or gender of the participating individuals.\n\nThe group was led by a facilitator who is one of the authors of this study. He has a master’s degree in health and work management, is a doctoral student in nursing and health, and has experience in training and developing work teams. The facilitator and the participants are from the same research laboratory and declared interest in the collective construction of the concept of rehabilitation, accepting to participate in the group.\n\nThe data were collected in three synchronous meetings, in May 2021, totalling 12 hours, in the Google Meet platform meeting room due to the COVID 19 pandemic. The meetings took place exclusively with the participants, and were supported by PowerPoint with manually annotated observations, conducted by the facilitator author. The first was attended by the 13 participants and provided, respectively: 1) brainstorming experience and 2) concept map development. It aimed at expressing the understanding of cognitive associations discussed over the years regarding the term. The experience of brainstorming was obtained as a product. Subsequently, a conceptual map of the knowledge on the subject was created, which was used as a methodological tool and didactic strategy to problematise and synthesise epistemological and scientific thoughts.13\n\nThe second meeting also had exclusively 13 participants, and involved the following activities: 3) associations around the propositional focal question; 4) discussion of concepts and propositions; The third meeting was for 5) synthesis and validation of ideas for cognitive and collective conceptualisation. For the synthesis, the participants were invited to provide statements that they considered adequate and meaningful to the concept of rehabilitation. Thus, they formed phrases and/or sentences connecting the expressed words.\n\nThe first meeting included (1) a brainstorming experience; after an informal course, the participants saw a slide with empty balloons and the word (RE)HABILITATION in the centre. Subsequently, they suggested words associated with the exposed content as they came to mind, regardless of order. The words and content were arranged in a cloud in the shape of a heart (Figure 1).\n\nConsequently (2), we proceeded to the elaboration of a conceptual map (Figure 2), where we queried about the meaning of (RE)HABILITATION as a focal theme, using the cloud to reorganise ideas and make connections. Therefore, it was necessary to understand the semantic units presented by each member and their association with the contextual universe (Table 1). Thus, the expressions suggested in column one were presented to the participants and they were asked to provide the semantic units in column two for each expression. The units in column two are all the expressions suggested as more adequate to the participants’ understanding of the research topic (RE)HABILITATION.\n\nThe subsequent processes (3 and 4) were used to answer the proposed question about the conception of the meaning of (RE)HABILITATION. The discussion led to the semantic evolution in which the words gained meanings that were expanded, valued, derived, and allocated according to the mental unit that visualised the object of rehabilitation care, i.e., the wholeness of the person. Afterwards (5), there was a synthesis and validation by the participants. They structured sentences from the provided connectives about rehabilitation, according to their understanding. Next, the material produced in the three meetings was read so that they could be confirmed/validated by the group participants.\n\nThis study aimed to explore the meanings attributed to a specific topic in the health area, configuring a public opinion that, according to Resolution 510/2016, Article 1, does not require registration and evaluation by the National Research Ethics Commission (CONEP), waiving ethical approval. The analysis was based on the perception of the participants and this analysis does not identify and does not offer physical or moral risks. Even so, all participants signed consent forms authorizing the publication of their data.\n\nThe analysis begins with notes, searching for meanings, ideas and coding schemes. After familiarization with the data, brainstorming was used to generate the initial codes (themes) that emerged from the main research theme – (RE)HABILITATION. Afterwards, the levels of approximation to the larger theme were verified through the connectives arranged in the conceptual map, as a thematic map of analysis.14 The themes were presented in column one of Table 1 and associated and discussed in their semantic relationships expressed in column two.\n\nDerived from the research theme – (RE)HABILITATION – 13 codes (themes) were precisely identified, mentioned by the participants and justified in their speech during the group meeting with simultaneous notes in the PowerPoint schemes and field diary. The description of the conceptual map used for decoding is shown in Figure 2. The data were manually managed in loco, without the use of software.\n\nAfter producing the map and discussing its contents, the participants who were not authors left the group, and the participating authors proceeded with (5): a synthesis of the data collected in the meetings (3), (4) to form the concept of the term rehabilitation through thematic analysis.14 The relationship between the words displayed on the map was established according to its degree of functionality, meaning and action in a rehabilitation process aimed at a whole person, as discussed with group participants. Therefore, it was essential to validate with the participants to analyse specific connectives (associations between the terms found associated with the larger theme – Rehabilitation) and provide cohesion to phrasal relationships and conceptual production. Above all, it was necessary for capturing the expression of the experience produced by the group of researchers in the concept and in the connections and disconnections of the constructive process of collective conception and confirm the statements.\n\n\nResults\n\nFrom the (RE)HABILITATION theme, which was pre-defined with the objective of understanding the perceptions of the participants, subcategories of words emerged from the brainstorming task. These were then analyzed in their proximity and synonymy (semantics), and the participants then proceeded with the synthesis of the concept.\n\nThinking about a term that encompasses as many meanings as rehabilitation is a task that requires us to delve deeper into the subject to reach common certainties and uncertainties that can be discussed and elaborated in a group. Thus, the idea of having a brainstorming session to create a conceptual map seemed applicable to this group. The objective of all the participants was to conceptualise rehabilitation as a health practice common to all professionals in the area. At first, several disconnected words were attributed to the term.\n\nField notes from the discussion were used to build a word cloud. In Figure 1, a word cloud in the shape of a heart shows the expression of the words that appeared in the brainstorming with their frequency and intensity (participants’ emphasis): intersubjectivity, well-living, praxis, reconstruction, resignification, becoming, empathy, diversity, identity, respect, esteem, love, and self-determination.\n\nThe proximity and synonymy of the ideas represented by different words, typically used in each specialty, indicated the need for deeper articulation to connect ideas and make a cohesive construction of collective thinking that could elucidate the concept of rehabilitation in the conception of the interdisciplinary group, which led to an overall view of the actions.\n\nAn analysis of the meaning through which each word was associated with the main term: (RE)HABILITATION was conducted. At that moment, semantic units appeared with their correspondents. The discussion consisted of finding the associated terms most appropriate to the context, as shown in Table 1.\n\nOnce the semantic units of the words that appeared associated with the concept of (RE)HABILITATION were discussed and understood, connectives were suggested and arranged between several linguistic elements to generate assertions to validate a meaning for the group in the universe of the person undergoing rehabilitation. The conceptual map (Figure 2) expresses the main ideas that generated the concept of rehabilitation conceptualised by the (RE)HABILITATE group. The connection of ideas through semantics and connectives allowed the articulation and cohesion of a sequence of expressions to construct a collective conception that gave rise to the basic concept of rehabilitation actions for the group.\n\nThe themes were reorganized in a circular fashion according to the participants’ understanding of the importance and proximity in the rehabilitation process, defining the levels of the process, and not organised as a hierarchy.\n\n\nDiscussion\n\nThe map (Figure 2) was analysed from the association with the term (RE)HABILITATION, represented from base to surface, in a circular way, in levels of processes, to express the intersubjectivity experienced by the authors involved in a rehabilitation process. A theoretical design that works on conceptual levels is obtained from deepening the conceptualisation of the terms, improving rehabilitation care.\n\nIn the group’s perception, the first level represents attributes for recognising the person in rehabilitation that permeates the relationship with care. At this level, close relationships of trust are built between the professional and the person undergoing rehabilitation. The premise of Honneth’s Recognition Theory15 is that the absence of intersubjective and social recognition causes conflicts and that the subject is built through relationships. Thus, potentiality needs to be recognised, so that the subject can develop and harmonise with the society in which they live. These attributes involved in care facilitate rehabilitation as an inclusive process.16\n\nAt the second level are the pillars of the (re)habilitation process: praxis, intersubjectivity, and well-living as a product. Praxis starts from the reflection between theory and practice, promoting the transformation (becoming) of the person being cared for and of their world.17,18 Intersubjective recognition relationships start from the professional’s and patient’s individualities, producing a relationship that is fundamental to maintain self-determination and well-being.19,20 Reciprocity leads to mutual recognition between those involved in the relationship. Human coexistence is based on experiences between people and on the processes arising from it: individuation and socialisation; that is, existing presupposed interaction and communication with others who are equal.21 Thus, praxis promotes the adaptation of intersubjectivity between the professional and the patient with the aim of promoting well-living.\n\nAt the third level, we found the dimensions of the wholeness of the person: spirituality in a more abstract plane, (re)signification of the meanings of life, functionality of biophysical structures, and biopsychosocial (re)construction in an environment where the dynamic constitution of identity is internalised, reconstructed from the rehabilitation process. The WHO and the World Psychiatric Association recognises spirituality in the area of health, contributing to the well-being of an individual.22–24\n\n(Re)signification, as a form of attribution to personal senses, aims to support the new context of life and provide internal security from support received in the external environment.25 The (re)signification is the cognitive correspondent and a behavioral motivator, not only from a biomedical point of view, considering the potential of each person, focusing on transformations and restoration possibilities aimed at well-living.26 Reconstruction involves the process of rehabilitation, encompassing the aforementioned dimensions with unique dynamics that emerge from relationships between the actors interacting as a labour movement with the aim of rehabilitation.\n\nThe fourth level presents diversity and becoming in the process of life. Becoming, as a movement, makes continuity or discontinuity possible, favouring transformations that emerge from actions and practices, assuming new identity positions.27 The ones involved in the universe of rehabilitation have peculiar, multifaceted characteristics that suggest the diversity and subsidises exchanges that favour transformations.\n\nAs a result of the cognitive exercise of critical thinking and in the complexity of the process, it was understood that praxis makes up the rehabilitation experience. The exercise of theoretical-practical studies and of conceptualisation contributed to the development of basic constructs used in a study organised by the research group in 2021.28\n\nThe understanding of rehabilitation permeates the holistic idea as a phenomenon carried out throughout the life cycle until the process of finitude, as in continuity in time and space, when pursuing the purpose of becoming, of maintaining emancipatory functionality with longevity and quality. This process is complete when integrated by connections of knowledge of interdisciplinary essence, of the linked specialties and, above all, of the subjects involved. It is a process governed by philosophical bases and biopsychosocial and spiritual conceptual designations, which move the actions. This will only make sense with the recognition of the person for their emancipation.\n\nThis study is strengthened by bringing together several mutually dependent facets of rehabilitative care, which aim at human integrality rather than dichotomous conceptions. It denotes the conception of a multidisciplinary group specializing in rehabilitation that works on research in this area. It shows how comprehensive person-centered rehabilitation practices can be strengthened.\n\nThis research extensively explored the conceptions of the participants, through the discussion of each term that appeared in the formation of the concept.\n\nHowever, there are limitations to the generalization of the concept, since other teams have not been tested, even due to the lack of joint work with the sole purpose of rehabilitation. Thus, further studies with multidisciplinary teams are suggested. The strengths and limitations of this study indicate the need to continue research in understanding the conception of care teams, since motivations influence rehabilitative care.\n\n\nConclusion\n\nThe concept of rehabilitation that recognises the person as a whole qualifies as care and is more likely to achieve its inclusive goals, as rehabilitation is a process based on the aegis of human attributes, facilitators or not of the process of transformation and (co)-construction of the person. This process must favour and authenticate singular recognition considering love, solidarity, and mutual respect. The rights defined in this scenario should aim at wholeness and, consequently, promote public policies, especially in health.\n\nScientific research in rehabilitation must presuppose person-centredness. Therefore, it should consider the interdisciplinary theoretical bases that underlie collaborative health practices due to the biopsychosocial and spiritual dimensions that encompass human wholeness.\n\nIn clinical practice, it is fundamental to unveil the rehabilitation process and consider the understanding of the involved factors, since the constructs generate actions, relationships, direct professional decision-making, and the role of the patient through expertise. Thus, evidence assumes the abstract field of subjectivation.\n\n\nFinancial support\n\nThe first author of this work is supported by the Coordination for the Improvement of Higher Education Personnel - Academic Excellence Program CAPES/PROEX, Brazil.",
"appendix": "Data availability\n\nfigshare: Collective Construction of the Group Rehabilitation Concept.pdf, https://doi.org/10.6084/m9.figshare.21648452.v5. 29\n\nThis project includes:\n\n• Portuguese File, Version 1 - Collective Construction of the Group Rehabilitation Concept.pdf (The Planning Meeting, Brainstorming, Brainstorming Results Cloud, Collective Understanding, Understanding the Universe, Design Considerations.).\n\n• English File, Version 2 - Group Rehabilitation Concept.pdf (The Planning Meeting, Brainstorming, Brainstorming Results Cloud, Collective Understanding, Understanding the Universe, Design Considerations.).\n\n• Field annotation diary - descriptive/reflective.pdf.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nCernich AN: Leadership of the ultimate interdisciplinary team: rehabilitation science at NIH. J. NeuroEngineering Rehabil. 2020; 17(67): 67. [published: 29 May 2020]. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: The World Bank. Relatório mundial sobre a deficiência. São Paulo:World Health Organization;2012. (accessed 12 Dec 2021).Reference Source\n\nJesus TS, Bright F, Kayes N, et al.: Person-centred rehabilitation: what exactly does it mean? Protocol for a scoping review with thematic analysis towards framing the concept and practice of person-centred rehabilitation. BMJ Open. 2016; 6: e011959. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRafn BS, Midtgaard J, Camp PG, et al.: Shared concern with current breast cancer rehabilitation services: a focus group study of survivors’ and professionals’ experiences and preferences for rehabilitation care delivery. BMJ Open. 2020; 10: e037280. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNegrini S, Levack WMM, Meyer T, et al.: Why do we need an internationally shared rehabilitation definition for clinical research purposes. Clin. Rehabil. 2021; 35(12): 1657–1660. [published: 31 August 2021]. PubMed Abstract | Publisher Full Text\n\nWade DT: Defining rehabilitation: an exploration of why it is attempted, and why it will always fail. Clin. Rehabil. 2021; 35(12): 1650–1656. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: Rehabilitation in health systems. Geneva:World Health Organization;2017. (accessed 12 Dec 2021).Reference Source\n\nPérez LI, Gutierrez GL, Maldonado AL: Brainstorming como recurso docente para desarrollar competência investigadora. Revista Iberoamericana de Educación. 2017; 74(1): 133–148. Publisher Full Text\n\nNovak JD, Gowin DB, Bob GD: Learning how to learn. Cambridge, UK:Cambridge University Press;2010.\n\nAusubel DP: Educational psychology: a cognitive view. Chicago, IL:Holt, Rinehart and Winston;1968.\n\nFarias MGG, Farias GB: Aplicación de mapas conceptuales como herramientas didáctico-pedagógicas en el área de recursos y servicios de información. Biblios. J. Librariansh. Inf. Sci. 2016; 63: 13–27. Publisher Full Text\n\nSantos AA, Pedreiral C, Freitas RA, et al.: Grupo focal como técnica de coleta de dados na pesquisa em enfermagem: um relato de experiência. Revista Eletrônica Acervo Saúde. 2019; 11(17): e1648. [published: 23 December 2019]. Publisher Full Text\n\nMáximo-Pereira M, Souza PVS, Lourenço AB: Mapas Conceituais e a elaboração de conhecimento científico na história da ciência: algumas aproximações teóricas. Ciência & Educação (Bauru). 2021; 27: e21017. [published: 30 April 2021]. Publisher Full Text\n\nBraun V, Clark V: Using thematic analysis in psychology. Qual. Res. Psychol. 2006; 3(2): 77–101. Publisher Full Text\n\nHonneth A: Luta por reconhecimento: a gramática moral dos conflitos sociais. São Paulo:Editora;2009; vol. 34. .\n\nFuhrmann N: Luta por reconhecimento: reflexões sobre a teoria de Axel Honneth e as origens dos conflitos sociais. Barbaroi. 2013 Jun; 38: 79–96. (accessed 18 Dec 2021).Reference Source\n\nBottomore T: Dicionário do pensamento Marxista. Rio de Janeiro, BR:Jorge Zahar Ed;2001.\n\nAbbagnano N: Dicionário de filosofia. São Paulo, BR:Martins Fontes;2007.\n\nSchoeller SD, Martins MMFPS, Ramos FRS, et al.: Cuidado em enfermagem de reabilitação e processo emancipatório. Revista de Enfermagem Referência. 2020; 2: 1–7. (accessed 15 Dec 2021).Reference Source\n\nCorner EJ, Murray EJ, Brett SJ: Qualitative, grounded theory exploration of patients’ experience of early mobilization, rehabilitation and recovery after critical illness. BMJ Open. 2019; 9: e026348. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVitorino-José RV, Silva BC: O modelo intersubjetivo do si mesmo produzido socialmente: Mead, educação e luta por reconhecimento. Educ. Soc. 2018; 39(142): 73–88. [published: Jan-Mar 2018]. Publisher Full Text\n\nWorld Health Organization: Fifty-second World Health Assembly, Geneva, 17-25 May 1999: verbatim records of plenary meetings and list of participants. Geneva:World Health Organization;1999. (accessed 26 Oct 2021).Reference Source\n\nWorld Psychiatric Association: WPA position statement on spirituality and religion in psychiatry. World Psychiatric Association;2016. (accessed 19 Dec 2021).Reference Source\n\nForti S, Serbena CA, Scaduto AA: Mensuração da espiritualidade/religiosidade em saúde no Brasil: uma revisão sistemática. Cien. Saude Colet. 2020 Apr; 25(4): 1463–1474. PubMed Abstract | Publisher Full Text\n\nRogers C: Tornar-se Pessoa. São Paulo:Editora Martins Fontes;2009.\n\nPaz AC Jr: The dichotomy. Dev. Neurorehabil. 2008 Jul; 11(3): 169–170. [published: 10 July 2009]. Publisher Full Text\n\nRibeiro JHS, Ribeiro MNS, Santo FHE, et al.: Cuidado: contextos e práticas interdisciplinares - saúde, filosofia e educação. Curitiba, BR:Appris;2021.\n\nSchoeller SD, Martins MM, Faleiros F, et al.: Enfermagem de reabilitação. Rio de Janeiro, BR:Thieme Revinter Publicações Ltda;2021.\n\nCunha TE, Schoeller SD, Martins MMFP d S, et al.:Construção Coletiva do Conceito Reabilitação Grupo.pdf. [Dataset]. figshare. 2022. Publisher Full Text"
}
|
[
{
"id": "162193",
"date": "27 Feb 2023",
"name": "Erico Gurgel Amorim",
"expertise": [
"Reviewer Expertise Health science an 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\nThe study brings a contribution to the understanding of rehabilitation and invites the transformation of orthodox practices into inclusive ones. Its relevance is translated into the interdisciplinarity that mediated the construction process of the research and the data that emerged to contemplate the detailed description of the methodological steps undertaken.\nFrom the formal point of view, it enriches the results of the study to understand the structuring and functioning of the rehabilitation laboratory, its origin, ideological foundations, and methodological perspectives undertaken by the group. Is it linked to post-graduation and/or scientific initiation program(s)?\nA gap identified is the information on whether or not the mediator/facilitator was involved in the calculation of the data, providing conceptual contributions and reflections for the data, or if he/she only participated in the analytical stage. It is also important to know if the third focus group had the same number of participants as the previous meetings.\nAnother detail to be clarified is that there was a record that the focus group participants were specialist researchers in the health sciences, yet it mentions that 15.38% of them were at the undergraduate level, which seems contradictory to the previous information, or if it was a complementary undergraduate degree?\nIn the communicative validation stage by the participants, were there proposals for content changes? How were possible divergent opinions moderated by the facilitator? Still, about the methodological procedures, it is important to know if the focus group meetings were recorded. If so, the results of the recordings were used by the researchers for the analysis stage. The 510/2016 Resolution mentioned should be referenced in the final section of the text.\nWhen mentioning analytical substrate by the authors in the thematic analysis referenced at the end of the text, its brief methodological contextualization is recommended to help the reader understand its assumptions and fundamental sequential operations. No less important, when surfacing the idea of emancipatory functionality as a product of rehabilitation, it is convenient to clarify what is the understanding of emancipation from the point of view of the inclusive process, so as not to confuse the reader with the traditional idea of independence. This distinction is fundamental.\nFinally, the text is intended to reach a readership interested in rehabilitation and its assumptions for inclusion. Its publication and reading are recommended for all those interested in contributing to the advancement of care in rehabilitation and inclusion.\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?\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": []
},
{
"id": "225151",
"date": "29 Dec 2023",
"name": "Mette Ryssel Bystrup",
"expertise": [
"Reviewer Expertise Neurorehabilitation approached holisticly"
],
"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 short: The manuscript concerns the exploration of health rehabilitation with a focus on interdisciplinary and huminitic dimensions. Various methodological approaches were used as well as various researchers participated in creating a collective and theoretical understanding of the concept of rehabilitation.\nA very needed and relevant topic to study the more human dimensions of rehabilitation.\nAn inspiring methodological approach with the inclusion of many different perspectives\n\nAbstract: What does \"Actions in structured levels\" mean? And what is the point in differentiating in levels?\nHealth rehabilitation – why not only rehabilitation which is mentioned later in the article?\nWhy is it relevant to distinguish between men and women? It is mentioned in the abstract but not explained why this might be relevant? and why is this distinguishing more relevant than other characteristics such as education etc. as mentioned later in the article?\nIntroduction: In the last paragraph there is reference to questions but there are no questions mentioned.\nMethods: What was the starting point of the participants to consider? How they experience rehabilitation in general?` In their practices? Or their visions of rehabilitation?\n\"The data were registered in a diary\" By whom? and why?\n\"Notably, 84.62% were professionals in addition to participating in the research group.\" what does this mean? I thought all were professionals?\n\"There is no relevance in relation to the sex and/or gender of the participating individuals\" what does this mean? why is it mentioned when it is not relevant?\n\"The facilitator and the participants are from the same research laboratory\" earlier it was mentioned that several regions are represented?\nWas each participant there to represent their own professional perspective or to consider rehabilitation from a more overall perspective? How does this influence the process of confirmation/validation by the group participants\nConfirmation/validation – consider power structures in the group setting and how this influence such confirmation/validation. Maybe discuss this in the discussion\nThe paragraph of methods is long and with many subheadings but also with repetitions. Maybe go through it again to shorten and avoid repetitions\nFigures: The idea of making figures is very relevant in this context. But figures should be overviewing and possible to understand at least when reading a supportive text connected to the figure.\nFigure 1: Is it possible to make a condensed version of the heart? It seems challenging to get hold of because the same words are mentioned several times. Why three color's and not only one or each word having the same color or each participant having their own color? I am not sure I understand the way it is illustrated right now\nFigure 2: I can not follow the expressions of levels since some are then illustrated on being on one line and others drawn in circles? Is there a hierarchy and why? The figure confuses me\nDiscussion: Which consequences does it have that rehabilitation is not distinguished from habilitation? Why is this not mentioned in the article?\nOn the one hand \"holistic\" and \"biopsychosocial\" is mentioned but on the other hand not much attention is placed on the surroundings (including social relations). Only in the introduction this is mentioned: \" This requires interdisciplinary research and planning that includes the person, the family, and the support network, meeting rehabilitation demands\". This was not further unfold in the rest of the manuscript. The social part is missing and should be given further attention in the article.\nAre the results country specific?\nAlmost only Spanish references and WHO… Why? Turns very local in this way but the topic is much more universal\nConclusion: \"In clinical practice\" I am not sure why it is only clinical practice which is referred to since the participants have various professions and rehabilitation is a broader term and not limited to a health care context?\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?\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? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-120
|
https://f1000research.com/articles/11-77/v2
|
08 Mar 22
|
{
"type": "Study Protocol",
"title": "Ex-vivo experimental strategies for assessing unconstrained shoulder biomechanics: a scoping review protocol",
"authors": [
"Jeremy Genter",
"Eleonora Croci",
"Hannah Ewald",
"Andreas M. Müller",
"Annegret Mündermann",
"Daniel Baumgartner",
"Eleonora Croci",
"Hannah Ewald",
"Andreas M. Müller",
"Annegret Mündermann",
"Daniel Baumgartner"
],
"abstract": "Background: Shoulder biomechanics cannot be measured directly in living persons. While different glenohumeral joint simulators have been developed to investigate the role of the glenohumeral muscles in shoulder biomechanics, a standard for these simulators has not been defined. With this scoping review we want to describe available ex-vivo experimental strategies for assessing unconstrained shoulder biomechanics. Objective: The scoping review aims at identifying methodological and/or experimental studies describing or involving ex-vivo simulators that assess unconstrained shoulder biomechanics and synthesizing their strengths and limitations. Inclusion criteria: All unconstrained glenohumeral joint simulators published in connection with ex-vivo or mechanical simulation experiments will be included. Studies on glenohumeral simulators with active components to mimic the muscles will be included. We will exclude studies where the experiment is static or the motion is induced through an external guide, e.g., a robotic device. Methods: We will perform database searching in PubMed, Embase via Elsevier and Web of Science. Two reviewers will independently assess full texts of selected abstracts. Direct backward and forward citation tracking on included articles will be conducted. We will narratively synthesize the results and derive recommendations for designing ex-vivo simulators for assessing unconstrained shoulder biomechanics.",
"keywords": [
"Biomechanics",
"glenohumeral joint",
"human",
"muscle",
"simulator"
],
"content": "Introduction\n\nThe shoulder or glenohumeral joint is one of the most complex joints in the human body. The size of the glenoid fossa is much smaller than the articulating humeral head thereby facilitating a large range of motion but also making the joint prone to instability. Different tissues are present in the shoulder to provide more stability including, most importantly, the rotator cuff muscles. Furthermore, the glenohumeral capsule and some other muscles play a minor role in stabilizing the joint1.\n\nThe glenohumeral joint and its stability has been studied in various conditions. Because joint load cannot be measured directly in the living person, previous studies have used ex-vivo approaches with shoulder simulators or in-silico methods such as musculoskeletal modelling approaches. Here, the focus on shoulder simulators aimed at investigating the passive biomechanics of the shoulder, such as joint stability due to joint reaction forces and its concavity2, glenohumeral capsule stability3 and overall stability of specific motions4. Some research groups have also investigated the role of the muscles for glenohumeral biomechanics. To mimic the forces exerted by the muscles, various shoulder simulators have been developed.\n\nExisting simulators usually consist of a clamping mechanism for the scapula and a cable pulley system that is attached to the tendons inserting at the humerus5–7. Although several simulators have been developed, to date there is no standard defining the design and technical requirements of such simulators. Depending on the specific research question, appropriate detailed simulators have been developed. In particular, shoulder simulators vary in three main aspects: the number of cables to mimic the investigated muscles; the degree of freedom (DOF) of the modelled joints; and the way the muscles are actuated. Existing simulators can be further categorized by the technical solution for generating muscle forces. The most trivial simulators have loaded the muscle cable pulley with passive loads such as springs or simply counterweights. More advanced simulators used active actuators such as pneumatic cylinders or motors to mimic the muscle forces. Although these simulators lack precision of the anatomical representation or physiological muscle recruitment, they are sufficient for answering many research questions and identifying new ones. Besides investigating solely the role of the muscles for shoulder biomechanics, these simulators are employed to address various research questions ranging from joint implants loading8 to the effect of the rotator cuff muscle activation on glenohumeral kinematics7 to the joint reaction forces during daily activity9.\n\nWe performed a preliminary search in Pubmed and JBI Evidence Synthesis, with the search function of the journal's homepage, was conducted and only one systematic review10 on the topic was identified. Williamson et al.10 have conducted a systematic review on ex-vivo experiments for studying rotator cuff tear and instability. While they identified various experimental setups, only few of the included studies used active muscle forces. Furthermore, they categorized the ex-vivo experiments into three main topics: scapular orientation and mobility, muscle activation and humeral motion and condition of the glenohumeral capsule. One of the main findings was that the rotator cuff muscles are loaded statically. Moreover, they found that most likely only two simulators had the ability to load the rotator cuff muscles dynamically but did not use the dynamic mode in the presented studies.\n\nIn this scoping review, we intend to broaden the search from experimental setups for rotator cuff repair and instability to glenohumeral joint experiments. Specifically, we will describe differences and commonalities of ex-vivo glenohumeral experimental set ups and their strengths and limitations.\n\nThis scoping review seeks to identify methodological and experimental studies that describe or involve glenohumeral joint simulators. The characteristics of these simulators will then be assessed to highlight their strengths and limitations. Particularly, the strengths and limitations will be described by answering the following research questions:\n\n• What is the state of art of glenohumeral simulators in research where the muscles are explicitly modeled?\n\n• How accurate are muscle insertion, glenoid fossa and other soft tissues replicated?\n\n• How are the muscles actuated?\n\n• How is the system controlled?\n\n\nProtocol\n\nThe proposed scoping review will be conducted in accordance with the Joanna Bricks Institute (JBI) methodology for scoping reviews11. In particular, the search strategy will be pre-defined. This strategy includes search terms, eligibly criteria and how the study selection is performed. The protocol is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for protocols (PRISMA-P)12. The full review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR)13.\n\nInclusion. Studies will be included if they are ex-vivo (cadaver) or mechanical simulation studies with anatomically accurate artificial humerus and glenoid, and if there are actuated muscle forces of the rotator cuff muscles and deltoid muscle. The motion in the experimental setup has to be induced by at least 3 distinguished actuators of which at least one must be the deltoid muscle and one representing the rotator cuff muscles. There will be no restriction on language and date of publishing.\n\nExclusion. All studies of in-vivo or animal nature will be excluded. A study will be excluded if the motion is constrained through something other than anatomical structures. Moreover, if the net forces or moments in the glenohumeral joint are applied externally, the study will be excluded. Passive movements of the humerus such as guidance through a robotic device are thus generally excluded. Static experiments and tendon extrusion experiments are excluded as well. Lastly, computational musculoskeletal simulation without integrating the results into an ex-vivo simulator will be excluded.\n\nA medical information specialist (HE) drafted the full search for PubMed using text words with synonyms and word variations as well as subject headings around the topic areas ex-vivo, simulator, shoulder muscles and biomechanics. These and possible further pertinent terms were discussed in the team. The search was translated using the Polyglot Search Translator14 and internally peer reviewed by another information specialist. The full search strategy15 was used to conduct searches on PubMed, Embase via Elsevier and the Web of Science Core collection.\n\nIn addition to the database search, we will conduct backward and forward citation tracking of the included studies using Scopus.\n\nAll retrieved references will be exported to Endnote 20 (Clarivate Analytics, 2020) and database duplicates removed according to the Bramer method (which includes using customized import/export filters and several rounds of manually changing the deduplication configuration to reduce the risk of false duplicate removal)16. Zotero could also be used to manage the retrieved references. Additional references identified in backward and forward citation tracking will also be managed the same way.\n\nFollowing a pilot test, titles and abstracts will then be screened by two independent reviewers for assessment against the inclusion criteria for the review. Potentially relevant sources will be retrieved in full and their citation details imported into Endnote 20 and retrieved from Endnote and through the University library Basel.\n\nThe full text of selected citations will be assessed in detail against the inclusion criteria by two reviewers. Reasons for exclusion of sources of evidence at full text that do not meet the inclusion criteria will be recorded and reported in the scoping review.\n\nAny disagreements that arise between the reviewers at each stage of the selection process will be resolved through discussion, or with an additional reviewer. The results of the search and the study inclusion process will be reported in full in the final scoping review and presented in a PRISMA-ScR flow diagram13.\n\nThe data extracted will include specific details about the ability of the shoulder simulators to simulate physiological conditions and motions. This will be reported in tabular form comprising the data listed below. The data extraction will not be limited to rotator cuff and deltoid muscle but all the glenohumeral muscles that are used in the reviewed studies will be reported. Furthermore, the cadaver preparation will be categorized in fresh frozen/embalming in fluids. Moreover, the condition of the soft tissue will be reported. A draft extraction form is provided (see Table 1). The draft data extraction form will be modified and revised as necessary during the process of extracting data from each included evidence source. Modifications will be detailed in the scoping review. Any disagreements that arise between the reviewers will be resolved through discussion and with an additional reviewer. If appropriate, authors of papers will be contacted to request missing or additional data, where required.\n\nWithin the framework of this scoping review, no quality appraisal is planned.\n\nThis data will be listed in a tabular form and the studies will be ordered from most to least physiological according to available data. If the physiological level is the same, then the studies will be ordered alphabetically.\n\nIn addition to the tabular view, we will narratively analyse the results in the review text. Together, these results will provide a comprehensive scope of past research methodologies on this topic and likely identify opportunities on how to further develop such simulators.\n\nThe completed review will be published in an open access peer-reviewed journal.\n\n\nStudy status\n\nStart date of search: June 2021; anticipated completion date of review: February 2022.\n\nCurrent study status: preliminary searches, yes; piloting of the study selection process, yes; formal screening of search results against eligibility criteria, no; data extraction, no; data analysis, no.\n\n\nData availability\n\nNo underlying data are associated with this article.\n\nZenodo: Ex-vivo experimental strategies for assessing unconstrained shoulder biomechanics: a scoping review's detailed search strategy. https://doi.org/10.5281/zenodo.573498215\n\nThis project contains the following file:\n\n- DOKU_Search-strat_Ex-vivo-Sim_20210712_hae.pdf: The search strategy of the scoping review, Ex-vivo experimental strategies for assessing unconstrained shoulder biomechanics: a scoping review, is elaborated in detail in this document.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nWe thank Christian Appenzeller Herzog, University Medical Library, University of Basel, Basel, Switzerland, for his valuable suggestions as part of the internal peer-review of the search strategy.\n\n\nReferences\n\nLugo R, Kung P, Ma C: Shoulder biomechanics. Eur J Radiol. 2008; 68(1): 16–24. PubMed Abstract | Publisher Full Text\n\nLippitt S, Matsen F: Mechanisms of Glenohumeral Joint Stability. Clin Orthop Relat Res. 1993; 291: 20–8. PubMed Abstract\n\nBilluart F, Devun L, Skalli W, et al.: Role of deltoid and passives elements in stabilization during abduction motion (0 degrees-40 degrees): an ex vivo study. Surg Radiol Anat. 2008; 30(7): 563–8. PubMed Abstract | Publisher Full Text\n\nClabbers K, Kelly J, Bader D, et al.: Effect of Posterior Capsule Tightness on Glenohumeral Translation in the Late-Cocking Phase of Pitching. J Sport Rehabil. 2007; 16(1): 41–49. PubMed Abstract | Publisher Full Text\n\nBaumgartner D, Tomas D, Gossweiler L, et al.: Towards the development of a novel experimental shoulder simulator with rotating scapula and individually controlled muscle forces simulating the rotator cuff. Med Biol Eng Comput. 2013; 52(3): 293–9. PubMed Abstract | Publisher Full Text\n\nKedgley AE, Mackenzie GA, Ferreira LM, et al.: The effect of muscle loading on the kinematics of in vitro glenohumeral abduction. J Biomech. 2007; 40(13): 2953–60. PubMed Abstract | Publisher Full Text\n\nWilliamson PM, Hanna P, Momenzadeh K, et al.: Effect of Rotator Cuff Muscle Activation on Glenohumeral Kinematics: A Cadaveric Study. J Biomech. 2020; 105: 109798. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAckland DC, Roshan-Zamir S, Richardson M, et al.: Muscle and Joint-Contact Loading at the Glenohumeral Joint after Reverse Total Shoulder Arthroplasty. J Orthop Res. 2011; 29(12): 1850–8. PubMed Abstract | Publisher Full Text\n\nHughes D, Hodgson S, Nabhani F: Validation of a novel mechanical testing rig for investigating forces in the glenohumeral joint. Current Orthopaedic Practice. 2012; 23(2): 140–145. Publisher Full Text\n\nWilliamson P, Mohamadi A, Ramappa A, et al.: Shoulder Biomechanics of RC Repair and Instability: A Systematic Review of Cadaveric Methodology. J Biomech. 2018; 82: 280–290. PubMed Abstract | Publisher Full Text\n\nPeters MDJ, Godfrey C, McInerney P: Chapter 11: Scoping Reviews (2020 version). In: Aromataris E, Munn Z (Editors). JBI Manual for Evidence Synthesis. 2020. Reference Source\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. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTricco AC, Lillie E, Zarin W, et al.: PRISMA extension for scoping reviews (PRISMA-ScR): Checklist and explanation. Ann Intern Med. 2018; 169(7): 467–473. PubMed Abstract | Publisher Full Text\n\nClark J, Sanders S, Carter M, et al.: Improving the translation of search strategies using the Polyglot Search Translator: a randomized controlled trial. J Med Libr Assoc. 2020; 108(2): 195–207. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGenter J, Croci E, Ewald H, et al.: Ex-vivo experimental strategies for assessing unconstrained shoulder biomechanics: a scoping review's detailed search strategy. 11 November 2021 [Online]. http://www.doi.org/10.5281/zenodo.5734982\n\nBramer WM, Giustini D, Jonge GB, et al.: De-duplication of database search results for systematic reviews in EndNote. J Med Libr Assoc. 2016; 104(3): 9. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "127793",
"date": "19 Apr 2022",
"name": "Louis Ferreira",
"expertise": [
"Reviewer Expertise in-vitro joint motion simulation",
"shoulder biomechanics",
"orthopaedic basic 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\nThe authors present the rationale and protocol for a review of current ex-vivo experimental methodologies used to study shoulder biomechanics. The main objectives of this study are to determine the state of art of glenohumeral simulators that explicitly model the muscles of the shoulder. The authors intend to determine the accuracy of tissue replication while highlighting how many muscles each system actuates and how those muscles are actuated. Study selection criteria is outlined, and search methodology is described. The authors provide a template that will be used to extract key data from each study reviewed.\nI commend the authors for performing this scoping review, which I believe will make it easier to place simulators in the landscape and understand where any gaps in the literature may be. The rationale for this study is clearly outlined. The objectives are clearly described and the need for this review is discussed given the limitations of existing literature review studies.\nThe authors’ study design is partly appropriate for the research question. Although the study design is largely appropriate for the research question, some adjustments to the data extraction form are recommended.\nFirstly, although a previous review has been conducted that examined scapular orientation, it is still important to consider scapular orientation/motion when reviewing simulators that replicate shoulder motion since scapular motion plays a significant role in shoulder biomechanics. The rhythm between the humerus and scapula is important to shoulder stability because as the arm abducts, the scapula rotates under to provide support against the gravity load vector. Some simulators offer simple uni-planar scapular rotation and others offer more complex six-axis scapular mobility. Therefore, I suggest that scapular motion methods also be included in the review of functionality.\nSecondly, in the “Muscle force estimation” and “Control concept” sections of the form, the questions appear to be tailored towards simulators that operate using force-based control. Although force-based control is the most common method of control, other control schemes exist that may be difficult to categorize based on the questions being asked about the control method. Control methods might be broadly categorized in a four-square in which tendon actuation is either force-based or excursion-based, and the control scheme is either closed-loop or open-loop. There are hybrids to these, but that would cover most. Therefore, I recommend to include some broader questions about the controller design to highlight the differences between control techniques.\nI agree with the authors approach that “a study should be excluded if the motion is constrained through something other than anatomical structures”. Some simulators use a rail or other passive guide to constrain the humerus within a particular elevation plane; however, the authors should be careful that some of these simulators use such a guide device as an adjunct which is removed for some protocols. It will be important not to exclude these simulators entirely, but I agree that if the complete motion pathway is not achieved without the guide then they should be excluded. The authors also state that “passive movements of the humerus such as guidance through a robotic device are thus generally excluded”. This is potentially more difficult to determine. Some simulators are augmented with a robot in order to generate varying external loads during motion, such as forces experienced in activities of daily living. In this scheme, the robot is supposed to be transparent in every other direction – meaning that it should impart zero forces other than the simulated load. In practice, this is very difficult to achieve because it requires near perfect real-time force response. Typically, the robot’s presence adds dampening to the whole system which provides a false stability to the motion controller. I suggest that if such a simulator is reported to produce the full motion without the robot, then it might be included; however, I suspect that this will be a difficult criteria to meet. I agree with the authors’ general strategy that if anything is in contact with the arm, then the first choice should be to exclude the simulator; though sometimes external augments are added for a purpose, so I would still search for other papers of that same simulator to determine whether it does have the ability to run unconstrained or unassisted.\nI see that the search term ‘in-vitro’ is included in the search strategy. This is important, as some groups use that term instead of ex-vivo. The applicability of the term ‘in-vitro’ is debatable but it is still important to give it equal weight in the search because some important simulators are not described by their authors as ex-vivo.\nThe study design is clearly described, and relevant papers are referenced to further describe the methodology. There is sufficient detail to allow replication by others.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\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": "9245",
"date": "31 Jan 2023",
"name": "Jeremy Genter",
"role": "Author Response",
"response": "Thank you for commending us to perform this scoping review. Regarding your first adjustment recommendation: In the extraction sheet, we will record this under DOF and constraints, although we agree it could be more clearly stated. Therefore, we amended the extraction sheet and elaborated how we plan to extract the data in section: Data extraction. Regarding your second adjustment recommendation: Thank you for pointing this out. We have amended the extraction sheet and elaborated how we plan to extract the data in section: Data extraction. Regarding your suggestion on constraint motion and robotic assistance: Thank you for this suggestion. There are indeed some simulators that constrain the motion in their first-generation of the simulator. We will still exclude these studies, but if the same simulator is unconstraint in another study, it then will be included. We agree that if an external force is applied with the sole purpose to perturb or induce an additional external load the study should be included. We have amended this in the exclusion subsection. Regarding the search terms: We agree that \"in vitro\" and \"ex vivo\" should be included, thank you."
}
]
},
{
"id": "156345",
"date": "11 Jan 2023",
"name": "Dirk Maier",
"expertise": [
"Reviewer Expertise Shoulder surgery",
"shoulder biomechanics",
"rotator cuff lesions"
],
"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 scoping review aims to benchmark the most advanced glenohumeral simulators. As reviews focusing on unconstrained simulators are scarce, this review provides a good overview of the development of such simulators and their limitations. Thus, it markedly contributes to the improvement of simulators of the next generation. In general, this may be of interest to orthopaedic surgeons and researchers of the shoulder joint, but especially to the biomechanical engineering community, as many aspects of developing and improving such a sophisticated device are being investigated.\nI agree with the authors to choose the design of a scoping review, since the literature provides a wide range of simulators and yields heterogenous data. Furthermore, this scoping review provides a good overview of simulators that avoid the usual simplification of constraining the humerus. Many simulators in the literature constrain the humerus to the abduction plane. This reduces the activation of the stabilizing muscles. On one hand this reduces the complexity to control the humerus, but on the other hand it reduces the importance of the rotator cuff muscles as well.\nThe systematic search is well set up and managed by an information specialist and a wide range of synonyms is used which should identify most relevant simulators.\nCurrent reviews lack the aspect of the control concept, whereas this scoping review aims to identify it. Another strength is that the preparation methods are looked at and how the setup is mechanically designed.\nAlthough I endorse this scoping review, some aspects should be considered. First, I agree with the previous reviewer that the scapula orientation and motion should be identified, as the joint reaction force varies with the orientation of the glenoid. Second, I also agree with the other reviewer that the robotic involvement should have been closer looked at. Although, I suspect there are only a few or no studies that only include a robot to perturbate the humerus.\nLastly, this review is a scoping review and not a systematic review but can be justified as there are too few simulators in the literature to be examined in a meta-analysis. Furthermore, the data is too heterogenous to be included in a statistical analysis.\nOverall, the study is thoroughly designed and well described, and relevant previous publications are referenced. In summary, I recommend publication of this scopiong review with some minor revisions.\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": "9246",
"date": "31 Jan 2023",
"name": "Jeremy Genter",
"role": "Author Response",
"response": "Thank you for highlighting the importance of this scoping review. Regarding your suggestion: Thank you for pointing out that the scapula orientation should be consider. We have amended this in section: Data extraction, where we elaborated how we plan to extract this data. We agree with you that a scoping review is the right choice of methodology. Thank you for recommending for publication of our protocol"
}
]
}
] | 2
|
https://f1000research.com/articles/11-77
|
https://f1000research.com/articles/11-415/v1
|
12 Apr 22
|
{
"type": "Research Article",
"title": "The social isolation enforced by the COVID-19 pandemic reduces the Health-Related Quality of Life score in the adult population of Metropolitan Lima, Peru",
"authors": [
"Valeria C. Morales-Ancajima",
"Cinthya Vasquez-Velasquez",
"Melany De la Cruz",
"Maria Marull",
"Vilma Tapia",
"Gustavo F. Gonzales",
"Valeria C. Morales-Ancajima",
"Melany De la Cruz",
"Maria Marull",
"Vilma Tapia",
"Gustavo F. Gonzales"
],
"abstract": "Background: The objective of this study was to determine the association between health-related quality of life (HRQoL) in adults in Metropolitan Lima, Peru, with experienced social isolation during the coronavirus disease 2019 (COVID-19) pandemic regardless of if the person was infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) adjusted by age, sex and body mass index (BMI). Methods: This cross-sectional study evaluated 256 men and 382 women living in Metropolitan Lima, who were administered the Health-Related Quality of Life (HRQoL) questionnaire (SF-20) virtually to assess their health-related quality of life. Results: Obesity (beta coefficient, 95%CI [95% confidence interval]: -262 – -116), female sex (beta coefficient, 95%CI: -151 – -59), the longest time of mandatory social confinement (beta coefficient, 95%CI: -6.8 – -0.2), and the existence of chronic disease (beta coefficient, 95%CI: -147 – -44) were associated with a low total score of the HRQoL questionnaire. Conclusions: Mandatory social confinement may have harmed the perception of health-related quality of life.",
"keywords": [
"COVID-19",
"Social isolation",
"Health-related quality of life"
],
"content": "Introduction\n\nCoronavirus disease 2019 (COVID-19) is an infectious pathology caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On 12 December 2019, the first case was detected in Wuhan, China,1 and the disease spread so rapidly globally that on 11 March 2020, the World Health Organization (WHO) declared it a pandemic.2 This pandemic has changed the lives of millions of people and has resulted in, as of 28 February 2022, 5,950,433 deaths around the world.3\n\nGovernments applied various public policies to reduce its spread, one of them being social isolation. This measure was applied in several countries around the world, Peru being one of them and probably the longest lasting.4\n\nTrials to test the efficacy of the vaccine were reported at the end of 2020, and vaccination officially began around that time in several countries.5 Vaccination in Peru began on 9 February 2021 and continues in various age groups around the country.6 Currently, 72% of the target population is immunized with two doses of the vaccine. As of 24 December 2021, 73.94% of Lima's population has received two doses of the vaccine.\n\nThe conditions of social confinement have had an impact on people's health, including a decrease in physical activity levels and an increase in sedentary behavior.7 According to a study in Chile, the increase in physical inactivity in the population could have important metabolic implications for the health of the population.8\n\nOn the other hand, the emergence of pandemic-related psychological reactions; cases in people without a pre-existing mental health problem have increased and pre-existing cases were accentuated by confinement.9 A study in China reported moderate to severe levels of stress in the population. The most emotionally affected age group according to this study was young people aged 18-30 years.10\n\nThe human response to a pandemic is not uniform and may vary by country and region within a country. Likewise, given that lethality differs by gender and age, it is possible that coping may also differ. Subjects with co-morbidities, males and older people have had higher case fatality rates.11,12 Peru is one of the countries with the highest case fatality and currently has COVID-19 mortality of 202, 424 people.13\n\nIn Lima, a study by the Consortium of Universities revealed that the mental health of students has deteriorated due to the situation of confinement. Academic factors had a greater impact on mental health, which may lead to a decrease in their performance. Higher levels of anxiety, depression, and stress symptoms were also found. Other factors such as fear of contagion, hours of sleep, and demographic conditions were also assessed as influencing mental health; however, they did not present statistical results that allow further analysis.14\n\nIt is therefore important to have instruments that allow us to assess health-related quality of life (HRQoL) in pandemic circumstances. For this purpose, there are several HRQoL questionnaires,15 which have been successfully applied in different parts of the world in situations other than the COVID-19 pandemic, and which can be applied to the general population or certain pathologies. They can be used to monitor both diseases16 and interventions.17 It would therefore be of utmost importance to use an instrument that assesses HRQOL and to be able to compare it in subjects who have suffered from COVID-19 with those who have not.\n\nThe best known and most validated HRQoL questionnaire for the Spanish-speaking population is the “short form-36” (SF-36). The SF-36, which contains 36 questions, assesses the personal perception of each individual's health in three components: physical, mental and general health component. Its application has been optimal in different age groups.18 This instrument, developed in the United States, has subsequently been translated and applied in Spain.19\n\nIn Peru, a variant of this HRQoL questionnaire called SF-20, containing 20 questions, has been validated for both sea level and high-altitude populations.20,21 Other groups have further reduced the questionnaire and developed the SF-12.17,20\n\n\nMethods\n\nThis was a cross-sectional analytical study. Participants were recruited by a convenience sample of males and females over 18 years of age and residents of Metropolitan Lima, capital of Peru for more than 1 year before the time of participation in the survey. Access to an electronic device was required. Participants who filled in the form after the established date and those who did not agree to participate in the informed consent were excluded.\n\nThis is a cross-sectional analytical study conducted during the months of October and December 2021. For data collection we worked with Google Forms, which contained the survey and informed consent form. The study was advertised on social networks and the contacts of workers from various companies were accessed with the support of the members of the study, and they were sent the link to the survey, which required access to an electronic device.\n\nThe initial sample size was calculated using a random sampling technique for a confidence level of 95% and a statistical power of 80% and was n=600 participants, however, we aimed to survey n=1000 participants. Finally, a population of 638 participants was studied, consisting of men and women aged 18 years or older who had been residents of Metropolitan Lima for more than 1 year before participation. Only 638 participants were evaluated since participants who completed the form after the established date and those who did not agree to participate in the informed consent were excluded. As well, the difficulty of the internet connection problems was a limitation to achieving the initial participant size.\n\nThe socio-demographic characteristics obtained through the survey were age, sex, level of education, place of birth, and current district of residence. Age (years completed) was analyzed as a continuous variable.\n\nAnthropometric measurements obtained from the survey included height (meters), weight (kg), abdominal circumference (cm), and neck circumference (cm) of each participant. Body mass index (BMI) was calculated using the formula: weight (kg) /height (m2). The calculated BMI was classified into the following categories according to the World Health Organization (WHO).18 Waist to height ratio (WHtR) and neck to height ratio (NHtR) were also calculated.\n\nThe data obtained from the questionnaire were: having had or not had illnesses in the last 12 months other than COVID-19, hospitalizations in the last 12 months, surgeries, or medical treatments in the last 12 months before completing the survey. In addition, respondents were asked whether they currently have a chronic illness, whether they are receiving treatment for a chronic illness, and whether they are seeing a psychologist.\n\nData were obtained on the presence of illness or symptoms related to COVID-19 and the time from the occurrence until the date the survey was completed; it was also recorded whether the participant underwent compulsory social isolation as a preventive measure or quarantine as a measure to avoid new infections after contracting COVID-19.\n\nThe type of test used to diagnose COVID-19 was also recorded. 31% were diagnosed by antigen test, 46.8% by polymerase chain reaction (PCR) and 22.2% by serological test.\n\nInformation on COVID-19 hospitalization, vaccination, perceived weight gain, stress, decreased physical activity due to social isolation, and participation in clinical trials of COVID-19 vaccines was included.\n\nCompulsory social isolation was assessed as a dichotomous variable and as a continuous variable by asking how long the respondent engaged in compulsory social isolation.\n\nThe SF-20 questionnaire contains 20 questions related to 7 dimensions: general health, physical function, physical role, emotional role, bodily pain, vitality, and mental health. This survey was translated into Spanish and validated for the Spanish-speaking population,22 determining a Cronbach's alpha greater than 0.7 in all dimensions (0.71-0.94), which indicates a good correlation. In Peru, it was validated for application in populations at sea level and high altitudes.13,17\n\nThe 20 questions of the questionnaire can be divided into 3 main components. The first is the physical component, which includes 8 questions corresponding to the dimensions of physical function, and bodily pain. The second is the mental component, which includes 7 questions. Finally, the third component is general health, which includes 5 questions.\n\nThe analysis was performed with the statistical package STATA version 16 (STATACorp, Texas USA, RRID:SCR_012763).\n\nFor descriptive analysis, continuous variables such as HRQoL score and its physical and mental components, anthropometric measures, and age were expressed as averages and standard deviations. Student's t-test was used to evaluate the differences between the two averages. Likewise, socio-demographic characteristics were evaluated with the Chi-square test, also by sex and COVID-19 status. Linear regression was used to determine the relationship between HRQoL with BMI and COVID-19 status. A value of p<0.05 was considered statistically significant.\n\nThe methodology of using virtual surveys limits the information to a group with the availability of electronic equipment; therefore, we tried to disseminate the survey to population groups of different ages and within the same socio-economic level.\n\nThe study was approved on 11 October 2021 by the Institutional Ethics Committee with code 206670. Each subject voluntarily accepted participation and signed an informed consent form. The data are kept confidential.\n\n\nResults\n\nBased on the inclusion criteria, data from 638 study participants (256 men, and 382 women) were analyzed.40\n\nThe characteristics of the population are shown in Table 1. In total, 40% of participants were men and the remaining 60% were women. Of the study population 56.9% (95% CI 52-59.9%) resided in central Lima, 20.60% (17.4-23.8%) in eastern Lima, 14.1% (11.3-16.8%) in northern Lima, and 3.3% (1.9-4.7%) in western Lima.\n\nIn total, 85.9% (95% CI 83.2-88.6%) of respondents performed compulsory social isolation. Quarantine, for cases where COVID-19 was detected, was performed by 96.9% (95% CI 92.1-99.1%) of those diagnosed with the disease. In the case of vaccines, 77.1% (95% CI 73.9-80.4%) of the study population had completed both doses of the vaccine.\n\nOverall, 19.5% of male respondents studied had COVID-19 while 20.4% of women had COVID-19 (p>0.05). No significant differences were found in anthropometric measurements between the groups with or without COVID-19. The same table shows the total Health-Related Quality of Life (HRQoL) scores and the scores corresponding to the 3 components in participants who had COVID-19 and those who did not. No significant difference was found concerning the final score or any of its components in people with COVID-19 compared to people without COVID-19 (p>0.05).\n\nAge correlated with BMI, waist circumference (WC), neck circumference (NC), HRQoL - mental component (MC) and time after vaccination (TAV); BMI with WC, NC, HRQoL - general health (GH), and time post-vaccination; WC correlated with NC, general health, and TAV (Figure 1).\n\nSpearman correlation *p<0.05, **p<0.01, BMI: body mass index, WC: Waist circumference, NC: neck circumference, HRQoL: health-related quality of life, PC: physical component, MC: mental component, GH: general health, Time of CSC: time of compulsory social confinement, TVA: time after vaccination.\n\nThe health-related quality of life (HRQoL) score correlated with the physical component (PC), mental component (MC), general health (GH) of HRQoL, and time in compulsory social confinement (CSC). The physical component (PC) of the SF-20 correlated with MC of HRQoL, GH of HRQoL, and time in compulsory social confinement (CSC); and finally, MC of HRQoL correlates with SG, time in compulsory social confinement (CSC), and TAV.\n\nThe results related to COVID-19 are presented in Table 2. Among subjects who had COVID-19 82.4% performed compulsory social isolation while in those who did not have COVID-19 86.3% performed compulsory social isolation (p>0.05). Of the subjects who had COVID-19, 96.9% (95% CI 92.1-99.1%) reported having quarantined themselves after diagnosis of the disease.\n\n* p<0.05, Chi-square test.\n\nOf the total subjects diagnosed with COVID-19, only 87.5% (95% CI 80.5-92.7%) had disease symptomatology. Of the subjects who were not diagnosed with COVID-19, 15.9% (95%CI 12.8-19.3%) reported having COVID-19 symptoms. Of the total subjects diagnosed with COVID-19, only 87.5% (95% CI: 80.5-92.7%) had disease symptomatology. Of the subjects who were not diagnosed with COVID-19, 15.9% (95% CI: 12.8-19.3%) reported having COVID-19 symptoms. The initial symptoms of COVID-19 infection are fever, headache, cough tiredness, absence of smell and taste; if they aggravate the disease, shortness of breath manifests.23\n\nThe difference between the two groups is highly significant (p<0.001). Of the subjects who had COVID-19 94.5% (89.1-97.8%) did not require hospitalization while 3.1% (0.9-7.8%) were hospitalized without requiring the intensive care unit (ICU), and 2.3% (0.5-6.7%) required ICU. Of the participants without COVID-19, none were hospitalized.\n\nIn total, 97.7% of subjects with COVID-19 received the COVID-19 vaccine, and in those without COVID-19 96.5% received the vaccine (p>0.05). Overall, 88.3% of subjects with COVID-19 and 84.6% of subjects without COVID-19 received the full dose of vaccine with or without a third booster dose (p>0.05).\n\nRegarding weight gain, 58.6% of COVID-19 subjects and 56.3% of non-COVID-19 subjects felt that they had gained weight from COVID-19 (p>0.05 between groups). Similarly, 68.85% of subjects with COVID-19 and 67.5% of subjects without COVID-19 felt that they had decreased physical activity during compulsory social isolation (p>0.05 between groups). The presence of anxiety or depression during compulsory social isolation was observed in more than half of the subjects evaluated, with no difference between the groups with or without COVID-19 (p>0.05) (Table 2).\n\nOf the population studied, 3.9% of subjects with COVID-19 and 4.3% of subjects without COVID-19 reported having participated in a clinical trial of the COVID-19 vaccine (p>0.05 between groups) (Table 2).\n\nTable 3 presents the results of the multivariate analysis to associate the HRQoL questionnaire total score controlling for the variables BMI, sex, age in years, whether or not hospitalized for COVID-19, time in compulsory social confinement, and history of chronic disease.\n\nIn the crude model, obesity, female sex, time in compulsory social confinement, and the presence of chronic disease are associated with lower total scores on the HRQoL questionnaire. These same variables remain significantly associated in the adjusted model.\n\nTable 4 presents the results of the multivariate analysis to associate the physical component of the HRQoL questionnaire. Obesity, female sex, older age, hospitalization in ICU, longer time in compulsory social confinement, and pre-existence of chronic disease are associated with low values for the physical component of the HRQoL questionnaire. In the adjusted model it is observed that obesity, female sex, longer time in compulsory social confinement, and the existence of chronic disease are associated with a low score on the physical component of the HRQoL questionnaire.\n\nTable 4 also shows the analysis for the association with the mental component of the HRQoL questionnaire. In the crude model, female sex, younger age, and time in compulsory social confinement were the variables associated with lower scores on the mental component of the HRQoL questionnaire. In the adjusted model, obesity, female sex, younger age, time in compulsory social confinement, and pre-existence of chronic disease were associated with lower scores on the metal component of the HRQoL questionnaire.\n\n\nDiscussion\n\nThe present study aimed to determine the perception of HRQoL in the population of Metropolitan Lima according to whether or not they had COVID-19. Health-related quality of life (HRQoL) is an indicator that helps us to measure people's self-perception of their health. This can be measured with the questionnaire validated in Peru, the SF-20,16,20 used in this study. Cronbach's alpha, which is the internal consistency reliability coefficient, shows a value of 0.71, which is considered acceptable.\n\nThe HRQoL score can also be disaggregated into its physical, mental, and general health components. These can be affected by one or all of them together by different factors.\n\nAccording to the results found in the present study, in a population residing in Metropolitan Lima, the capital of the country with approximately 10 million inhabitants and considered a mega-city, the main factor associated with lower HRQoL is the time of compulsory social confinement.\n\nThis variable in the crude and adjusted models showed a statistical significance where the longer the time of confinement, the lower the total HRQoL score and the lower the score in the mental and physical components of HRQoL.\n\nAssociated with this, other factors affecting HRQoL were also observed, such as obesity, female sex, and a history of chronic illness. In itself, having or not having COVID-19 did not affect the HRQoL score. This is an important finding as it is assumed that COVID-19 can lead to health impairment.24 There are likely ethnic or idiosyncratic differences in the response to COVID-19 following an illness. A recent study in Peru shows that patients with COVID-19 do not have a higher rate of postoperative complications than patients without COVID-19.25 Further studies will be needed to follow patients with COVID-19 for longer-term follow-up and to have a clearer conclusion on post-COVID-19 effects.\n\nInterestingly, the health perception of the study participants is affected more by the compulsory social confinement than by the disease itself. A recent study on psychiatric teleconsultations in Peru shows that the third leading cause of psychiatric consultation was related to compulsory social isolation (19.7%), the first two being related to control, follow-up, or worsening of mental health problems before the pandemic (41.9%) and related to the appearance or increase of intrafamily conflicts (21.4%).26\n\nIn similar situations, as in the case of Middle East respiratory syndrome (MERS) in 2015 in South Korea, mandatory social confinement for two weeks showed negative effects on mental health even 4-6 months after the end of social isolation.27 Likewise, a study of 1008 young adult (18-35 years old) residents of the USA reported that higher the level of isolation and lack of social interaction during the context of the COVID-19 pandemic, higher mental disturbances and poorer the performance.28\n\nSeveral factors influence the impact that disease outbreaks can have on the mental state of the population, such as lack of knowledge of the possible means of virus transmission, uncertainty about the future, misinformation, and quarantine. These stressful events negatively affected various behaviors, such as eating habits, sleep, physical activity, and sedentary lifestyles.29 They also cause an increase in anxiety and depression.30\n\nDuring the pandemic, an increase in sleep disturbance and insomnia has been reported, as stress and anxiety affect the quality of sleep during the night and even alter the state of energy during the day.29,30 In addition, although our study has not focused on sleep disorders associated with the pandemic, this has been reported in several studies.31,32 Social confinement times have been shorter than those observed in Peru.\n\nDuring social isolation, the adoption of bad habits increased, such as higher consumption of caloric and unhealthy foods; lower consumption of fresh fruit and vegetables; and a move away from the Mediterranean diet, which is considered to be healthy.29\n\nIn the case of physical activity, the total blockade, the closure of sports facilities, social restriction, and the increase in hours in front of an electronic device, due to work and study, among others, has caused a decrease in physical activity, and in turn an increase in sedentary lifestyles.29\n\nThus, although COVID-19 disease has been described as a fatal disease, it was not the main cause of the damage to the quality of life of the population, but during compulsory social confinement, health risk behaviors increased.\n\nIt can be seen from our results that compulsory social confinement was not an intervention that could have reduced SARS CoV-2 infections. Indeed, the percentage of subjects who underwent compulsory social confinement was similar in those subjects who presented COVID-19 than in those who did not. This is since compulsory social confinement was prolonged, but there was access to massive exposure, such as in the case of markets, banks (government bonds), and public transport, which allowed many people to become infected, who may have been asymptomatic and eventually carried the infection home, infecting other family members with varying degrees of severity.\n\nIn Metropolitan Lima, a greater number of food markets was associated with higher incidence and mortality of COVID-19 (p<0.01 for both); these associations persisted when cases (r=0.49; p<0.01) and deaths (r=0.58; p<0.01) were adjusted for population density.33\n\nIn our study, obesity is a risk factor for lower HRQoL. This corroborates findings from other studies.34 The results of our study show that 57% of the surveyed population perceived weight gain and 67% had a decrease in physical activity during social confinement. According to the Peruvian College of Nutritionists, during the pandemic Peruvians gained an average of 7.7 kg, the main causes being increased caloric food intake and a sedentary lifestyle.35\n\nIn other pathologies, despite having the same care, women show lower HRQoL scores.36 Our results show that women have lower total scores on the HRQoL questionnaire, as well as on its physical and mental components, confirming what has been observed in other pathologies.\n\nA history of chronic illness is also associated with lower scores on the HRQoL questionnaire.37,38 The same has been confirmed in our study.\n\nAge has shown different results in our study. For the total score and the mental component, younger age is associated with lower HRQoL scores, while for the physical component older age is associated with lower HRQoL scores.\n\nThe young population in compulsory social confinement has been subjected to a high degree of stress and anxiety due to the suspension of the face-to-face university and non-university classes and the use of tele-education involving many hours of the day in front of the computer. In our study more than half of the population studied showed cases of anxiety and/or depression during the period of compulsory social confinement. This would be one of the probable conditions for lower scores on the HRQoL questionnaire.\n\nHaving been vaccinated shows a trend towards better HRQoL scores with the second and third doses of the vaccine. The non-significance may be since the number of subjects vaccinated with two or three doses is still insufficient to show statistical significance. Further studies will show whether or not this trend becomes significant.\n\nFor healthy people in mandatory social confinement, lifestyle changes, fear of contracting COVID-19 disease, young age, female sex, history of mental illness and lower coping capacity for stress appear to be risk factors for insomnia.39\n\nIn Peru, the impact of social isolation may have been greater because of the time in which it has occurred. This confinement has not only been inefficient as events with crowds of people occurred simultaneously while in other situations, such as the suspension of classes for school and university students, but it has also significantly affected our educational level. In addition, the long-standing compulsory confinement has not only failed to reduce infections and deaths, but Peru has one of the highest mortality rates in the world, with more than 200,000 Peruvians having died to date.\n\nThe strength of this study was the methodology, which shows within the context of the pandemic the use of technological tools is valuable for an understanding of society and its relationship with health. The instrument used included diverse sections of information, including a validated questionnaire (SF-20) to evaluate de HRQoL, which allowed a wider perspective to analyze causes for the results obtained. This study also shows how the application of health policies or measures should be based on the evaluation and social context.\n\nThis study presents certain limitations as well. First, our database was recollected by convenience; therefore, the results present in this paper cannot be generalized for the entire Peruvian population. However, our results show tendencies consistent with other studies. Also, due to social distancing and COVID-19 regulations, the anthropometric measurements were not able to be taken by health workers but were self-reported by the participants. This is a limitation since the margin of error increases; nevertheless, the correlation between measurements was high. Another limitation present was the research tool, the electronic questionnaire, which was more often completed by respondents with higher education and residents of high-income districts, probably also due to the better quality of Internet connection. Therefore, a follow-up is recommended according to the ethnicity and culture of each country or city.\n\nIn conclusion, although it is not a study that can be extrapolated to a large population, due to the type of design, this study allows us to have prior knowledge about health-related quality of life and how it has been affected to a large or medium extent in the context of the COVID-19 pandemic. The research team proposes longitudinal follow-ups of the population to avoid adverse outcomes in later life.\n\n\nData availability\n\nFigshare: The social isolation enforced by the COVID-19 pandemic reduces the Health-Related Quality of Life score in the adult population of Metropolitan Lima. https://doi.org/10.6084/m9.figshare.19248635.40\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nWHO: Novel Coronavirus – China.2020 [citado 15 de diciembre de 2021]. Reference Source\n\nWHO: COVID-19: cronología de la actuación de la OMS.2020 [citado 15 de diciembre de 2021]. Reference Source\n\nJohns Hopkins University: COVID-19 Dashboard.[citado 1 de marzo de 2022]. Reference Source\n\nPresidencia de Consejo de Ministros: Decreto Supremo N° 044-2020-PCM.[citado 1 de diciembre de 2021]. Reference Source\n\nKarthika C, Swathy Krishna R, Rahman MH, et al.: COVID-19, the firestone in 21st century: a review on coronavirus disease and its clinical perspectives. Environ Sci Pollut Res Int. 1 de octubre de 2021; 28: 64951–64966. Publisher Full Text\n\nGobierno del Perú: DECRETO DE URGENCIA-N° 051-2021.2021 [citado 13 de diciembre de 2021]. Reference Source\n\nPinho CS, Caria ACI, Aras Júnior R, et al.: The effects of the COVID-19 pandemic on levels of physical fitness. Rev Assoc Medica Bras 1992. 2020; 66(Suppl 2): 34–37. Publisher Full Text\n\nCelis-Morales C, Salas-Bravo C, Yáñez A, et al.: Inactividad física y sedentarismo. La otra cara de los efectos secundarios de la Pandemia de COVID-19. Rev Médica Chile. junio de 2020; 148(6): 885–886. PubMed Abstract | Publisher Full Text\n\nCullen W, Gulati G, Kelly BD: Mental health in the Covid-19 pandemic. QJM Int J Med. 30 de marzo de 2020; 113: 311–312. Publisher Full Text\n\nRepišti S, Jovanović N, Kuzman MR, et al.: How to measure the impact of the COVID-19 pandemic on quality of life: COV19-QoL – the development, reliability and validity of a new scale. Glob Psychiatry. 25 de junio de 2020. Publisher Full Text\n\nMiličić Stanić B, Maddox S, de Souza AMA , et al.: Male bias in ACE2 basic science research: missed opportunity for discovery in the time of COVID-19. Am J Physiol-Regul Integr Comp Physiol. junio de 2021; 320(6): R925–R937. PubMed Abstract | Publisher Full Text\n\nLiu B, Spokes P, He W, et al.: High risk groups for severe COVID-19 in a whole of population cohort in Australia. BMC Infect. Dis. 16 de julio de 2021; 21(1): 685. PubMed Abstract | Publisher Full Text\n\nMINSA: Plataforma Nacional de Datos Abiertos.[citado 23 de diciembre de 2021]. Reference Source\n\nChau C, Cassaretto M, Espinoza Reyes M d C, et al.: Salud mental en universitarios del Consorcio de Universidades durante la pandemia. Departamento de Psicología; 2021 [citado 23 de diciembre de 2021]. Reference Source\n\nKarimi M, Brazier J: Health, Health-Related Quality of Life, and Quality of Life: What is the Difference?. PharmacoEconomics. julio de 2016; 34(7): 645–649. Publisher Full Text\n\nShrestha K, Tamrakar N: Health Related Quality of Life of Diabetic Patients. Kathmandu Univ Med J KUMJ. diciembre de 2019; 17(68): 316–321. PubMed Abstract\n\nGonzales-Arimborgo C, Yupanqui I, Montero E, et al.: Acceptability, Safety, and Efficacy of Oral Administration of Extracts of Black or Red Maca (Lepidium meyenii) in Adult Human Subjects: A Randomized, Double-Blind, Placebo-Controlled Study. Pharm Basel Switz. 18 de agosto de 2016; 9(3): E49. Publisher Full Text\n\nSolans-Domènech M, Pane S, Estrada M-D, et al.: Health-Related Quality of Life Measurement in Children and Adolescents: A Systematic Review of Generic and Disease-Specific Instruments. Value Health J Int Soc Pharmacoeconomics Outcomes Res. 1 de julio de 2008; 11: 742–764. PubMed Abstract | Publisher Full Text\n\nAlonso J, Prieto L, Antó JM: The Spanish version of the SF-36 Health Survey (the SF-36 health questionnaire): an instrument for measuring clinical results. Med Clin (Barc.). 27 de mayo de 1995; 104(20): 771–776.\n\nGonzales GF, Rubio J, Gasco M: Chronic mountain sickness score was related with health status score but not with hemoglobin levels at high altitudes. Respir Physiol Neurobiol. 15 de agosto de 2013; 188(2): 152–160. PubMed Abstract | Publisher Full Text\n\nCaballero T, Prior N: Burden of Illness and Quality-of-Life Measures in Angioedema Conditions. Immunol Allergy Clin N Am. 1 de agosto de 2017; 37(3): 597–616. PubMed Abstract | Publisher Full Text\n\nAlonso J, Prieto L, Antó JM: The Spanish version of the Nottingham Health Profile: a review of adaptation and instrument characteristics. Qual Life Res Int J Qual Life Asp Treat Care Rehabil. diciembre de 1994; 3(6): 385–393. PubMed Abstract | Publisher Full Text\n\nKhalaf K, Papp N, Chou JT-T, et al.: SARS-CoV-2: Pathogenesis, and Advancements in Diagnostics and Treatment. Front Immunol. 2020; 11: 570927. PubMed Abstract | Publisher Full Text\n\nNovak P, Mukerji S: Multisystem Involvement in Post-Acute Sequelae of Coronavirus Disease 19 - Novak - 2022. Annals of Neurology - Wiley Online Library. [citado 1 de marzo de 2022]. Publisher Full Text\n\nHuamán Egoávil E, LaGrone L, Ugarte Oscco R, et al.: SARS-CoV-2 infection is not associated with a higher rate of post-operative complications in adult appendectomy patients in Peru: Cross-sectional study. Ann Med Surg 2012. septiembre de 2021; 69: 102582. PubMed Abstract | Publisher Full Text\n\nAlva-Arroyo LL, Murillo JN d P, Martínez M d CEA, et al.: Experiencias de telesalud en un hospital especializado en salud mental durante la pandemia de COVID-19 en Perú. Rev Peru Med Exp Salud Pública. 13 de diciembre de 2021; 38(4): 653–659. Publisher Full Text\n\nJeong H, Yim HW, Song Y-J, et al.: Mental health status of people isolated due to Middle East Respiratory Syndrome. Epidemiol Health. 5 de noviembre de 2016; 38: e2016048. PubMed Abstract | Publisher Full Text\n\nQi M, Li P, Moyle W, et al.: Physical Activity, Health-Related Quality of Life, and Stress among the Chinese Adult Population during the COVID-19 Pandemic - PubMed.[citado 1 de marzo de 2022]. Reference Source\n\nSchmidt RD, Feaster DJ, Horigian VE, et al.: Latent class analysis of loneliness and connectedness in US young adults during COVID-19. J Clin Psychol. 7 de febrero de 2022. PubMed Abstract | Publisher Full Text\n\nZhang Y, Ma ZF: Impact of the COVID-19 Pandemic on Mental Health and Quality of Life among Local Residents in Liaoning Province, China: A Cross-Sectional Study. Int J Environ Res Public Health. enero de 2020; 17(7): 2381. PubMed Abstract | Publisher Full Text\n\nRossi R, Socci V, Talevi D, et al.: COVID-19 Pandemic and Lockdown Measures Impact on Mental Health Among the General Population in Italy. Front Psych. 2020; 11: 790. PubMed Abstract | Publisher Full Text\n\nVoitsidis P, Gliatas I, Bairachtari V, et al.: Insomnia during the COVID-19 pandemic in a Greek population. Psychiatry Res. julio de 2020; 289: 113076. PubMed Abstract | Publisher Full Text\n\nPaz-Aparicio VM, Parras-Garrido E, Gonzales GF, et al.: Association between air pollution in Lima and the high incidence of COVID-19: findings from a post hoc analysis.2021 [citado 1 de marzo de 2022]. Reference Source\n\nYounossi ZM, Henry L: Fatty Liver Through the Ages: Nonalcoholic Steatohepatitis. Endocr Pract. 1 de febrero de 2022; 28(2): 204–213. PubMed Abstract | Publisher Full Text\n\nGestión: COVID-19: peruanos aumentaron en promedio más de 7 kilos por pandemia nndc|PERU|GESTIÓN.[citado 1 de marzo de 2022]. Reference Source\n\nLerma C, Lima-Zapata L, Amaya-Aguilar J, et al.: Gender-Specific Differences in Self-Care, Treatment-Related Symptoms, and Quality of Life in Hemodialysis Patients.[citado 1 de marzo de 2022]. Reference Source\n\nSu LJ, O’Connor SN, Chiang T-C: Association Between Household Income and Self-Perceived Health Status and Poor Mental and Physical Health Among Cancer Survivors. Front Public Health. 2021 [citado 1 de marzo de 2022]; 9. PubMed Abstract | Publisher Full Text\n\nGutteling JJ, de Man RA , Busschbach JJV, et al.: Overview of research on health-related quality of life in patients with chronic liver disease. Neth J Med. agosto de 2007; 65(7): 227–234. PubMed Abstract\n\nMedina-Ortiz O, Araque-Castellanos F, Ruiz-Domínguez LC, et al.: Trastornos del sueño a consecuencia de la pandemia por COVID-19. Rev Peru Med Exp Salud Publica. octubre de 2020; 37(4): 755–761. Publisher Full Text\n\nVasquez-Velasquez C: The social isolation enforced by the COVID-19 pandemic reduces the Health-Related Quality of Life score in the adult population of Metropolitan Lima. figshare. Dataset. 2022. Publisher Full Text"
}
|
[
{
"id": "146543",
"date": "16 Aug 2022",
"name": "Lucie Ecker-Ledesma",
"expertise": [
"Reviewer Expertise Epidemiology",
"Public health",
"antibiotic resistance",
"Infectious disease",
"vaccines"
],
"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 work is important but an improvement of some aspects have to be done in order to present the data in the best way. Additionally, spelling should be checked across the whole document.\nThe importance of this work needs to be better explained. Why is this important? Conclusion of the abstract mentions that: \"Mandatory social confinement may have harmed the perception of health related quality of life\". Is the message that the perception is harmed, or the quality of life?\nWhat is the relation of obesity and HRQoL? This has to be described more deeply.\nReferences are missing in some parts of the document: \"Currently, 72% of the target population is immunized with two doses of the vaccine....\"Ref. \"For this purpose, there are several HRQoL questionnaires\" only one is referenced.\nReference for SF-20 questionnaire mentions Nottingham questionnaire, not SF-20.\nSample size calculation is not clearly defined. Population has to be defined more precisely. It mentions random sampling technique, however participants were selected by convenience.\nAnthropometric measures are presented, however it is not mentioned how they were obtained in methods (if this was an online survey, were they taken by the participants?) This has to be mentioned and the limitation of not having a standardized method to obtain those has to be assessed.\nThe modified SF-20 questionnaire has to be attached as complementary web appendix.\nThe result section mentions inclusion criteria, these have to be mentioned before.\nTables and figures have to be improved:\nTable 1. mentions as description of the values presented mean+/- SD(95% CI), however it seems that ranges are also included? Please clarify. Comparison of the two groups can be made in table 1 in order to see if they are comparable. In table 2, the p-value should be included. It is unclear if the question answer is yes/no for the the questions that involves \"feelings\" presented in table 2, or is it a likelihood scale? p-values should be added in table3. Coefficient of sex in the adjusted model is wrong it should be negative (according to the CI)? Residuals should be discussed. Table 4: please review, some coefficients and CI are mixed up.\n\nDiscussion should mention all the limitations, and this data cannot be generalized for the 10 million inhabitants of Lima, Perú, at the beginning of the discussion, it seems that the study refers to this population. Main results have to be discussed more accurately.\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? 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": []
},
{
"id": "152677",
"date": "19 Oct 2022",
"name": "Bruna Brondani",
"expertise": [
"Reviewer Expertise Epidemiology. Public Health. Pediatric Dentistry. Quality of Life. Social Determinants of Health. Iniquities."
],
"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\nComments to the Author This cross-sectional study evaluated the association between social isolation due COVID-19 and HRQoL in 638 adults in Lima, Peru. Sociodemographic characteristics and anthropometric measures were also collected. As the main result, obesity, female sex, the longest time of mandatory social confinement, and the existence of chronic disease were associated with a low total score of the HRQoL questionnaire.\nWhile the study addressed an interesting topic, there are issues that need to be clarified and improved. In my opinion, the authors fail to present a more sophisticated rationale for the study, since similar articles have been recently published. In this sense, the authors should state what the new information provided and the innovation for international dentistry. I suggest detailing some methodological points that were not addressed or were not clear. Also, it is necessary to rethink the conduct of statistical analysis. Further insights into the text should be provided as follow:\nComments\n\nAbstract\nIn the methods section of the abstract, I find it interesting to mention the age group of the evaluated participants and the statistical analysis conducted.\n\nI suggest including the names of the effect measures obtained by the statistical analysis in the methodology section of the abstract [i.e. \"Beta coefficient (β) and 95% confidence intervals (CI) were calculated\"].\n\nIntroduction\nIn the sentence “This pandemic has changed the lives of millions of people and has resulted in, as of 28 February 2022, 5,950,433 deaths around the world.3”, I suggest that the author update this data.\n\nIn my opinion, the description of SF-20 in the introduction of the manuscript is not necessary. This information could be more useful in the methods section.\n\nThe introduction would benefit from a contextualization of what is already known about social isolation due to COVID-19 and HRQoL. In this sense, the authors could state more clearly what this study adds to the existing literature. Previous studies have already evaluated the impact of COVID-19 on psychosocial outcomes. Therefore, it is questioned why this study become special compared to others already published. The authors should justify more clearly what is the differential of this article.\n\nAt the end of the introduction section, I suggest the insertion of the aim of the study and the conceptual hypothesis, as it guides the investigation itself and is recommended by STROBE guidelines.\n\nMaterial and methods\nI recommend using the STROBE guideline checklist, as well as mentioning its use in the manuscript1.\n\nSome information should be given about the context (Lima, Peru). How many inhabitants are in total in Lima? How many citizens over 18 years of age live in the city? We can see a part of this information in the discussion session. However, this should be clarified in the methods.\n\nIn addition, some information should be given about the study population. What age group is covered in the study? How were participants selected for the survey? How did the researchers find and select the participants?\n\nThe sample calculation provided lacks additional information necessary for its understanding. Were similar parameters used in studies conducted in the literature? Why did the authors want to evaluate 1000 participants?\n\nIn data collection and management, the authors must comment on how the variables were collected, categorized, and worked on in the analysis. For example, it is not possible to understand how the level of education was measured and categorized. Authors must provide response options for each variable collected before reporting how they were categorized for analysis.\n\nSince the participants were supposed to take their own anthropometric measurements, were they given any instructions on how the measurement should be taken?\n\nIn the sentence “Data were obtained on the presence of illness or symptoms related to COVID-19 and the time from the occurrence until the date the survey was completed”, how to know if it was really COVID-19? Symptoms are common to other infectious diseases, such as influenza, for example.\n\nRegarding the SF-20 questionnaire, some additional information should be provided for readers' better understanding. For example, what are the response options for this questionnaire? What is the score variance? Does a higher score indicate a worse HRQoL?\n\n“The methodology of using virtual surveys limits the information to a group with the availability of electronic equipment; therefore, we tried to disseminate the survey to population groups of different ages and within the same socio-economic level.” I believe that the attempt to include a larger sample number compromised the external validity of the results, since representativeness, already limited by non-probability sampling, was already a factor that compromised the representative sample.\n\nWere the participants selected according to the city areas? If that’s the case, a correction factor for this type of sample should be considered to perform the descriptive analysis (sample weight).\n\nIn the statistical analysis, the authors used a multiple linear regression analysis to assess the predictors in the outcome. Again, I recommend that statistical analyses should consider the sample weight or the multilevel structure: participants (level 1) nested into a neighborhood or city area (level 2). Multilevel models take into account the spatial clustering of individuals within areas [Snijders; Boske, 2003]. In this sense, the social isolation due to COVID-19 in HRQoL can be influenced by the environment. The analysis should consider this factor2.\n\nThe data analysis description lacks a clear theoretical framework and referenced to explain the relationship between exposures and outcomes, which are mediated and confounded. Did the authors build this statistical model based on any previous theoretical model? This explanation should be strengthened and need a broad and consistent theoretical framework.\n\nResults\n“Based on the inclusion criteria, data from 638 study participants (256 men, and 382 women) were analyzed.40” What were the inclusion criteria adopted This information must be clarified in the methods section.\n\nIn all tables, add captions for the terms used in the abbreviated form [i.e. “BMI, SD, 95% CI”]. Enter information about the missing data [i.e. \"Unmatched values due to missing data\"].\n\nSome variables are not seen in the tables. For example - socioeconomic level is a factor that can influence the outcome. Also, why didn't the authors collect income? It is also something that can influence. The authors say that individuals belonging to higher socioeconomic levels responded more to the questionnaires. But where is this information?\n\nTable 2 is not clear. For each variable, it must have the category - yes or no - and the values expressed in their respective lines. Thus, the reader cannot interpret the table without having to look for help in the text of the article.\n\n“In the crude model, obesity, female sex, time in compulsory social confinement, and the presence of chronic disease are associated with lower total scores on the HRQoL questionnaire. These same variables remain significantly associated in the adjusted model.” According to table 3, age was also significantly associated with the outcome, right?\n\nWhy did the authors decide to individually assess only the physical dimension of the FS-20 questionnaire?\n\nDiscussion\nI suggest introducing in the first paragraph of the discussion the confirmation/rejection of the hypothesis described in the introduction, as well as reinforcing the originality and contribution of the study to the literature.\n\n“The strength of this study was the methodology, which shows within the context of the pandemic the use of technological tools is valuable for an understanding of society and its relationship with health. The instrument used included diverse sections of information, including a validated questionnaire (SF-20) to evaluate de HRQoL, which allowed a wider perspective to analyze causes for the results obtained.” Are there any studies that prove that this method adopted is reliable and as good as face-to-face interviews and assessments? The fact that participants must measure their own anthropometric measurements is a limitation for me. I question the claim that methodology is a strong point of this 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? 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? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-415
|
https://f1000research.com/articles/12-113/v1
|
30 Jan 23
|
{
"type": "Systematic Review",
"title": "Genome-wide association studies (GWAS) for orthopedic diseases: a systematic review",
"authors": [
"Mir Sadat-Ali"
],
"abstract": "Background and Objective: The objective of this review is to examine genome-wide association studies (GWAS) and whether they have helped treat orthopedic diseases in general and in the Middle East in particular. Methods: Between 2005 and May 2022, we searched MEDLINE, Scopus, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and the Science Citation Index. Our criteria for manuscript analysis included articles involving patients with the presence or absence of the gene and single nucleotide polymorphism (SNP) that were published in the English language. The exclusion criteria included review articles and correspondence. We reviewed all of the articles manually for risk of bias and found no discrepancies in the papers selected. Results: There were 53,652 GWAS articles that reported on the Human Genome Project, out of which 439 studies reported on orthopedics. In total, 38 studies with data from 1,489,834 patients was analyzed. Conclusions: We identified many novel loci that can cause disease processes. We expected these studies to help in predicting diseases and developing new diagnostic procedures, preventive strategies, and better clinical care; however, this has not happened yet. It appears that we must investigate further before translating this knowledge in patient care.",
"keywords": [
"Genome Wide Association Studies",
"Human Genome Project",
"Orthopedics",
"Middle East"
],
"content": "Introduction\n\nJohann Gregor Mendel (1822-1884) developed the concept of genes and inheritance through his work on pea plants (Roberts 1929). The inception of the Human Genome Project (HGP) was first put on paper in 1988 and aimed to map all human genes. It took over 30 years to complete and the final gapless assembly was finished in January 2022. The main goals of the HGP were to determine the correct sequence of 3 billion nucleotide that makes up the whole of human DNA and to find all human genes, sequence the entire genome, and eliminate disease-causing genes. Genome-wide association studies (GWAS) are blueprints that are used to link recognizable associations between genetic variants and diseases among the people, which could eventually predict the occurrence of diseases and identify ideal prevention strategies and treatment modalities. This has led to an increase in GWAS in many countries to identify heritable phenotypes and to institute therapeutic interventions (Uffelmann et al. 2021). To date, GWAS have been carried out on millions of people and have identified 40 diseases that are influenced by the genes they carry (Manolio et al. 2008).\n\nMany GWAS have been carried out to find the genetic influence on orthopedic diseases that run in families, such as adolescent idiopathic scoliosis (AIS) (Kou et al. 2019; Man et al. 2019; Khanshour et al. 2018), developmental dysplasia of the hip (DDH) (Hatzikotoulas et al. 2018), osteoarthritis of the knee (OAK) (Zengini et al. 2018; Soul et al. 2018), osteoarthritis of the hip (OAH) (Styrkarsdottir et al. 2017; Evans et al. 2015), and osteoporosis-related fragility fractures (Guo et al. 2012). The objective of this review is to report the GWAS performed on all orthopedic diseases and to ascertain whether any preventive strategies and treatments were established and succeeded.\n\n\nMethods\n\nBetween 2005 and May 2022, we searched in MEDLINE, Scopus, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and the Science Citation Index with the following key words: orthopedics, Human Genome Project, GWAS, target genes and clinical translation. We supplemented our searches by manually reviewing the bibliographies of eligible studies and relevant review articles. Keywords were used instead of full sentences or questions in multiple search boxes. The keywords were supplemented with synonyms combined by “OR” and all forms of a keywords were garnered by using an asterisk symbol (*) after the root of a keyword. The database search limits were for English Language only.\n\nThe inclusion criteria included studies involving patients that were published in the English language. The exclusion criteria included review articles and correspondence.\n\nThe data was retrieved to find out the number of studies performed, the specific diseases identified and the total number of subjects screened. We pooled the numbers of each disease studied and compared the diseases and number of subjects. Lastly, the data was meticulously searched for any recommended preventive strategies and suggestive treatments. All of the articles were reviewed by the author for risk of bias, who found no discrepancies in the papers selected because only the presence or absence of the gene and SNP was considered. This review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Moher et al. 2009; Sadat-Ali & Sadat-Ali 2022).\n\n\nResults\n\nThere were 53,652 GWAS that reported on the Human Genome Project, out of which 439 studies reported on GWAS and orthopedics. After the inclusion and exclusion criteria were considered, 38 studies with data from 1,489,834 patients were analyzed (Figure 1). Table 1 displays the data from those 38 studies. In total, 21 orthopedic conditions were studied, with the majority being osteoarthritis (867,648), back pain (158,000), AIS (125,015), ligament injuries (102,979), bone mineral density (BMD) (64,765) and osteonecrosis of the femur head (60,217) (Figure 2). Overall, 18 countries were represented in the studies, with the United States of America (16), United Kingdom (14) and China (14) being the most common (Figure 3). Unfortunately, none of the studies were carried out in the Middle East. Based on the review, the GWAS were unable to predict any diseases but were able to help develop treatments for ankylosing spondylitis and osteoporosis.\n\nList of all published GWAS analyzed.\n\n\nDiscussion\n\nThis review shows that the Human Genome Project and GWAS have done tremendous work in genetic mapping many diseases in general and a few common orthopedic diseases. The GWAS on osteoarthritis (OA), which affects more than 300 million people around the world, has some positive findings and identifies 100 independently associated risk variations, out of which 52 were not described or known to be associated with OA (Boer et al. 2021). The other sites of osteoarthritis, such as the hip and knee, were also studied (Soul et al. 2018; Styrkarsdottir et al. 2017; Evans et al. 2015; Panoutsopoulou et al. 2017). Osteoarthritis of the knee (OAK) was reported to be common in over 53% of men and 60.9% of women in Saudi Arabian populations and has continued to increase. In 2011, funding was requested by the author but not awarded to assess the association between genetic polymorphisms and OA among Saudi Arabian men and women. (Al-Omran, Sadat-Ali and AlHammam 2011).\n\nAIS was the second most common disease that the GWAS found was genetically influenced. It affects 0.47-5.2% of healthy children and during growth spurts, the curves increase (Konieczny et al. 2013). Overall, 25 different loci were identified in a variety of ethnic groups (Kou et al. 2019; Man et al. 2019; Khanshour et al. 2018; Zhu et al. 2015; Grauers et al. 2015). Further sub group analysis highlighted two SNPs (rs1190870 and rs678741) that were significantly associated with the presence of right thoracic curves (Man et al. 2019). None of the studies were conducted on Middle Eastern populations, even though a target gene and three SNPs were identified for AIS in the Saudi Arabian population (Sadat-Ali et al. 2011; Al-Othman et al. 2017). In the Middle East, most female children remain covered from the neck down, allowing the AIS to remain undetected until it’s too late. A clinical translation of the GWAS could promote early diagnosis of AIS and prevent surgery that causes tremendous morbidity.\n\nDevelopmental dysplasia of the hip (DDH) was another disease that the GWAS examined. Hatzikotoulas et al. (2018) performed a GWAS on DDH in the United Kingdom and reported that there is strong genetic association locus at GDF5 (rs143384). At the same time, the author and his associates in Saudi Arabia conducted a study with 473 subjects (100 patients, 200 parents, 73 siblings and 100 healthy controls) (Sadat-Ali et al. 2018) and reported that there was a definite relationship between GDF5 (SNP rs143383) and DDH. For the first time, it was found that the genotype TT and the T allele were overly expressed in the patients and the fathers. In the United Kingdom, it was reported that 1-2 babies out of 1000 require DDH treatment (https://www.nhs.uk/conditions/developmental-dysplasia-of-the-hip/). A recent meta-analysis found that in Saudi Arabia, incidence of DDH was 10.46 out of 1000, and in over 40% of patients was the result of family history. The meta-analysis found an average of 22,336 cases at any given time in the country with 7,119 new cases added yearly (Sadat-Ali 2020). Many cases of DDH are clustered in specific towns and cities. If the GWAS can be clinically translated, early diagnosis will provide clinically beneficial improvements in patient care and ensure that children can have non-surgical DDH treatment, which could limit the long term morbidity and complications of surgical treatments.\n\nThe other diseases that GWAS showed were genetically influenced and common in clinical practice included back pain, ligament injuries, osteonecrosis of femur heads and osteoporosis related issues. Clinical translation based on GWAS could improve prediction and progression for some diseases. These studies could identify therapeutic targets leading to therapeutic agents. Unfortunately, even after screening over a million patients, the benefits in drug discovery were inappreciable. From an orthopedic surgeon’s perspective, GWAS linked two genes that were identified as RANKL/ESR1 and TNFR1/PTGER4/TYK2. The former allowed drugs like denosumab, a potent antiresorptive, to be developed, whereas the other allowed fostamatinib to be developed for ankylosing spondylitis (Schwarz and Ritchlin 2007; Tak and Kalden 2011).\n\nOn the aspect of disease prediction, ScolioscoreTM is supposed to identify patients whose curve will progress in AIS (Visscher et al. 2017). Unfortunately, the independent validation could not confirm this (Carlson 2011).\n\nOur study has certain limitations. First, we did not discuss all of the orthopedics diseases reported in the GWAS in this review in detail. Second, the review showed that a limited number of diagnostic procedures could predict the diseases based on the GWAS studies. Moreover, the ScolioscoreTM that could predict the progression of curves in AIS that came out of these studies still needs to be independently validated. Compared to the rest of the world, GWAS in Middle Eastern countries are so low that the magnitude of reports is markedly incomparable (99.99 to 0.01%) (Suri et al. 2018).\n\nIn conclusion, HAP and GWAS have produced and identified many novel loci that can cause disease processes. Many more studies are being conducted to find new loci and genetic ancestries and these studies were expected to help predict diseases and develop new diagnostic methods, preventive strategies and better clinical care, but this has not happened yet. Our review showed that a limited number of drugs came into existence based on the GWAS studies. One test that could predict the progression of curves in AIS came out of these studies, but it still needs to be independently validated. It appears that we must continue investigating instead of translating this knowledge to improve patient care.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nPRISMA checklist for ‘Genome-wide association studies (GWAS) for orthopedic diseases: a systematic review’, 10.6084/m9.figshare.21347628.v1 (Sadat-Ali 2022).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAl-Omran AS, Sadat-Ali M, AlHammam N: Genetic Susceptibility to osteoarthritis of knee of the among Saudi Arabians. A personal communication.2011.\n\nAl-Othman AA, Sadat-Ali M, Amer AS, et al.: Genetic Markers for Adolescent Idiopathic Scoliosis on Chromosome 19p13.3 among Saudi Arabian Girls. Asian Spine J. 2017; 11(2): 167–173. PubMed Abstract | Publisher Full Text\n\nArbeeva L, Yau M, Mitchell BD, et al.: Genome-wide meta-analysis identified novel variant associated with hallux valgus in Caucasians. J. Foot Ankle Res. 2020; 13(1): 11. PubMed Abstract | Publisher Full Text\n\nBaek SH, Kim KI, Yoon KS, et al.: Genome-wide association scans for idiopathic osteonecrosis of the femoral head in a Korean population. Mol. Med. Rep. 2017; 15(2): 750–758. PubMed Abstract | Publisher Full Text\n\nBoer CG, Konstantinos H, Southam L, et al.: Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell. 2021; 184(18): 4784–4818.e17. PubMed Abstract | Publisher Full Text\n\nCarlson B: ScoliScore AIS Prognostic Test Personalizes Treatment for Children With Spinal Curve. Biotechnol. Healthc. 2011; 8(2): 30–31.\n\nCheung JPY, Kao PYP, Sham P, et al.: Etiology of developmental spinal stenosis: A genome-wide association study. J. Orthop. Res. 2018; 36(4): 1262–1268. PubMed Abstract | Publisher Full Text\n\nEvans DS, Cailotto F, Parimi N, et al.: Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis. Ann. Rheum. Dis. 2015; 74(10): 1861–1867. 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PubMed Abstract | Publisher Full Text\n\nKim SK, Roos TR, Roos AK, et al.: Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy. PLoS One. 2017; 12(3): e0170422. PubMed Abstract | Publisher Full Text\n\nKim SK, Nguyen C, Jones KB, et al.: A genome-wide association study for shoulder impingement and rotator cuff disease. J. Shoulder Elb. Surg. 2021a; 30(9): 2134–2145. PubMed Abstract | Publisher Full Text\n\nKim SK, Nguyen C, Avins AL, et al.: Identification of Three Loci Associated with Achilles Tendon Injury Risk from a Genome-wide Association Study. Med. Sci. Sports Exerc. 2021b; 53(8): 1748–1755. PubMed Abstract | Publisher Full Text\n\nKim SK, Nguyen C, Horton BH, et al.: Association of COA1 with Patellar Tendonitis: A Genome-wide Association Analysis. Med. Sci. Sports Exerc. 2021c; 53(11): 2419–2424. PubMed Abstract | Publisher Full Text\n\nKonieczny MR, Senyurt H, Krauspe R: Epidemiology of adolescent idiopathic scoliosis. J. Child. Ortho. 2013; 7(1): 3–9. PubMed Abstract | Publisher Full Text\n\nKoster R, Panagiotou OA, Wheeler WA, et al.: Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients. Int. J. Cancer. 2018; 142(8): 1594–1601. PubMed Abstract | Publisher Full Text\n\nLin X, Li L, Liu X, et al.: Genome-wide analysis of aberrant methylation of enhancer DNA in human osteoarthritis. BMC Med. Genet. 2020; 13(1): 1. PubMed Abstract | Publisher Full Text\n\nMan GC, Tang NL, Chan TF, et al.: Replication Study for the Association of GWAS-associated Loci With Adolescent Idiopathic Scoliosis Susceptibility and Curve Progression in a Chinese Population. Spine (Phila Pa 1976). 2019; 44(7): 464–471. PubMed Abstract | Publisher Full Text\n\nManolio TA, Brooks LD, Collins FS: A HapMap harvest of insights into the genetics of common disease. J. Clin. Invest. 2008; 118(5): 1590–1605. PubMed Abstract | Publisher Full Text\n\nMirabello L, Koster R, Moriarity BS, et al.: A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma. Cancer Discov. 2015; 5(9): 920–931. 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\n\nNakajima M, Takahashi A, Tsuji T, et al.: A genome-wide association study identifies susceptibility loci for ossification of the posterior longitudinal ligament of the spine. Nat. Genet. 2014; 46(9): 1012–1016. Publisher Full Text\n\nPanoutsopoulou K, Thiagarajah S, Zengini E, et al.: Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis. Ann. Rheum. Dis. 2017; 76(7): 1199–1206. PubMed Abstract | Publisher Full Text\n\nPei YF, Hu WZ, Yan MW, et al.: Joint study of two genome-wide association meta-analyses identified 20p12.1 and 20q13.33 for bone mineral density. Bone. 2018; 110: 378–385. PubMed Abstract | Publisher Full Text\n\nRangkasenee N, Murani E, Brunner RM, et al.: Genome-Wide Association Identifies TBX5 as Candidate Gene for Osteochondrosis Providing a Functional Link to Cartilage Perfusion as Initial Factor. Front. Genet. 2013; 4(4): 78. Publisher Full Text\n\nRoye BD, Wright ML, Matsumoto H, et al.: An Independent Evaluation of the Validity of a DNA-Based Prognostic Test for Adolescent Idiopathic Scoliosis. J. Bone Joint Surg. Am. 2015; 97(24): 1994–1998. Publisher Full Text\n\nRoos TR, Roos AK, Avins AL, et al.: Genome-wide association study identifies a locus associated with rotator cuff injury. PLoS One. 2017; 12(12): e0189317. PubMed Abstract | Publisher Full Text\n\nRoberts HF: Plant Hybridization before Mendel. Princeton:Princeton University Press;1929.\n\nSadat-Ali M, Al-Omran AS, Al-Othman AA: Genetic markers for idiopathic scoliosis on chromosome 19p 13.3 among Saudi Arabian girls. A pilot study. Ind. J. Human Genetics. 2011; 17(1): 13–16. PubMed Abstract | Publisher Full Text\n\nSadat-Ali M, Al-Habdan IM, Bubshait DA: Genetic Influence in Developmental Dysplasia of the Hip in Saudi Arabian Children Due to GDF5 Polymorphism. Biochem. Genet. 2018; 56(6): 618–626. PubMed Abstract | Publisher Full Text\n\nSadat-Ali M: Developmental Dysplasia of the Hip (DDH) in Saudi Arabia: Time to Wake up. A Systematic Review (1980-2018). Open J. Epidemiol. 2020; 10: 125–131. Publisher Full Text\n\nSadat-Ali M, Sadat-Ali M:PRISMA_2020_checklist.docx. figshare. [Dataset].2022. Publisher Full Text\n\nSchwarz EM, Ritchlin CT: Clinical development of anti-RANKL therapy. Arthritis Res. Ther. 2007; 9(Suppl 1): S7. PubMed Abstract | Publisher Full Text\n\nSakamoto Y, Yamamoto T, Sugano N, et al.: Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head. Sci. Rep. 2017; 7(1): 15035.\n\nSkuladottir AT, Bjornsdottir G, Ferkingstad E, et al.: A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome. Nat. Commun. 2022; 13(1): 1598. PubMed Abstract | Publisher Full Text\n\nSood RF, Westenberg RF, Winograd JM, et al.: Genetic Risk of Trigger Finger: Results of a Genomewide Association Study. Plast. Reconstr. Surg. 2020; 146(2): 165–176.\n\nSoul J, Dunn SL, Anand S, et al.: Stratification of knee osteoarthritis: two major patient subgroups identified by genome-wide expression analysis of articular cartilage. Ann. Rheum. Dis. 2018; 77(3): 423. PubMed Abstract | Publisher Full Text\n\nStyrkarsdottir U, Stefansson OA, Gunnarsdottir K, et al.: GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures. Nat. Commun. 2019; 10(1): 2054. PubMed Abstract | Publisher Full Text\n\nStyrkarsdottir U, Helgason H, Sigurdsson A, et al.: Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis. Nat. Genet. 2017; 49(5): 801–805. PubMed Abstract | Publisher Full Text\n\nSuri P, Palmer MR, Tsepilov YA, et al.: Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. PLoS Genet. 2018; 14(9): e1007601. PubMed Abstract | Publisher Full Text\n\nTak PP, Kalden JR: Advances in rheumatology: new targeted therapeutics. Arthritis Res. Ther. 2011; 13(Suppl 1): S5. PubMed Abstract | Publisher Full Text\n\nTashjian RZ, Granger EK, Farnham JM, et al.: Genome-wide association study for rotator cuff tears identifies two significant single-nucleotide polymorphisms. J. Shoulder Elb. Surg. 2016; 25(2): 174–179. PubMed Abstract | Publisher Full Text\n\nUffelmann E, Huang QQ, Munung NS, et al.: Genome-wide association studies. Nat. Rev. Methods Primers. 2021; 1: 59. Publisher Full Text\n\nVisscher PM, Wray NR, Zhang Q, et al.: 10 Years of GWAS Discovery: Biology, Function, and Translation. Am. J. Hum. Genet. 2017; 101: 5–22. PubMed Abstract | Publisher Full Text\n\nWei J, Li M, Gao F, et al.: Multiple analyses of large-scale genome-wide association study highlight new risk pathways in lumbar spine bone mineral density. Oncotarget. 2016; 7(21): 31429–31439. PubMed Abstract | Publisher Full Text\n\nZengini E, Hatzikotoulas K, Tachmazidou I, et al.: Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat. Genet. 2018; 50(4): 549–558. PubMed Abstract | Publisher Full Text\n\nZhu Z, Tang NL, Xu L, et al.: Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls. Nat. Commun. 2015; 22(6): 8355.\n\nZhu Z, Xu L, Leung-Sang TN, et al.: Genome-wide association study identifies novel susceptible loci and highlights Wnt/beta-catenin pathway in the development of adolescent idiopathic scoliosis. Hum. Mol. Genet. 2017; 26(8): 1577–1583. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "187936",
"date": "29 Aug 2023",
"name": "Mehdi Momen",
"expertise": [
"Reviewer Expertise Quantitative genetics and 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 aims to evaluate the impact of genome-wide association studies (GWAS) on understanding and treating orthopedic diseases, particularly in the context of the Middle East. The study collected and analyzed GWAS articles related to orthopedic diseases between 2005 and May 2022, focusing on articles published in English. The study concludes that while GWAS have identified genetic markers linked to orthopedic diseases, these findings have not yet led to substantial improvements in patient care, predictive strategies, or the development of new treatments. Overall, while the paper presents interesting findings about the role of GWAS in orthopedic diseases, it's important to consider these limitations when interpreting its conclusions and implications. So it can be indexed after a major revision.\nMajor issues:\n\nThe paper doesn't provide details about the methods used in individual GWAS studies, including their study design, genotyping platforms, and statistical approaches. Important information about the quality of included studies, such as their sample sizes, study populations, and potential confounders, is not extensively discussed.\n\nFigure Descriptions: It appears that the figure descriptions need more improvement. For example, in Figure 2, the percentages of certain diseases have not clearly presented. Additionally, Figure 3 lacks a label for the y-axis.\n\nFigure 1 Description: The description provided for Figure 1 seems to be incomplete and might needs further elaboration and additional details.\n\nLanguage and Sentence Structure: The manuscript could benefit from improvements in language and sentence structure. For instance, in the abstract, the section titled \"Background and Objective\" requires a comprehensive revision. Similarly, in the \"Methods\" section, the placement of \"Between 2005 and May 2022\" appears to be incorrect.\n\nResults Elaboration: It would be valuable to have more comprehensive elaborations on the results to better understand the findings.\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? No\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
},
{
"id": "193284",
"date": "18 Sep 2023",
"name": "Serra Kaya",
"expertise": [
"Reviewer Expertise Computational genomics"
],
"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 this systematic review paper, the author's primary objective was to identify genome-wide association studies (GWAS) related to orthopedic diseases published worldwide within the years 2005-2022, with a specific focus on the Middle East. He concluded that out of 53,652 GWAS articles, only 38 were related to orthopedic diseases. These findings were summarized in a table, which included the results of these studies, supplemented by some discussion on novel loci associated with these diseases.\nThe objective of this review was to comprehensively report on GWAS conducted on orthopedic diseases. Nevertheless, it's worth noting that there are some notable articles related to conditions like OA or osteoporosis that appear to be absent from this review. For instance, studies such as Morris et al. 2019 in Nature Genetics1 and Tachmazidou et al. 2019, also in Nature Genetics2, provide valuable insights in these areas.\nFurthermore, a substantial issue arises as 21 out of the 38 studies are merely listed in a table without detailed explanations in the main text. A comprehensive review should provide adequate descriptions and analyses of the cited papers within the main body rather than relegating them solely to a table.\nAdditionally, the author's discussion appears somewhat biased, as it predominantly delves into the author's own papers in detail while providing only brief mentions of other relevant studies. For a more impartial and informative review, it's essential to offer consistent treatment of all relevant papers discussed.\nAddressing specific sections, the abstract states that review articles were excluded, but if any related review articles exist, they should be cited and their differences from the author's review should be highlighted.\nThe author's claim of \"analyzing\" 38 studies in the abstract and results section may cause confusion. This is a review paper, not an analysis; thus, it should be explicitly stated as a comprehensive overview of the literature.\nIn the discussion section, there is an irrelevant detail regarding “funding requested in 2011 but not awarded”. This information should be omitted. Furthermore, if a citation regarding associations of SNPs and OA is included, it should be followed by a concise summary or conclusion of the study's findings.\nRegarding Figure 1, improving the flowchart is essential. The author should briefly mention which databases were used to obtain the initial 439 articles and provide criteria for excluding 377 articles. These details may be covered more extensively in the main document but should be added to the flowchart briefly.\nIn Figure 2, the overlapping percentages should be repositioned for clarity, and the legend and title need adjustments to reflect that this is a pie chart displaying percentages, not absolute numbers.\nFinally, for Table 1, an additional column specifying the database(s) used for the GWAS would enhance its utility.\nThese revisions will contribute to a more informative and well-structured review of the 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? 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? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-113
|
https://f1000research.com/articles/12-112/v1
|
30 Jan 23
|
{
"type": "Opinion Article",
"title": "The whole is other than the sum of its parts: the untapped potential of spatial data from archaeological fieldwork",
"authors": [
"Peter McKeague"
],
"abstract": "Spatial data is fundamental to documenting our past, underpinning research questions and informing the decisions we – and others – take in the protection, understanding and stewardship of the historic environment. Investing in organising and sharing spatial data typically delivers a benefit to cost ratio of up to sixteen times the outlay. In contrast, existing practices are saturated with inefficiency. Even if the spatial data reaches an archive, it can be hard to find, access and use. It is often in the wrong format and incompatible with similar data from different projects. Through the European Union Infrastructure for Spatial Information in Europe (INSPIRE) Directive curators of protected sites data (scheduled monuments, listed buildings etc.) are required to publish metadata, view and download services. In contrast to these ‘curated’ datasets there is neither the mandate, nor the mechanisms to coordinate, curate and share, data created through archaeological fieldwork and research. The degree of standardisation in documenting fieldwork recording and archival deposition varies considerably, posing challenges to the reuse of data. Both are key factors in not realising the potential of ‘collated data’ from multiple sources. The opportunities to develop a consistent approach for making greater use of data routinely created through fieldwork and research are explored using case studies from Scotland. Despite the obvious benefits of developing a consistent approach to spatial data from fieldwork, the framework, standards, specifications, guidance and infrastructure to realise that potential are absent. Archaeological data can and should contribute to delivering wider societal benefits, including environmental monitoring, digital twins and climate change. To contribute meaningfully to these and other societal challenges, archaeological data needs to be accessible and consistent.",
"keywords": [
"Archaeology",
"Data Standards",
"Environment",
"Geospatial data",
"Heritage",
"Societal benefit"
],
"content": "Introduction: reasons for and benefits of harmonising data at scale\n\nThe benefits of collating and sharing spatial data systematically from multiple providers, to address a range of environmental issues or to underpin research, have long been recognised. Developed in response to ever increasing environmental challenges such as flooding and pollution on a trans-national scale, the European Union Infrastructure for Spatial Information in Europe (INSPIRE) Directive (2007) provides the mandate and framework for public organisations to share environmentally related datasets within their own and neighbouring countries to improve public access, inform decision making and improve the stewardship of the environment. Initiatives like One Geology, a partnership of 190 organisations from 121 countries, have developed their own network developing the framework, infrastructure and standards for their discipline. Collating data from multiple sources and many countries is also at the heart of the multi-disciplinary The Role of Culture in Early Expansion of Humans (ROCEEH) project.1\n\nFor marine data, The Marine Environment Data Information Network (MEDIN) provides the coordination and acts as a data hub for a broad range of offshore datasets managed by accredited data archive centres (DACs). The seven DACs cover Bathymetry, Water Column Oceanography, Geology and Geophysics Flora, Fauna and Habitat, Meteorology, Fisheries and the Historic Environment. Each DAC contributes key metadata about project datasets to the MEDIN portal. The portal enables users to search across over 17,225 marine datasets from over 600 UK organisations.\n\n\nBenefits of harmonising and sharing spatial data from multiple providers\n\nA number of studies demonstrate the value of harmonising data across multiple providers. A cost benefit analysis2 undertaken by environmental economists and marine consultants on behalf of MEDIN demonstrated a benefit to cost ratio (BCR) of 8.2. A review of a range of marine spatial data infrastructures (SDIs) in New Zealand found the BCR to range from 2 to 18.2.3 Benefits include efficiency of data collection and reuse, supporting marine science and more effective marine spatial planning.\n\nThere is already a lot of good practice in the stewardship of historic environment data. National Heritage Agencies and Local Authority Historic Environment Records manage inventories for their respective jurisdictions. A recent study4 of the impact of local authority archaeologists in Britain, informed by information in Historic Environment Records (HERs), estimates that archaeology in development management had a BCR of 15, contributing £218m to local economies from commercial archaeology and saving up to £1.3 billion in delay and emergency excavation costs. Project archives resulting from fieldwork and research may be deposited in a relevant archive, including Core Trust Seal accredited archives at Historic Environment Scotland (HES) and the Archaeology Data Service. An analysis5 of the value and impact of the Archaeology Data Service in 2013 estimated a two- to eight-fold return through additional reuse of data deposited in their digital archive, though not everything reaches an archive, or is deposited in a reusable format.\n\nDespite the seemingly impressive benefits for the stewardship of data, are we really realising the value and potential of historic environment data, particularly that captured from primary archaeological fieldwork and research? The following sections explore the different approaches to publishing spatial data from organisations responsible for creating and maintaining spatial data - curated data – and the range of data created through primary field work by many organisations for a broad range of purposes, data that needs to be collated to realise real benefit.\n\n\nSpatial Data and the historic environment - curated data\n\nGood data is at the heart of decision making and stewardship of the historic environment. It should also be an important contributor to wider societal challenges including climate change, automation and complex modelling of our environment through eco-system services and digital twins. Good data should deliver efficiencies to a broad range of users outside of, but interacting with, heritage.\n\nThrough The INSPIRE (Scotland) Regulations 2009 key protected sites datasets, including scheduled monuments and listed buildings, are readily accessible through national and organisational metadata portals. These are curated datasets where organisations are responsible for the creation and maintenance of content to deliver their business objectives. Publication of these datasets includes Discovery Metadata, View and Download services.\n\nThe Historic Environment Scotland portal provides access to the statutory data HES is responsible for, as well as access to point data from the National Record of the Historic Environment, published through Canmore. For most datasets users may download data as zipped shape files or access Web Map and Web Features services or an Atom feed. Historic land use data may also be accessed through a more restrictive licence. Two web map browsers, The Designations Map Search and PastMap provide location-based services. PastMap also allows users to view and search Canmore and most HER data providers, to query, select and download point data from across searchable datasets in csv or kml format, and to view content on linked web pages hosted by the data contributor. Canmore offers both text and map based searches.\n\nHES key datasets are also added to the SpatialData.gov.scot metadata portal, which enables users to find, share and reuse spatial data provided by Scottish public sector organisations. These records are harvested by and added to the Data.gov.uk open data portal.\n\nMost HERs maintain or have access to databases recording information about monuments and events (specific activities that lead to the recognition of or add to the understanding of a monument). As well as contributing to PastMap, monument and event data is provided to The Spatial Hub. Established by The Improvement Service (the national improvement organisation for Local Government in Scotland), The Spatial Hub provides the coordination and infrastructure for harmonising and transforming 138 datasets across Scotland’s 32 local authorities and other partner organisations, for use by the Scottish public sector bodies and their contractors under the Public Sector Mapping Agreement. Academic researchers may access the data through EDINA.\n\n\nSpatial data and the historic environment - collated data\n\nPrimary archaeological fieldwork, research and analysis, often referred to as ‘events’, are unique activities that happen once over a discrete period of time – often through research, stewardship of the historic environment or in discharge of a condition required under planning consent. Fieldwork routinely creates a wealth of spatial data whose reuse potential is largely unrealised beyond short-term project delivery. Results are typically presented in a pdf report or more traditional publication such as the Royal Commission on the Ancient and Historical Monuments of Scotland (RCAHMS) survey of the Mar Lodge Estate, Aberdeenshire (Figure 1),6 where the spatial data is fossilised to the page orphaned from its broader landscape context.\n\nOrdnance Survey licence number 100057073.\n\nThe underlying data might be deposited with a formal archive such as the Historic Environment Scotland Archives or The Archaeology Data Service (ADS): both Core Trust Seal certified repositories. A study by the Association of Local Government Archaeology Officers (ALGAO):England, working with the ADS, estimated that at best, 2-3% of commercial projects had been digitally archived with the ADS.7 The proportion of archives from fieldwork in Scotland deposited with HES remains unquantified.\n\nEven within the archive, the data may not be easily found and retrieved. Archival discipline necessarily compartmentalises data by collection and project (Figure 2) greatly understating the value of the spatial component.\n\nNotable exceptions include the HES National Collection of Aerial Photography and the National Library of Scotland Map Library who both publish online map bowsers as finding aids to their respective collections. All too often it falls to individual initiatives or individual enthusiasm and project-based solutions to realise the potential of spatial data preserved in archives. Creating these collated datasets requires considerably more investment to collect, preserve, harmonise and publish than curated data. Critically, the mandate provided for curated data to provide that coordination is lacking.\n\nRecord enhancement is a key function of both the HERs and HES. Existing practice is for the curator to enhance the record through extracting key data from project reports produced as part of the discharge of a planning condition, or from summary (often interim) reports published in Discovery and Excavation in Scotland, an annual digest of fieldwork. Since 2007, fieldwork can be reported through an online application: OASIS (Online AccesS to the Index of archaeological investigationS).8,9 The OASIS form ensures that fieldwork reporting is standardised, meeting the MIDAS Heritage Standard by drawing on controlled vocabularies published on Heritagedata.org to ensure a degree of consistency at project level. Additionally, the project reports should be uploaded and shared with the relevant HER and HES before release to the Archaeology Data Service. The latest iteration, OASIS V, encourages users to upload project extents, albeit with restricted geometries, to accurately locate projects and share with curators under an open CC-BY licence. There is also an option to upload more detailed geometries for complex project extents, or for details of trench extents. Nevertheless, project extents are still often digitised from raster images designed for inclusion in a data structure report or publication – a process ingrained with inefficiency and inaccuracy. OASIS addresses standardisation and harmonisation at project level but major barriers remain in routinely accessing and sharing more detailed spatial data including interoperability across datasets from multiple providers.\n\nThe Scottish HERs published specifications for documenting the basic ‘event’. These specifications provide a baseline, or vanilla, record for an event (the who, what, why, and when) enough to meet HER requirements in documenting where activities have taken place. The specifications do not and are not intended to address the increasing sophistication of primary datasets from a range of non-invasive and invasive techniques to systematically document content within data types or act as finding aids or spatial indexes to associated archives. For instance, as well as seeing the extent of a geophysical survey, a user should be able to assess the usefulness of the dataset through viewing the technical metadata (instrumentation, resolution of survey etc) – all captured through the geophysical module in OASIS10 with a link to the related archive, where known.\n\nWith data created by a broad range of professional organisations, in academia and through community led projects for a wide-range of purposes, the absence of relevant data standards, specifications and reference vocabularies presents a challenging environment for data harmonisation or homogenisation. Even if data is internally consistent from a single provider – and that is not always the case - interoperability across data providers remains challenging.\n\n\nCase studies\n\nScotland’s past is a rich and diverse resource ranging from the lowlands to the highlands, from rural to urban and from subtle archaeology revealed as cropmarks and increasingly recognised through a range of remote sensing analysis to upstanding archaeological sites and landscapes. The following examples explore the potential for sharing spatial data from separate projects and a range of techniques – to build something other than the sum of the parts.\n\nExcepting a small number of university research projects, for many decades systematic archaeological field survey was the almost exclusive preserve of two national, public-sector organisations. RCAHMS compiled inventories of monuments and Britain’s National mapping agency, The Ordnance Survey, surveyed and published depictions of archaeological monuments as topographic on their paper maps. Both organisations established robust mapping conventions to interpret and present individual site depictions consistently.11 With the need for environmental impact assessments and planning requirements, walk over surveys are now an important part of many infrastructure projects. Spatial data standards have not, however, kept pace with the growth of a thriving private sector.\n\nThe RCAHMS Afforestable Land Survey was established in 1989 to undertake strategic targeted surveys in areas where the archaeological potential had not been recognised through low levels of archaeological recording. The survey programme evolved to use a range of digital equipment from electronic distance measurement equipment (EDMs) to differential global positioning systems (dGPS) to map the archaeological landscape. With the advent of Geographic Information Systems (GIS), data initially gathered to produce maps of the archaeological landscape for archive and publication (Figure 3) could be combined across survey projects to present a seamless view of mapped survey areas.\n\nBackground mapping © Crown Copyright HES [2023]. Ordnance Survey licence number 100057073.\n\nThe approach is extensible. It could and should form the basis of specifications to realise the potential of mapped data fossilised in project reports from the ever-increasing number of commercial, community and research projects.\n\nTranscribing or mapping archaeological features from oblique and vertical aerial photography on a site-by-site basis is a long-established technique. What was a slow and laborious manual process has been transformed through computerised rectification programmes. In Scotland, an Airborne Mapping programme has been undertaken by RCAHMS/HES for over thirty years. Again, the potential to combine individual site transcriptions within the GIS to present a seamless view contextualising individual site transcriptions within a wider archaeological landscape (Figure 4) was quickly realised through development of consistent data specifications similar to, but not identical to, that for field survey mapping.\n\nGeophysical survey techniques reveal anomalies which can be interpreted as archaeological features and sites. The techniques of airborne laser scanning or LiDAR (light detection and ranging) analysis offer fresh opportunities for identifying and mapping archaeology, beyond the rich arable lowlands, into the upland and penetrating the tree canopy. Techniques and methodologies may differ, but the outputs from the interpretation need to be consistent across approaches, with particular attention to the terminology used. Local vocabularies need to reference formal, accessible, shared, and broadly applicable language for knowledge representation to improve interoperability (The ‘I’ of the FAIR Data Principles).\n\n\nTaking the holistic approach\n\nConsistent application of spatial data specifications is an essential prerequisite to develop a holistic understanding of complex archaeological landscapes from a range of non-invasive and invasive techniques and researchers. The rich archaeological landscape at Inveresk, East Lothian has been mapped through the Airborne Mapping programme and subject to numerous small-scale excavations (Figure 4). Airborne mapping recorded the complex multi-period cropmark landscape, including features identified as Roman temporary camps and a Roman field system overlying a Neolithic Cursus monument. Excavation extents and key features were digitised from the interim report12 to map the archaeology at Inveresk. Excavations on the line of a new bypass in 1984 were designed to confirm that the linear cropmarks were part of the Roman temporary camp. The results confirmed the interpretation of the western linear features as Roman, but also that the eastern linear features, previously interpreted as a Roman road, were Neolithic in date.\n\n\nPresenting results\n\nA common product of any research is the presentation of the analysis or interpretation of the results. A prerequisite is a standardised terminology. Although HES airborne mapping and field survey mapping data both acknowledge the Scottish Monument Thesaurus, the poly-hierarchical relationship between a concept, broader terms and top-level terms introduces enough uncertainty and inconsistency to group and present related feature types in a meaningful way cartographically. Development and promotion of micro-thesauri to group the many hundreds of monument terms succinctly and inform the map legend would help address this challenge and help deliver interoperability across a range of observed data.\n\n\nUntapped potential\n\nThose best placed to document the extents and detail from fieldwork are those undertaking that work. Technological advances help. Widespread availability of high precision surveying equipment coupled with a marked growth in both developer-funded archaeology from the 1990s and community-led projects has democratised survey, be it on excavation, from survey or analysis.13 In keeping with the INSPIRE principle that data should be collected once and maintained at a level where this can be done most effectively,14 primary spatial data should be routinely shared with data curators. For instance, a tabulated gazetteer of sites recorded from a large walkover survey embedded in a pdf is far less useful than the equivalent data presented as a csv file, or preferably as a GIS dataset mapping site extents supported by detailed attribution. Similarly, a plan fossilised as an image in a pdf has less reuse potential than the original georeferenced data.\n\nSophisticated digital datasets require much richer attribution than ‘entry level’ event data required for established record purposes and basic information discovery. Appropriate attribution should enable a potential user to explore the character of the data15 at landscape (GIS layers) not project level (pdf).\n\nThere are already many highly skilled surveyors and geomatics officers working in archaeology. However, approaches are organisation focused rather than industry based. This is starting to change with large scale infrastructure projects like High Speed 2 which require consistent approaches across multiple contractors and sites. The profession needs to invest in developing and promoting the necessary data standards and demonstrate the benefits of a coordinated approach across techniques and organisations.\n\n\nThe bigger picture\n\nWith the establishment of the Geospatial Commission in 2018, the UK government aims to accelerate the delivery of economic, social and environmental benefits derived from geospatial data, products and services across the private and public sector. A key infrastructure project is the National Underground Asset Register, with the Scottish Community Apparatus Data Vault (VAULT) in Scotland, which is coordinating the complexity of buried services from multiple utilities to save time in decision making and save lives on site. In the same vein, archaeologists need to move beyond sensitivity mapping of known areas of high archaeological interest and locations of excavations, to routinely map and share buried archaeological contexts, the location of significant features and key contexts to deposit modelling. If the highly competitive construction industry can coordinate data sharing at scale, so can archaeology.\n\nArchaeological and built heritage data needs to engage with digital twins: virtual models that accurately represent the physical city above and below ground. To do so requires access to detailed, accurate models of our heritage. Without those models, and as remote access to geospatial data for decision-making increases, the absence of archaeological data poses a risk to our past. If that data is invisible or inaccessible within an archive in the wrong format, it has no value in the emerging geospatial ecosystem. Developing consistent archaeological datasets not only makes managing that data more efficient, but also unlocks economic value through saving time and money.16\n\nSpatial data is essential for the stewardship of the historic environment, not only in terms of managing specific risks at sites but informing the management of the wider landscape. Using a range of spatial data techniques, HES monitors the condition of and risk to properties in its care. In 2010 HES surveyors created a digital model of Skara Brae, a well-preserved Neolithic settlement and UNESCO World Heritage Site on Orkney, to inform site conservation, interpretation and engagement.17 A cyclical monitoring programme every two years enables comparison of the data over time against the 2010 benchmark to gain a better understanding of the effects of coastal erosion on the environs of the site. The data is not only essential for the stewardship of the site but also forms a case study for Dynamic Coast, a pan-government partnership developing an evidence base of national coastal change across Scotland.\n\nTo remain relevant in an increasingly digital society and realise the potential of expensively gathered data, archaeology needs to develop a shared infrastructure, to capture, share and publish a broad range of spatial data adhering to the FAIR Data principles. The manifesto is straightforward:\n\nVision\n\nWe will create an environment in which spatial data from archaeological research is shared openly, maximising its contribution to the study and stewardship of the past, and engages positively with the broader geospatial environment.\n\nMission\n\nTo develop a sustainable approach to collecting and sharing spatial data from archaeological research that increases efficiency within our discipline and releases the full potential of that data to the broader geospatial environment.16\n\nThe value of curated data is already recognised through statutory requirements for spatial data, but the potential of primary archaeological data remains largely unrealised, compartmentalised by project and archive. With advances in geospatial technologies, it is increasingly essential to standardise and share data. Most of the building blocks needed to realise the potential of spatial data from primary archaeological data are in place18,19 but we lack agreed standards and infrastructure to harmonise and share that data. Without the relevant blueprints, we cannot transform data into information and knowledge effectively (Figure 5).\n\nUser requirements and specifications can be addressed through a collaborative approach between data curators, archivists and those creating data through fieldwork and research supported by robust training resources. The substantive challenge is developing, hosting and maintaining the relevant infrastructure to manage the long-term delivery of that spatial data to realise the both the societal and financial benefits of good data stewardship.",
"appendix": "Acknowledgements\n\nThe arguments for developing a Spatial Data Infrastructure for archaeological data have benefited from discussions with colleagues at Historic Environment Scotland, the wider archaeological community in Scotland and from participants at conference and workshop sessions over many years. I would like to thank Susan Hamilton for reviewing an earlier draft of the paper and supporting the funding request.\n\n\nReferences\n\nKandel A, Haidle MN, Sommer C: Human Origins – Digital Future An International conference about the future of Archaeological and Paleoanthropological Databases. Propylaeum:Heidelberg University Library;2022. Publisher Full Text\n\nMEDIN: MEDIN Cost Benefit Analysis Final Report.November 2019. Reference Source\n\nGriffin E, Coote A, Crompvoets JA: A marine spatial data infrastructure in New Zealand: A systematic review on the cost-benefits. J. Spat. Sci. 2019; 64: 33–47. Publisher Full Text\n\nRocks-Macqueen D, Lewis B: Archaeology in Development Management. It's contribution in England, Scotland and Wales.2019. Reference Source\n\nBeagrie N, Houghton J: The Value and Impact of the Archaeology Data Service. A Study and Methods for Enhancing Sustainability. Salisbury, UK:Charles Beagrie Ltd; 2013. Reference Source\n\nRCAHMS: Mar Lodge Estate Grampian: an archaeological survey 1995 Edinburgh with link to digital copy.Reference Source\n\nTsang C: Red Sky at Night: digital archiving in England 2020. Internet Archaeol. 58. Publisher Full Text\n\nHardman C, Richards JD:OASIS Dealing with the Digital Revolution.Doerr M, Sarris A, editors. The Digital Heritage of Archaeology: CAA 2002. Computer Applications and Quantitative Methods in Archaeology. Proceedings of the 30th CAA Conference, Heraklion, Crete, April 2002. Archive of Monuments and Publications, Hellenic Ministry of Culture: Heraklion, Greece.2003; pp. 325–329.\n\nRichards J: Twenty Years Preserving Data: A View from the United Kingdom. Adv. Archaeol. Pract. 2017; 5(3): 227–237. Publisher Full Text\n\nMcKeague P:Historic Environment and INSPIRE - A View from Scotland.Ioannides M, Fritsch D, Leissner J, et al., editors. Progress in Cultural Heritage Preservation, EuroMed 2012, Lemessos, Cyprus, October 29 -- November 3, 2012, Lecture Notes in Computer Science. 2015; Vol. 7616: pp. 833–840.\n\nMcKeague P, Cowley D: From Paper to Digital, and Point to Polygon — The Application of GIS in a National Body of Survey and Record. Int. J. Herit. Digit. Era. 2013 December; 2(4): 677–694. Publisher Full Text\n\nHanson W: Amongst the field systems 1: Monktonhall.In Bishop M.C. (ed) Roman Inveresk. Past, Present and Future: Papers from a Seminar Held at the National Museum of Scotland on Wednesday 8th December 1999. The Armatura Press; 2002; pp. 52–61.\n\nMcKeague P:Cartography and heritage: past practice and future potential for mapping Scotland’s cultural heritage.Giligny F, Djindjian F, Costa L, et al., editors. CAA2014. 21st Century Archaeology. Concepts, methods and tools. Proceedings of the 42nd Annual Conference on Computer Applications and Quantitative Methods in Archaeology. Oxford: Archaeopress.2015; pp. 315–322.\n\nFry D: Inspire Directive. GIS Professional. 2007; 15: 18.\n\nShaw R, Corns A, McAuley J: Archiving archaeological spatial data: standards and metadata. Online Proceedings Computer Applications to Archaeology 2009 Williamsburg, Virginia, USA. March 22-26, 2009 1–15. (accessed on 23 September 2022).Reference Source\n\nMcKeague P, Corns A, Larsson Å, et al.: One Archaeology: A Manifesto for the Systematic and Effective Use of Mapped Data from Archaeological Fieldwork and Research. Information. 11: 222. Publisher Full Text\n\nWilson L, Rawlinson A, Mitchell DS, et al.: 3D documentation of global historic sites: The “Scottish Ten” project and its applications for cultural heritage. Int. Arch. Photogramm. Remote. Sens. Spat. Inf. Sci. 2011; XXXVIII-5/W16: 39–44. Publisher Full Text\n\nMcKeague P, van‘t Veer R, Huvila I, et al.: Mapping Our Heritage: Towards a Sustainable Future for Digital Spatial Information and Technologies in European Archaeological Heritage Management. J. Comput. Appl. Archaeol. 2019; 2(1): 89–104. Publisher Full Text\n\nMcKeague P, Corns A, Posluschny A: Why the Historic Environment needs a Spatial Data Infrastructure. Internet Archaeol. 2017; 43. Publisher Full Text"
}
|
[
{
"id": "161843",
"date": "20 Feb 2023",
"name": "David Novák",
"expertise": [
"Reviewer Expertise Archaeological data archiving",
"GIS",
"research infrastructure management",
"landscape archaeology"
],
"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\nPeter McKeague's paper addresses the very important issue of archaeological spatial data management. There is no doubt that spatial data are far from fulfilling their potential to be the lingua franca linking individual archaeological datasets and data from other disciplines involved in landscape research. The author shows very well and with appropriate examples the difference between reporting the location of archaeological sites or monuments using maps and plans, and the creation of digital corpora of harmonized spatial data rich in information potential.\nTo the author's point of view, it can be noted that the harmonization of descriptive metadata is easier and, in a way, a secondary problem. The main challenge is to set up an archiving system for archaeological datasets that fully integrates spatial data describing archaeological research and its results, ideally in 3D space. Although there are already some attempts to grasp this problem, the barriers to realistic scaling up are countless. Even with appropriate standards in place, the actual competence of archaeologists and related positions to produce valid spatial data remains a significant problem. This is alluded to between the lines by the author at the end of the article, but it would be useful to emphasize this line a bit more.\nThe issues of data models, thesauri and especially coordinate systems are very complex and require the involvement of appropriate data management and GIS specialists from the very beginning of archaeological projects. Again, this is an issue of organisation and planning on the one hand, and of resources to fund similar positions and activities on the other. It is questionable whether, for example, current trends emphasizing the intrinsic value of FAIR scientific data (e.g. activities related to the building of EOSC in Europe) could not also be used as a suitable way to promote better care of spatial data in archaeology.\nIn principle, it still appears that the fundamental problem is the approach to archiving the fieldwork results as such, which is primarily archiving PDF reports instead of archiving the primary data. This is confirmed by a recent survey carried out in collaboration between SEADDA and EAC (publication in preparation). It can certainly be argued that the letter \"R\" is the least fulfilled in the FAIR principles in the case of archaeological datasets, as the straightforward application of general archiving and descriptive standards leads to suppression of re-usability. Only a combined effort on various levels, especially organizational, competence, technical, and financial, can lead to change.\nI am convinced that unless central organisations and key players in the industry fundamentally lower the threshold for other organisations, systemic change will not happen. It can be lowered both by providing support and education, but especially through widely applicable tools and services, with a very well-developed user interface and a quality backend. Until recording quality spatial data in archaeology is as simple as producing PDF reports, change will be very difficult to achieve.\nIt is unfortunate that the actual organizational issues and the problem of quality tools are more or less avoided by the author, and it would be interesting to add some of this insight. It would also have been helpful to focus more on the overall vision of how to achieve change, as the criticisms are undoubtedly valid, but without setting out a clearer path, the discussion will continue to stagnate or only be difficult to translate into practice.\nIn terms of readability of the text, the loose transition between general descriptions of the issues and specific case studies is sometimes problematic. This applies to roughly the second half of the paper. In this respect, better structuring and a slight reorganisation of the text would have helped. The positioning of the chapter 'Presenting results' is also not very clear, as it completely breaks out of the flow of the text. Also, the headings tend to be somewhat redundant and not very instructive ('Taking the holistic approach' / 'The bigger picture', etc.).\nHowever, the article is undoubtedly a valuable call to action, and I fully agree with the views presented. The comments above are merely suggestive for the author's consideration, to improve readability and increase the potential impact. The proposed modifications are not of a fundamental nature.\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? Yes\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? Yes",
"responses": []
},
{
"id": "161844",
"date": "03 Apr 2023",
"name": "Dan Trepal",
"expertise": [
"Reviewer Expertise Industrial Archaeology",
"Digital Humanities",
"GIS"
],
"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 this paper, Peter McKeague highlights the ongoing disjuncture between the capabilities of spatial infrastructure with regard to the universal archival and sharing of archaeological data on the one hand, and our lack of actual exploitation of that potential on the other. The author presents a series of succinct examples of the significant and ongoing challenges: chief among these are, first, the continued production of field data in static document form including spatial data that is \"fossilised\" (in the author's words); a byproduct of compliance-centered regimes that limits the future use of the data.\nA second major challenge McKeague correctly highlights are the obstacles faced in developing universal archaeology data standards for what is still a very heterogeneous metadata landscape. Looking towards the future, projects aimed at creating a universally applicable ontology for capturing cultural heritage data, such as CIDOC CRM, may point towards the most comprehensive solution, but even if such ambitious undertakings meet their goals, they still require broad adoption across many frontiers to achieve their promise, something that not even the most optimistic visions see as a short-term likelihood.\nMcKeague rightly points out that such a level of data sharing is being achieved elsewhere (the INSPIRE spatial data infrastructure, for example); additionally, the ‘building blocks’ for a major paradigm shift in archaeology are already available. Indeed, the primary spatial data being generated by most current archaeological fieldwork encompasses a relatively small set of geospatial standards and formats, and this data could be easily and quickly collated into national and international archives. This would leave the thornier questions of metadata compatibility to the next generation of development of such an infrastructure but, as an alternative to the proliferation of parallel efforts, it is certainly attractive.\nMy own collaborative work (Trepal, Lafreniere, and Stone (2021)1) has attacked the problem from the opposite end, building a discrete community-focused heritage project incorporating data from the archaeological and historical records using standard GIS-based tools. This is driven by a desire to foreground the community heritage value of the data to boost the profile of the archaeological data within community heritage regimes. The chief danger of this bottom-up approach in the long term is of course the proliferation of idiosyncratic small-scale digital projects. However, once again - and, I think, to McKeague’s point in this paper - the primary spatial ‘building blocks’ of the archaeological data within such projects are still readily compatible with most other standard archaeological primary geospatial data being collected worldwide, and could be collated into an international-scale spatial data infrastructure, with all the ‘value-added’ interpretive content and digital middleware reserved for the community-focused project that generated it.\nThe general thrust of the paper’s argument, that most archaeological data remains ‘siloed’, both within and without the discipline, even though the basic primary data is (in principle) easily interconnected using current off-the-shelf approaches, is therefore sound and articulates an urgent challenge given the increasing pervasiveness of geospatial data. With that being said, the author's examples offer a relatively narrow slice of what is truly a global problem within archaeology and cultural heritage. The situation in North America, despite the long-term development and maintenance of the Digital Archaeology Record (tDAR), is arguably worse than in Europe, where EU-funded work on digital ontologies and infrastructures for archaeology and heritage more broadly are at least grappling with the challenges inherent in creating international-scale data archives from the first. There is even less discussion within the discipline regarding developments outside Europe and North America, suggesting that even the bluntest critiques may be understating the scale of the challenge.\nThe case studies section does lose focus somewhat, with the subheadings not providing the same sharp focus as the introductory and concluding sections, even if the case studies bring forth some illuminating details. This paper’s impact could be substantially enhanced if it were to include a critical review of the patchwork of archives currently in existence that attempt to curate digital, spatial archaeological data. Literature covering digital archaeology and heritage topics ages quickly, and the steady stream of digital initiatives being launched year on year means that reviews of the state of the field cannot come too often if we are all to collectively keep up. What is perhaps most lacking in the paper is a prescriptive roadmap towards a solution, even if only in outline form. For example, to what extent could INSPIRE serve as a direct model for an archaeological counterpart?\nCritiques aside, this paper represents a cogent call for action in an area within archaeology that needs far more attention in the published literature than it receives at present, and to which the author has made, and continues to make, an outsized and well-appreciated contribution.\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? Yes\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? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-112
|
https://f1000research.com/articles/12-111/v1
|
30 Jan 23
|
{
"type": "Systematic Review",
"title": "Association between gambling and financial trading: A systemic review.",
"authors": [
"Uibin Lee",
"Lauren E. Lewis",
"Devin J. Mills",
"Uibin Lee",
"Lauren E. Lewis"
],
"abstract": "Background: Financial trading is often categorized separately from traditional forms of gambling (e.g., blackjack, poker, lottery, slot machines), as it is often viewed from an investing lens. However, the arbitrary line separating investing from gambling has become increasingly questioned, especially as it relates to high-risk trading behaviors (e.g., day trading, trading on margin) and riskier financial assets (e.g., options, cryptocurrencies). Further, the risk of gambling-related harms among financial traders appears to be amplified by new financial technologies, which have increased access to riskier financial assets and have encouraged riskier trading behaviors. Thus, the aim of the present study is to systematically review the literature assessing problem gambling among financial traders as well as the association between financial trading frequency and problem gambling. Methods: Twelve articles from three databases (SCOPUS, PsycINFO, and Web of Science) met the inclusion criteria, and were reviewed. Results: The prevalence of problem gambling was generally higher among individuals who engage in trading financial products, but rates varied substantially (1.4% to 47.2%) due in large part to differences in the study population, the problem gambling measures used, and the cutoff scores employed. Similarly, financial trading frequency was consistently associated with more severe problem gambling, but the strength of these associations ranged across studies. Conclusion: Collectively, while findings from these studies suggest that financial traders are at greater risk for problem gambling, it is evident that trading riskier assets and engaging in riskier trading behaviors place individuals at a substantially greater risk for problem gambling. Recommendations for future research include focusing on at-risk populations, practical implications for the intervention and policy, and emerging issues of digital technologies.",
"keywords": [
"Investing",
"Financial trading",
"Gambling",
"Systematic review",
"Cryptocurrency",
"Day-trading",
"Gambling disorder",
"Speculation"
],
"content": "Introduction\n\nDecades of research underscored the severity of gambling-related harms (Browne et al., 2017; Langham et al., 2016; Shannon et al., 2017) which unsurprisingly is associated with greater severity of problem gambling. Also, while the literature on gambling-related harms and problem gambling has generally focused on “traditional” gambling activities (e.g., poker, blackjack, sports betting, casino table games, lotteries), gambling has always existed within various financial markets (Kumar, 2009; Statman, 2002). Trading financial products can itself be problematic and will often mirror that of problem gambling. From the study of Turner (2011), in a first-person account, David speaks to his experiences as someone engaging in problematic stock trading, which included increasing the frequency and value of financial trading, becoming preoccupied with the financial markets, borrowing money to fund higher value trades, and lying to friends and family about his level of involvement in the stock market. Ultimately, David experienced huge losses and sought counseling for his struggles with online stock trading. David’s experiences are not isolated. The Financial Times reported a substantial increase of calls to problem gambling hotlines for issues surrounding financial trading (Darbyshire, 2021). Thus, the risk of problem gambling among financial traders is an area of concern.\n\nThese concerns are further amplified by the changes over the last 20 years that have propelled traders to increase their risk exposure. Consider, for example, the context in which David was trading versus the context of today. David’s story spans from 1999 to 2009, which included the dot-com bubble and the 2008 recession. But his trading career did not include the rise of cryptocurrencies nor the recent technological advances that have placed stock trading on smartphones. Recent data shows that these changes have facilitated a substantial increase of speculating versus investing within the financial markets. Pelster et al. (2019) revealed a substantial increase in the trading frequency and use of leverage (i.e., borrowing money to increase a position) following an initial cryptocurrency trade. Similarly, Kalda et al. (2021) found that financial trading on smartphones was associated with purchasing riskier assets compared to other platforms (e.g., personal computer, calling brokerage directly, etc.) among the same investor. In other words, the same investor appears to adopt a riskier trading strategy on smartphones versus other trading platforms. The reasoning for the differences between trading platforms remains unclear. Finally, it should also be noted that the industry has largely adopted commission-free trading, which has increased access and contributed to an ever-increasing population of retail investors.\n\nCollectively, the present context and current literature underscores the need to assess the state of the field with regards to (1) the prevalence of problem gambling among financial traders and (2) the association between financial trading and problem gambling. Within the present review, we aim to achieve these two objectives, and cultivate recommendations for further research in this area.\n\nSince the primary purpose of trading within financial markets is to build wealth through investing, a central question is whether or not investing is dissimilar from gambling. This is a long-debated topic and will not be fully discussed here. Nonetheless, we provide a brief overview for context. First, a survey of nearly 13,000 North American adults by Williams, Stevens, and Nixon (2011; as cited by Williams et al., 2017) collected data on individuals’ personal perspective of what counts as gambling. Activities ranged from buying lottery tickets, horse betting, purchasing insurance, and starting a business. Expectedly, traditional gambling activities (e.g., scratch tickets, slot machines, casino table games) were identified as gambling-related activities by at least 75% of the sample. However, their findings also show that 36.5% view “buying ‘blue chip’ stocks” as a form of gambling, suggesting that even when buying shares of high-value, high-quality companies, a meaningful part of the population views this as a form of gambling. Additional data from this survey revealed 57.2% view “buying high-risk stocks” to be a form of gambling. For clarification, it is expected that most individuals define high-risk stock as shares of low-value, low-quality companies that often trade for less than $5 a share qualifying them as “penny stocks.” It is also possible that this includes recent start-ups of high-quality but still high-risk due to the amount of debt these companies take-on during their initial phases. It is perhaps a bit surprising that a greater proportion of individuals perceived high-risk stock trading to be gambling than “betting on sports,” which was viewed as a gambling activity by 52.5% of North American adults. Findings from this survey suggest that whether or not stock trading is viewed as gambling appears to depend on the quality of the underlying company and individual perspectives. Moreover, every activity was rated to be a gambling activity by some participants suggesting that the public view more activities to be gambling-related than many scholars’ definitions allow for. But, when it comes to the contrast between investing versus gambling, a more conceptual review is required.\n\nArthur et al. (2016) provide the most extensive review of the conceptual similarities and differences between investing and gambling to date. They argue that investing is a low-risk activity with positive expected values due to buying and holding assets across a long time period with no definitive event. On the other hand, gambling is a high-risk activity with negative expected values due to staking positions (versus purchasing assets) over a short (often instant) time period that includes a definitive event. Interestingly, Arthur and colleagues do not dismiss the role of chance for both investing and gambling, and rate its influence as high for both activities. Thus, investing and gambling are chance-based activities based on their review.\n\nIn addition to investing and gambling, Arthur et al. (2016) define speculating as an activity that rests somewhere between investing and gambling. The definition of speculating is a bit more ambiguous, perhaps purposely so. It is usually a high-risk activity with mixed expected values due to purchasing assets as well as staking positions over both short and long time periods that usually include a definitive event. Despite the ambiguity in the definition of speculating, it appears at face value to be accurate. For instance, day-trading is where individuals purchase assets but hold them for less than a day, which constitutes a short time period. Because of the short duration it is not investing but it is also not gambling. Another example is the purchase of long-dated options contracts (for an overview of options contracts, see Hargrave, n.d.). Again, due to the long duration, it is not gambling but it also not investing since no assets are purchased, only the “option” to buy or sell an underlying asset. Therefore, the takeaway from Arthur and colleagues is the complexity of delineating between investing and gambling, and that speculating may be a better term to highlight the increased exposure to risk.\n\nBeyond the complexity of distinguishing investing from gambling, researchers have considered the psychological characteristics that either distinguish individuals who engage in financial trading versus those who engage in gambling or explore the similarity between the two activities. Moreover, financial traders and gamblers share similar psychological characteristics including personality traits, cognitions-related to gambling, and gambling motivations.\n\nPersonality traits such as sensation-seeking and risk-taking were found to be common in both gamblers and financial traders (Powell et al., 1999; Wong & Carducci, 1991). For instance, in a simulation among college students, the frequency of financial investment was positively associated with risk-taking propensity (Markiewicz & Weber, 2013). Additionally, competitiveness is predictive of both trading and gambling frequency, while emotional instability and impulsivity were only positively related with trading frequency, not gambling frequency (Jadlow & Mowen, 2010). Therefore, collectively traders appear to share some psychological similarities with gamblers.\n\nResearch has also found evidence of similar erroneous cognitions between traders and gamblers. For example, traders and gamblers are often over confident in their abilities, and possess both illusion of control (Barber & Odean, 2001), and confirmation bias (Barber & Odean, 2001; Rabin & Schrag, 1999). Also, individuals who engage in financial trading and gambling show similar motives (i.e., fun, excitement) for engagement (Binde, 2013; Dorn & Sengmueller, 2009; Neighbors et al., 2002). These similarities in psychological characteristics can place individuals at an increased risk for problem gambling.\n\nConsequently, it would be expected that a relation would exist between financial trading and problem gambling since trading is similar to gambling, and the individuals participating in the activity share similar traits and cognitions. However, there are some questions that need to be answered due to the neutral attribute of both financial trading and gambling. To what extent is it dangerous or problematic behavior? How can we explore the potential relationship between the two similar constructs? How can we find the tangible evidence for intervention, prevention and decision making for policy? Similar debates have been discussed in previous research, resulting in a collective effort to develop diagnostic standards or specific assessment tools such as the Problem Gambling Severity Index (Ferris & Wynne, 2001) and South Oaks Gambling Screen (Lesieur & Blume, 1987). Thus, the present review focused on the studies which used clear assessment for measuring the degree of gambling problems or harm.\n\nA growing body of literature has shown financial trading to be associated with problem gambling, however, no review has yet attempted to synthesize these findings. The two similar behaviors have only recently been explored together through preliminary studies that measure the co-occurring behavior or prevalence. An empirical study with a Canadian sample investigated the relationship between engaging in financial trading and gambling and showed that high-risk stock traders were more likely to engage in gambling, which was also found in an Australian sample of day traders (Arthur et al., 2015; Arthur & Delfabbro, 2017). Cox et al. (2020) applied the gambling disorder criteria on trading behavior and described speculative features of financial market investors who met the diagnostic criteria. Håkansson et al. (2021) insisted that stock trading, typically in the case of excessive day trading, may cause gambling disorder and related problems. Therefore, the authors emphasize the need for more in-depth research given the current pandemic period when volatile financial trading behavior surges. Moreover, cryptocurrency trading has rapidly become accepted as a trading instrument worldwide over the past few years. Since this novel form of trading has much higher volatility, there were concerns that cryptocurrency trading behavior could be linked to gambling behavior (Delfabbro et al., 2021). One of the preliminary studies, Mills and Nower (2019) suggested that cryptocurrency trading can have more risk to gamblers with high gambling severity.\n\nWhile many view investing and gambling as separate, there is increasing evidence of gambling within financial markets as well as greater problem gambling severity among financial traders. However, there is a lack of studies that review the research on both entities together. Thus, the present study aims to review the literature on financial trading and gambling, by examining the prevalence of participation in both, and the relationship between problem gambling and trading behavior.\n\n\nMethods\n\nIn this review of the literature, an electronic search was conducted using the Scopus, PsycINFO, and Web of Science databases. The search strategy and protocol were developed in consultation with a specialist in behavioral addiction research and registered with PROSPERO (CRD42022374861). We chose search terms for financial trading and gambling (see Table 1) with the filters of year of publication (2013 to 2022), document type (Article), and language used (English). The initial search identified 2,220 related articles from the three databases. The criteria for study selection that was used to evaluate each article, listings of the initial articles, as well as the final selection of articles, are provided in the Data Availability statement.\n\nThe study selection process followed PRISMA guidelines, and was completed by two independent researchers, with a review and consultation stage for each step in the process. Consistent with the study objectives, eligibility criteria included studies that assessed the prevalence of problem gambling among financial traders and/or the association between financial trading and problem gambling. As such, studies must either assess problem gambling either in conjunction with an assessment of financial trading frequency or among financial traders to be included in the review. Following the exclusion of duplicates across the three databases, 1,444 articles were identified. Titles and abstracts were independently reviewed by two trained graduate students to assess each article’s eligibility for a full-text review. Any discrepancies in the ratings were resolved through consultation, and the 21 articles were deemed to be eligible for a full-text review. Again, the full-text of each article was independently reviewed by two trained graduate students to assess each article’s eligibility for inclusion. Any discrepancies in the ratings were resolved, and the 12 articles were deemed to be eligible for inclusion into the present systematic review (see Figure 1). The process and criteria used for study selection can be found under Extended data (Lee, 2023).\n\nThis systematic review used the synthesis without meta-analysis (SWiM) guidelines and checklist (Campbell et al., 2020) (See supplemental material in Reporting guidelines). Researchers extracted characteristics of the studies (i.e., sampling method, sample size and characteristics, and the prevalence of gambling among samples) and the relationship between gambling and financial trading (i.e., effect size) using Microsoft Excel. The data extraction protocol was pilot tested with two randomly selected studies and refined to include prevalence of problem gambling accordingly. The first and second author read all selected studies using the data extraction protocol independently. Disagreements regarding extracted data were few and resolved via mutual discussion. The third author then revisited all the studies to confirm the accuracy of extracted data. For data synthesis, the selected articles were grouped by the type of financial trading. Since the identified associations between gambling and financial trading were investigated with various method and populations, the standardized metric or transformation method were not used. The prevalence of engagement to gambling activities and problem gambling was used to investigate the possible heterogeneity across the groups. Also, the results of group comparison, bivariate or multivariate analysis were used. The certainty of evidence is assessed by the p-value if applicable. The synthesized results are described in Table 3.\n\n\nResults\n\nThe characteristics of the articles are presented in Table 2. Many of the articles were published in 2021, with a significant increase after 2019, demonstrating a steady interest in this topic. All of the included articles were designed for cross-sectional study using quantitative data from population-based surveys. While the sampling method varied, most of the articles used a convenience or purposive sampling method, except three of the articles which used probability samples of large population data collected by national level surveys. Three articles used samples of individuals who reported having trading experience, or financial trading products, two of the articles used gambling experience solely as inclusion criteria for participants, and two articles employed samples of individuals who engaged in both financial trading and gambling. The remaining two articles used general populations for the study sample. Six of the twelve articles recruited participants via online crowdsourcing platforms (e.g., Mturk, Prolific, Embrain) or panels (e.g., Norstat, KMPMORF), while the other half used traditional online methods (e.g., social media, email).\n\nMost of the study samples have more male participants than female, and the ratio ranges from 44.3% to 96.7% male. The sample sizes ranged from 203 participants to 23,952, with a median sample size of 876. Specifically, five of the studies had a sample size under 1,000, three of the studies had a sample size of 500–999, and the remaining four articles had a sample size of 200–400. The samples were from various nations including Europe (e.g., United Kingdom, Turkey, Finland), Asia (e.g., South Korea), North America (e.g., United States, Canada, Mexico), South Africa, and Australia. The mean age ranges from 32.2 to 48.5 years, and the median age was 40.1 years from nine articles.\n\nThe identified articles primarily used two gambling measures, the Problem Gambling Severity Index (PGSI; Ferris & Wynne, 2001) and South Oaks Gambling Screen (SOGS; Lesieur & Blume, 1987), with one article having used the Diagnostic and Statistical Manual 5 (DSM-5) criteria of gambling disorder. These measures were used to assess gambling participation, as well as the presence and severity of problem gambling. One article also assessed family history of gambling through a single item. The scores indicating problem gambling are reported in Table 2, and overall prevalence ranged from 0.4% - 47.2% total, while specific investor group problem gambling ranged from 3.5% - 30.7%. Since the prevalence rates for problem gambling were highly dependent on the type of trading participants engaged in, the results section below will first discuss stock traders, followed by day traders, and then cryptocurrency traders.\n\nStock trading\n\nFive of the 12 articles focused on individuals who participate in stock trading (Arthur et al., 2015; Mosenhauer et al., 2021; Whiting et al., 2019; Williams et al., 2022; Youn et al., 2016). Frequency of trading was the most used indicator, but other dimensions such as trade size, portfolio value, and turnover (volume of trades relative to portfolio value) were also measured. One article used a specific stock trading measures, the Stock Addiction Inventory (Youn et al., 2016). The results for gambling engagement revealed a wider range of gambling experience in those who participate in high-risk stock trading than those who do not. Williams et al. (2022) reported 78.3% of those who engaged in any form of trading within the last year also participated in gambling, compared to 66.1% of those who did not. Further, Williams et al., found stock traders also participated in sports betting and casino table games at a significantly higher rate than non-traders. Additionally, a significantly higher gambling frequency for high-risk traders reported by Arthur et al. (2015) (MHR = 9.4, MNHR = 6.7). Problem gambling prevalence ranged from 2.1% to 41.5%, with a median of 6.7% among 8 stock trading samples of these 5 articles.\n\nYoun et al. (2016) reported that stock addiction scores were higher in those with a high level of problem gambling (SOGS ≥ 5), and were positively correlated with pathological gambling scores. Whiting et al. (2019) stated that there was no significant difference in stock participation for recreational gamblers compared to problem gamblers when reporting t-test results, but Arthur et al. (2015), who used two different samples, did find a difference. In both samples presented in the article, the high-risk trading group had more participants who scored five or more on the CPGI, than non-high-risk traders (MHR = 5.7, 7.6, MNHR = 2.1, 3.3), and when predicting gamblers who engaged in high-risk trading, problem gambling had a positively significant relationship (B = 1.43).\n\nWilliams et al. (2022) reported the result of a logistic regression predicting past year speculation and found that higher gambling frequency was the strongest predictor (OR = 1.65), and higher PGSI was also a significant predictor (OR = 1.07). In an article using a Prolific sample of individuals who had experience with gambling and current investments (Mosenhauer et al., 2021), risk for problem gambling predicted high trading frequency (i.e. turn over) over and above the other predictors (i.e. age, sex, overconfidence, and financial literacy).\n\nDay-trading\n\nWhile day trading is often aggregated with other trading activity, one article by Arthur and Delfabbro (2017) investigated day trading behavior as a distinctive type of financial trading. Day trading is described as trading activity that occurs within the same market day, or before the market closes. While there is no specific measure of day trading, they assessed day trading through three questions. Participants were asked if they bought and sold financial instruments within one market day, what type of financial products they traded in, and the amount of money they accessed in a day to conduct such trading. Prevalence of day trading in the sample was found to be 0.66%, which was lower than forms of other gambling-related activities such as lottery (55.5%), EGM (26.5%), and sports betting (6.1%). Similarly, of the 158 high-risk traders surveyed in Arthur’s 2015 paper (N = 8,498), only 16 participated in day trading alone, and 15 reported participating in day trading along with stocks, option, and futures. Most of the day traders (84.4%) traded in stocks, and 90.8% of them participated in any form of gambling. The rate of gambling compared to the general adult population in that area was found to be significantly different (z = 3.7), and the problem gambling rates among those day traders were significantly higher than individuals who did not participate in day trading, 7.6% compared to 1.4% (z = 4.1). The final finding by Arthur and Delfabbro (2017) was that problem gambling significantly predicted the differences between day traders and non-day traders (B = .40), day traders and gamblers (B = .30), and day traders and skill-based gamblers (B = .23) in a binary logistic regression. A limitation discussed in the current literature was the lack of disaggregation for day traders, because while the prevalence may be low, the risk for gambling problems are high.\n\nCryptocurrency trading\n\nFinally, six articles (Aslan & Kilincel, 2021; Delfabbro et al., 2021; Kim et al., 2020; Mills & Nower, 2019; Oksanen et al., 2022; Sonkurt & Altınöz, 2021) investigated cryptocurrency traders. In most of the articles, cryptocurrency trading was measured by trading frequency, but one article used the Pathological Trading Scale (Guglielmo et al., 2016) to capture pathological trading behaviors (Sonkurt & Altınöz, 2021). The proportion of crypto traders vary depending on inclusion criteria within the recruiting process (ranging from 3.6 to 100%) and are typically higher in younger males. Gambling engagement, and cryptocurrency trading frequency were positively correlated with greater frequency of gambling activities in multiple papers. Casino games are the most commonly used among cryptocurrency traders (53.6%) according to findings by Delfabbro et al. (2021), but Mills and Nower (2019) reported that casino gambling had a negative relationship with cryptocurrency trading frequency, while sports betting and daily fantasy sports predicted higher engagement in cryptocurrency trading. In addition, those who engaged in both cryptocurrency trading and sports betting gambled at higher rates in casino games, race betting, and slots than those who engaged in either sport betting or cryptocurrency alone (Delfabbro et al., 2021). Problem gambling prevalence ranged from 2% to 47.2% with a median of 9.5% among 5 samples of the 4 articles available.\n\nIn line with gambling engagement, risk for problem gambling was significantly higher in people with experience in cryptocurrency trading. Sonkurt and Altınöz (2021) reported the bivariate relation that pathological trading scores were positively correlated with pathological gambling scores (r = .20). Also, PGSI scores predicted cryptocurrency investment, trading frequency, and related behaviors (i.e., daily monitoring, daily trading hours), but it was not a significant predictor of stock investing (Kim et al., 2020). Delfabbro et al. (2021) reported 30.7% of individuals who engage in sports betting and cryptocurrency investment together are at high risk for problem gambling, and it was significantly higher than those who engaged in either sport betting or cryptocurrency alone. Another finding by Kim et al. (2020) confirms problem gambling risk, reporting a significant difference in K-CPGI scores for bitcoin investors compared to stock investors (t = 7.2). This same article also found problem gambling scores predictive of bitcoin investment (B = .80). Aslan and Kilincel (2021) compared SOGS scores of individuals who purchased bitcoin and those who did not and found a significant difference. Within the sample of frequent gamblers in Mills and Nower’s article (2019), 47.2% scored in the high-risk category of the PGSI, and the PGSI was predictive of crypto trading frequency (β = .11). In another paper, problem gambling scores were higher for crypto traders than regular investors and investors who use real-time platforms for regular investments (IRR = 5.98; Oksanen et al., 2022). All of these findings highlight the importance of understanding the connection between cryptocurrency use and problem gambling.\n\n\nDiscussion\n\nThe problems of speculative behaviors in various forms of financial trading and investments have been increasingly sprawling with respect to their gambling-like features. This review is the first to synthesize the research regarding problem gambling and financial trading, and complements a recent review on the relation between cryptocurrency trading and problem gambling (Johnson et al., 2023). The aim of the current review is to provide an overview of the literature assessing the risk of problem gambling among financial trading, which included stock traders, day-traders, and cryptocurrency traders. Our review included 12 studies, and findings were generally consistent across these studies - financial trading is associated with an increased risk for problem gambling, and the risks are amplified for those engaging in more speculative trading behaviors such as day-trading and cryptocurrency trading.\n\nOverall, financial trading activities have potential risk for problem gambling. The prevalence of problem gambling ranged from 1.4% to 47.2% with 7.6% of median across the samples who engage in trading financial products in all the articles, which is higher than the general prevalence of problem gambling.\n\nAn association between financial trading and gambling was observed throughout the three types of financial market traders identified in this study (i.e., Stock traders, day traders, cryptocurrency traders). An overlap between gambling and stock trading was found in the present review, and the closer the stock trading is to speculative investments, the more apparent the overlap is. Both gambling participation and risk of problem gambling are significant predictors of high-risk or speculative stock trading. Specifically, one of the typical examples of speculation, day trading, shows significantly higher gambling frequency and problem gambling prevalence. The studies propose evidence of a behavioral relationship between gambling and speculative stock trading, induced by similarity in psychological characteristics.\n\nIn terms of cryptocurrency trading, there is also a relationship with gambling participation and problem gambling. Cryptocurrency traders have a relatively higher risk of problem gambling than traders engaging in other financial products. Furthermore, when crypto trading is combined with sports betting, the risk for problematic gambling is higher, presenting evidence that more speculative behavior increases risk for problem gambling. This can be explained by the high accessibility and volatility embedded in the nature of the cryptocurrency market. The high prevalence of pathological trading among cryptocurrency traders might stem from those risky characteristics of cryptocurrency trading, resulting in expanded gambling activities and severe problem gambling. Also, given that sports betting, a certain type of gambling, turned out to have potential harm when combined with cryptocurrency trading, future research needs to more fully explore the profile of cryptocurrency traders to identify the highest risk profiles among individuals who engage in cryptocurrency trading more accurately. In conclusion, the present review reveals empirical evidence for the conceptual similarities of financial trading, speculative trading, and gambling, which have been discussed previously in the literature.\n\nThe supported argument of the relationship between financial trading and problem gambling was also explored in articles excluded from the present review. Håkansson et al. (2021) considered stock trading as a form of gambling and highlighted the risk of day trading due to the association between day trading and problematic gambling. A qualitative study of excessive financial traders reported a link between excessive trading and gambling disorder, with common individual characteristics such as incapacity to stop and chasing losses within both groups (Dixon et al., 2018). Also, Grall-Bronnec et al. (2017) conducted a case study for outpatients with excessive trading, seeking treatment in a problem gambling unit. The results pointed out high event frequency and short event duration in financial trading, which are characteristics frequently found in gambling disorder. Moreover, the researchers proposed that profit from financial trading increased the participants’ belief (e.g., I have special skills necessary to understand the stock markets; I was so close to succeed though I lost after all) that is similar to the concepts of illusion of control and near miss in gambling literature.\n\n\nLimitations and suggestions for further study\n\nAcross the body of research, despite the increasing severity of problematic financial trading, there have not been many studies investigating problem gambling among financial trading directly. In line with the lack of research on this topic, there are limitations regarding alienated research populations and limited research for practical implication. Finally, there are important areas future studies must be mindful of in terms of development of digital technology.\n\nAll the articles included adult populations and the participants across the articles were more likely to be male. We assume that it reflects the results of previous literature regarding financial trading or gambling (see review by Calado & Griffiths, 2016). Among cryptocurrency traders, there is the dominant tendency of young males being the majority participants, which mirrors the findings of other literature (Johnson et al., 2023) and highlights the need to study this population in future studies. Individuals entering the early adult stage have been considered the primary users of the cryptocurrency market given their engagement with novel technological innovation (Ross, 2017). Due to the high prevalence of cryptocurrency content on social media, Johnson et al. (2023) emphasize the importance of social media in cryptocurrency trading research. Specifically, many of Generation Z (those born after 1996) are increasingly seeking financial advice on social media and those young people are likely to invest in cryptocurrency as a result of being overexposed to cryptocurrency contents on social media (Glenski et al., 2019; King et al., 2014). Adolescents are experiencing gambling behaviors all over the world, and gambling recently became one of the most frequently observed addictions among adolescents (Calado et al., 2017).\n\nMost articles revealed that people have experience in trading financial products and/or gambling. Studies using random sampling show relatively low ratios of problem gambling prevalence within participants. These differences based on study samples offer the idea that when it comes to intervention or prevention for harmful outcomes of financial products or gambling, it will be more efficient to focus on at-risk samples to find observable tendencies. In addition, arguments about the prevalence and relations of gambling among traders of financial products are largely supported by panel samples of online platforms. In the present review, we found that half of all existing articles used data from panel samples collected by crowdsourcing. Therefore, we argue that using panel data is a stable method for research of gambling and financial trading and future research should continue to do so.\n\nAlthough certain standards for capturing specific features of financial trading activities provided a more subdivided understanding of safe or risky investments, more research is needed to make appropriate treatment applications in the field. We propose further research captures the precise profiles of problematic and non-problematic behaviors in financial trading and gambling. For example, the development of sensitive measures is required to understand what cryptocurrency trading looks like among individuals who engage in gambling without problems (i.e., recreational gamblers). Expanding the argument, we need to have a more thorough understanding of trading across all types of financial products to answer questions such as what proportion of a problematic gambler’s portfolio is dedicated to more speculative assets or trading behaviors. Therefore, further investigations are required to develop these arguments and create practical implications to be applied to effective prevention interventions and building regulation policies.\n\nIn addition, in the context of ‘digital convergence’, the rapid evolution of gambling brought new challenges for regulators and policymakers, communities, and treatment providers, requiring new approaches to understanding and addressing gambling harms that arise from these new technologies (Lawn et al., 2020). Traders have also experienced rapid changes from traditional stock market to cryptocurrency trading and online investment. The changes in financial trading are embedded in digitization. Global shifting induced by development of networks and mobile technologies, offer a new ecology of financial trading. Using online apps and platforms, financial market traders have access to diverse fast paced opportunities and risks. These new methods enable traders to overcome existing limitations by providing free trading without charging commission (e.g., Robinhood) or offering broader options in terms of access time and choices (e.g., 24/7 real-time trading, cryptocurrency trading). In response to this new phenomenon, there has been concern over gamification in the financial trade market, leading to the argument by Warren Buffett who said the stock market is becoming more like a casino through the introduction of trading applications (Fitzgerald, 2021).\n\nAnother issue induced by the development of digital technologies is play-to-earn gaming (PTE). PTE allows those who play the game to receive monetary rewards for their gameplay. This new form of gaming has been focused on with increasing interest in cryptocurrency, however, there have been concerns regarding harmful effects embedded in the monetized structure. Similar to the evidence found in studies of gambling-like aspects of monetized games, such as buying loot box in game (Carey et al., 2022), the monetary reward may be more appealing to individuals who are at risk of problem gambling or have strong financial need. Delic and Delfabbro (2022) argued that engaging in PTE may pose the risk of being motivated by extrinsic forces leading to temptation to grind out rewards, thus a monitoring system is required, especially for vulnerable players. The changes created by the development of new technologies are ongoing, therefore, it is essential that researchers keep up with changes in financial products and gambling phenomenon to provide appropriate policies and regulations in response to new technologies in this area.\n\nThe present review has several limitations that should be outlined for consideration while interpreting the findings. First, it only includes articles based on specific criteria built into this review. Second, the review includes articles published within 10 years of the search, therefore the time span of research includes the COVID-19 pandemic period. As Håkansson et al. (2021) argued, this global situation brought about various impacts on people including online investments. Considering the events during the pandemic period that have potential effects on the result of trading research, such as lockdown and gambling restrictions, the results may be different depending on the time or country. Therefore, it is required to have a time-sensitive perspective when trying to apply the review of this study.",
"appendix": "Data availability\n\nOSF: Association between gambling and financial trading: A systematic review. https://doi.org/10.17605/OSF.IO/FWUT2 (Lee, 2023).\n\nThis project contains the following underlying data:\n\n- Search strategy_OSF.pdf (Description for search strategy used in data collecting stage)\n\n- Final included articles.ris (Final list of articles included in analysis)\n\n- Included articles.xlsx (Final list of articles included in analysis)\n\n- Full_text screen articles.ris (Total list of articles from data search)\n\n- Psy_144(101_144).ris (Results of initial search with search terms in PsycINFO database)\n\n- Psy_144(1_50).ris (Results of initial search with search terms in PsycINFO database)\n\n- Psy_144(51_100).ris (Results of initial search with search terms in PsycINFO database)\n\n- scopus_0928_776.ris (Results of initial search with search terms in SCOPUS database)\n\n- WOS_1000.ris (Results of initial search with search terms in Web of Science database)\n\n- WOS_300.ris (Results of initial search with search terms in Web of Science database)\n\nThis project contains the following extended data:\n\n- Appendix.pdf (Eligibility criteria of data selection)\n\n- Figure 1_PRISMA.pdf (Figure of PRISMA process)\n\nOSF: Association between gambling and financial trading: A systematic review. DOI: https://doi.org/10.17605/OSF.IO/FWUT2 (Lee, 2023).\n\n- PRISMA checklist.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\n* indicates articles that are included in the current systematic reviewArthur J, Williams R, Delfabbro P: The conceptual and empirical relationship between gambling, investing, and speculation. J. Behav. Addict. 2016; 5(4): 580–591. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBarber BM, Odean T: The Internet and the Investor. J. Econ. Perspect. 2001; 15(1): 41–54. Publisher Full Text\n\nBinde P: Why people gamble: A model with five motivational dimensions. Int. Gambl. Stud. 2013; 13(1): 81–97. Publisher Full Text\n\nBrowne M, Greer N, Rawat V, et al.: A population-level metric for gambling-related harm. Int. Gambl. Stud. 2017; 17(2): 163–175. Publisher Full Text\n\nCalado F, Alexandre J, Griffiths MD: Prevalence of Adolescent Problem Gambling: A Systematic Review of Recent Research. J. Gambl. Stud. 2017; 33(2): 397–424. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCalado F, Griffiths MD: Problem gambling worldwide: An update and systematic review of empirical research (2000–2015). J. Behav. Addict. 2016; 5(4): 592–613. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCampbell M, McKenzie JE, Sowden A, et al.: Synthesis without meta-analysis (SWiM) in systematic reviews: Reporting guideline. BMJ. 2020; 368. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCarey PAK, Delfabbro P, King D: An Evaluation of Gaming-Related Harms in Relation to Gaming Disorder and Loot Box Involvement. Int. J. Ment. Heal. Addict. 2022; 20(5): 2906–2921. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCox R, Kamolsareeratana A, Kouwenberg R: Compulsive gambling in the financial markets: Evidence from two investor surveys. J. Bank. Financ. 2020; 111: 105709. Publisher Full Text\n\nDarbyshire M: Traders phone up gambling helplines as game-like broker apps spread. Financial Times. 2021, October 6; Reference Source\n\nDelic A, Delfabbro P: Profiling the Potential Risks and Benefits of Emerging “Play to Earn” Games: A Qualitative Analysis of Players’ Experiences with Axie Infinity. Int. J. Ment. Heal. Addict. 2022. Publisher Full Text\n\nDixon MR, Giroux I, Jacques C, et al.: What Characterizes Excessive Online Stock Trading? A Qualitative Study. J. Gambl. Issues. 2018; 2018(38): 8–26. Publisher Full Text\n\nDorn D, Sengmueller P: Trading as entertainment? Manag. Sci. 2009; 55(4): 591–603. Publisher Full Text\n\nFerris J, Wynne H: The Canadian Problem Gambling Index: Final report. Canadian Centre on Substance Abuse. 2001; Reference Source\n\nFitzgerald M: Warren Buffett says Robinhood is catering to the gambling instincts of investors. CNBC.2021. Retrieved December 20, 2022.Reference Source\n\nGlenski M, Saldanha E, Volkova S: Characterizing Speed and Scale of Cryptocurrency Discussion Spread on Reddit. The World Wide Web Conference. 2019; pp. 560–570. Publisher Full Text\n\nGrall-Bronnec M, Sauvaget A, Boutin C, et al.: Excessive trading, a gambling disorder in its own right? A case study on a French disordered gamblers cohort. Addict. Behav. 2017; 64: 340–348. PubMed Abstract | Publisher Full Text\n\nGuglielmo R, Ioime L, Janiri L: Is Pathological Trading an Overlooked Form of Addiction? Addict. Health. 2016; 8(3): 207–209. PubMed Abstract\n\nHåkansson A, Fernández-Aranda F, Jiménez-Murcia S: Gambling-Like Day Trading During the COVID-19 Pandemic – Need for Research on a Pandemic-Related Risk of Indebtedness and Mental Health Impact. Front. Psych. 2021; 12(July): 10–13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHargrave M: Options Contract: What It Is, How It Works, Types of Contracts. Investopedia;n.d. Retrieved December 17, 2022.Reference Source\n\nJadlow JW, Mowen JC: Comparing the Traits of Stock Market Investors and Gamblers. J. Behav. Financ. 2010; 11(2): 67–81. Publisher Full Text\n\nJohnson B, Co S, Sun T, et al.: Cryptocurrency trading and its associations with gambling and mental health: A scoping review. Addict. Behav. 2023; 136: 107504. PubMed Abstract | Publisher Full Text\n\nKalda A, Loos B, Previtero A, et al.: Smart (Phone) Investing? A within Investor-time Analysis of New Technologies and Trading Behavior. National Bureau of Economic Research;2021. Publisher Full Text\n\nKing DL, Delfabbro PH, Kaptsis D, et al.: Adolescent simulated gambling via digital and social media: An emerging problem. Comput. Hum. Behav. 2014; 31: 305–313. Publisher Full Text\n\nKumar A: Who Gambles in the Stock Market? J. Financ. 2009; 64(4): 1889–1933. Publisher Full Text\n\nLangham E, Thorne H, Browne M, et al.: Understanding gambling related harm: A proposed definition, conceptual framework, and taxonomy of harms. BMC Public Health. 2016; 16(1): 80. Publisher Full Text\n\nLawn S, Oster C, Riley B, et al.: A literature review and gap analysis of emerging technologies and new trends in gambling. Int. J. Environ. Res. Public Health. 2020; 17(3). PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee U, Lewis LE, Mills DJ: Association between gambling and financial trading: A systematic review.2023. Publisher Full Text\n\nLesieur H, Blume S: The South Oaks Gambling Screen (SOGS): A New Instrument for the Identification of Pathological Gamblers. Am. J. Psychiatry. 1987; 144(9): 1184–1188. PubMed Abstract | Publisher Full Text\n\nMarkiewicz Ł, Weber EU: DOSPERT’s Gambling Risk-Taking Propensity Scale Predicts Excessive Stock Trading. J. Behav. Financ. 2013; 14(1): 65–78. Publisher Full Text\n\nNeighbors C, Lostutter TW, Cronce JM, et al.: Exploring college student gambling motivation. J. Gambl. Stud. 2002; 18(4): 361–370. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPelster M, Breitmayer B, Hasso T: Are cryptocurrency traders pioneers or just risk-seekers? Evidence from brokerage accounts. Econ. Lett. 2019; 182: 98–100. Publisher Full Text\n\nPowell J, Hardoon K, Derevensky JL, et al.: Gambling and risk-taking behavior among university students. Subst. Use Misuse. 1999; 34(8): 1167–1184. Publisher Full Text\n\nRabin M, Schrag JL: First impressions matter: A model of confirmatory bias. Q. J. Econ. 1999; 114(1): 37–82. Publisher Full Text\n\nRoss E: Nobody Puts Blockchain in a Corner: The Disruptive Role of Blockchain Technology in the Financial Services Industry and Current Regulatory Issues. Catholic University Journal of Law and Technology. 2017; 25(2).Reference Source\n\nShannon K, Anjoul F, Blaszczynski A: Mapping the proportional distribution of gambling-related harms in a clinical and community sample. Int. Gambl. Stud. 2017; 17(3): 366–385. Publisher Full Text\n\nStatman M: Lottery Players/Stock Traders. Financ. Anal. J. 2002; 58(1): 14–21. Publisher Full Text Reference Source\n\nTurner NE: The addictiveness of online brokerage services: A first person account. J. Gambl. Issues. 2011; 25: 113–129. Publisher Full Text\n\nWilliams RJ, Stevens RMG, Nixon G: Gambling and problem gambling in North American Aboriginal people. University of Manitoba Press;2011; 166–194.Reference Source\n\nWilliams RJ, Volberg RA, Stevens RMG, et al.: The definition, dimensionalization, and assessment of gambling participation [Technical Report]. Canadian Consortium for Gambling Research. 2017. https://opus.uleth.ca/handle/10133/4838\n\nWong A, Carducci BJ: Sensation seeking and financial risk taking in everyday money matters. J. Bus. Psychol. 1991; 5(4): 525–530. Publisher Full Text\n\n*Arthur J, Delfabbro P, Williams R: Is There A Relationship between Participation in Gambling Activities and Participation in High-Risk Stock Trading?. J. Gambl. Bus. Econ. 2015; 9(3): 34–53. Publisher Full Text\n\n*Arthur J, Delfabbro P: Day Traders in South Australia: Similarities and Differences with Traditional Gamblers. J. Gambl. Stud. 2017; 33(3): 855–866. PubMed Abstract | Publisher Full Text\n\n*Aslan E, Kilincel O: The effect of social isolation on psychological stress and gambling in the COVID-19 pandemic. Ann. Clin. Anal. Med. 2021; 12(01). Publisher Full Text\n\n*Delfabbro P, King D, Williams J, et al.: Cryptocurrency trading, gambling and problem gambling. Addict. Behav. 2021; 122: 107021. PubMed Abstract | Publisher Full Text\n\n*Kim HJ, Hong JS, Hwang HC, et al.: Comparison of Psychological Status and Investment Style Between Bitcoin Investors and Share Investors. Front. Psychol. 2020; 11. 502295. PubMed Abstract | Publisher Full Text | Free Full Text\n\n*Mills DJ, Nower L: Preliminary findings on cryptocurrency trading among regular gamblers: A new risk for problem gambling? Addict. Behav. 2019; 92: 136–140. PubMed Abstract | Publisher Full Text\n\n*Mosenhauer M, Newall PWS, Walasek L: The stock market as a casino: Associations between stock market trading frequency and problem gambling. J. Behav. Addict. 2021; 10(3): 683–689. PubMed Abstract | Publisher Full Text | Free Full Text\n\n*Oksanen A, Mantere E, Vuorinen I, et al.: Gambling and online trading: Emerging risks of real-time stock and cryptocurrency trading platforms. Public Health. 2022; 205: 72–78. PubMed Abstract | Publisher Full Text\n\n*Sonkurt HO, Altınöz AE: Cryptocurrency investment: A safe venture or a new type of gambling? J. Gambl. Issues. 2021; 47. Publisher Full Text\n\n*Whiting SW, Hoff RA, Balodis IM, et al.: An Exploratory Study of Relationships Among Five-Factor Personality Measures and Forms of Gambling in Adults With and Without Probable Pathological Gambling. J. Gambl. Stud. 2019; 35(3): 915–928. PubMed Abstract | Publisher Full Text | Free Full Text\n\n*Williams JN, Williams RJ, Gooding NB, et al.: Financial speculation in Canada: Prevalence, correlates and relationship to gambling. Int. Gambl. Stud. 2022; 1–14. Publisher Full Text\n\n*Youn H, Choi JS, Kim DJ, et al.: Development and validation of a stock addiction inventory (SAI). Ann. General Psychiatry. 2016; 15(1): 16. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "163584",
"date": "16 Mar 2023",
"name": "Luke Clark",
"expertise": [
"Reviewer Expertise psychology of gambling & harmful gambling",
"including emerging forms of gambling"
],
"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 enjoyed reading this paper which systematically reviews the literature on links between problem gambling and financial trading. This is a hot area and one with considerable policy relevance in light of the rapid growth of ‘retail trading’ apps and their associated marketing. The review is well conducted and well written, drawing the intuitive conclusion (to those in the gambling field) that these constructs are closely related. I’ll list my comments in order.\nAbstract: The first line of the Conclusions should probably be rewritten. The “while” implies some contrast between the 2 clauses, when they both point in the same direction. An issue that recurs elsewhere is the term ‘risk for problem gambling’, inferred from the PGSI. Although the PGSI does label its categories as ‘risk’ categories, it is fundamentally a current (or past 12 month) symptom severity scale; risk should not be taken to imply a future risk in the sense of vulnerability. Lastly, is the second clause in this sentence (“trading riskier assets and riskier trading behaviours”) simply referring to the frequency associations? It’s not clear to me from their results whether they can draw any links to particular kinds of trading.\nThe first lines of the introduction could also be reviewed – it’s not clear how gambling related harm and severity of problem gambling are different as constructs, and I’m not sure it’s even necessary to raise ‘harm’ in this article, given that all the measures are of problem gambling.\nWhen the authors say “gambling has always existed within financial markets”, there is a distinction here between a phenomenological overlap versus the actual definition of gambling. The authors return to definitions at the bottom of pg 3 (the Arthur et al. review) at a basic level, it is hard to create a definition of gambling that would clearly exclude most forms of financial investment. Similarly, the authors refer to speculation in paragraph 2 but do not define this term until pg 4. Some of these issues might be resolved with a glossary box or just by more signposting that these terms will be defined later on.\nParag 2 “the reason for the differences between trading platforms remains unclear” – intuitively, there are many reasons why platforms like Robinhood are likely to amplify risky behaviour (gamified features, round the clock availability with the potential for repeatedly checking one’s stock etc). The authors consider these issues late in the paper, and might consider moving that text earlier. Alternatively, the point that they may be looking to make here is that there is virtually no empirical research on the effects of specific ‘product features’ in the context of trading apps (new paper by Flayelle et al 2023 Nat Rev Psych may be helpful here).\nPg 4. In defining speculation, the authors refer to gambling having a ‘definitive event’ (based on Arthur et al. 2016). Perhaps this is obvious, but I didn’t really understand what qualified as an event in the case of speculation activities (e.g. day trading).\nPg 4 last line (Mills & Nower 2019) – this is another place where the term ‘risk’ is problematic; again, I think the finding here is of a cross sectional link with PG severity, not future risk. From another angle, I would say it’s particularly important in this article, because the authors regularly refer to risk in a different, second sense (i.e. a risky asset).\nSearch details (pg 5) – please explain why 2013 was taken as the search start. Please confirm if all papers until the end of 2022 were captured in the search. After introducing concept of speculation in intro, why was speculation not included among the search terms?\nMy understanding of PRISMA guidelines is that a Systematic Review should include a quality assessment; was this undertaken here? If not, the exercise may be better described as a scoping review.\n“eligibility criteria included” – pet peeve of mine, but ‘included’ implies there are some other things that you are not telling us. Suggest “eligibility criteria were”.\nTable 2. My understanding is that the PGSI is the 9 item screening tool that is part of the wider CPGI; in which case, Table 2 need only refer to the PGSI. For the first few rows in Table 2, it’s notable that the PGSI and SOGS thresholds seem a little wonky, and this should be discussed somewhere (there is a section on pg 10 where this could fit). The Williams & Arthur papers tend to use a 5+ threshold on the PGSI, when the original threshold was 7+. For Aslan & Kilincel’s study on the SOGS, nobody uses an 8+ threshold on the SOGS to my knowledge, please confirm whether this is a typo.\n\nIn the results, the authors refer to 2 trading scales, the Stock Addiction Inventory by Yuan, and the Pathological Trading Scale by Guglielmo. To what extent are these scales validated? Joel Billieux’s argument about the circularity of detecting new addictions by changing the word drug/gambling to trading seems relevant here.\nPg 12 the studies that were excluded from the review, but support the argument: there is no reason given for why the Hakansson study was left out. (This study is also mentioned earlier on, and is one of the few to directly consider the COVID impact)\nThe authors refer to loot boxes late in the paper. One possible account that has been raised in the loot box literature is the possibility that gamers score high on measures like the PGSI because they consider loot boxes (or in this case, trading) to actually be gambling (Sidloski et al. 2022 Add Behaviors). This is a different explanation from what is implied in this paper, that traders score on the PGSI because they are also involved in conventional gambling (slots etc). I’m curious what the authors think about this argument.\nSorry this is such a long review, but I did enjoy reading the paper and I commend the authors for a useful addition to the literature. Signed, Luke Clark\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",
"responses": []
},
{
"id": "170612",
"date": "08 Jun 2023",
"name": "Roy Kouwenberg",
"expertise": [
"Reviewer Expertise 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\nThe article systematically reviews 12 articles about problem gambling and trading in the financial markets. The conditions for including an article in the systematic review appear to be the following: 1. The study fielded an established measure of problem gambling in a survey (either SOGS, CPGI, PGSI, or DSM-5). 2. The study also included data about the financial investments or financial trading behaviour of the respondents. The main finding of the systematic review is that the proportion of problem gamblers tends to be substantially higher among people who trade in financial markets, compared to the prevalence in the general population. This suggests that either financial markets attract people with problem gambling issues, and/or that financial traders are at a higher risk of becoming problem gamblers.\nThe review contributes to an active field of study about speculative financial trading strategies that resemble traditional forms of gambling, and whether those trading strategies can lead to gambling problems (e.g., difficulties to stop trading, hiding losses, relational problems, etc.). The topic has become more urgent as during the COVID-19 pandemic many new retail investors started trading stocks and cryptocurrencies, often on their mobile phones. Further, some trading platforms use gamification to entice people to trade actively and focus on short-term gains. In addition, cryptocurrency markets are extremely volatile, while regulation and investor protection are still lacking, making them especially suited for gambling-like trading strategies.\nI enjoyed reading this relevant paper, which reviews literature on the link between problem gambling and financial trading. Below I provide some suggestions for improving the exposition of the paper, and to make it easier to understand the eligibility criteria used.\nSuggestions for improvement\n- The objectives of the literature review could have been be defined more clearly. One page 5 of the article, the aim is stated as: “Thus, the present study aims to review the literature on financial trading and gambling, by examining the prevalence of participation in both, and the relationship between problem gambling and trading behavior.” Most of the 12 studies selected for the review are not suited to estimate the prevalence of problem gambling, nor the “prevalence” of trading behavior, as they do not have representative sample of the population. For example, some selected studies only include gamblers in the sample, while others only include investors. To me it seems that this systematic literature review’s aim is narrower: to summarize evidence on the relation between standard problem gambling scales measured in surveys (SOGS, CPGI, PGSI, or DSM-5) and the respondents’ financial trading behavior.\n- The eligibility criteria for including studies in the systematic review are not clearly stated. The search starts really broadly with 1,444 articles from a keyword search. Then a subjective assessment narrows down the list to only 12 articles. The criteria for eligibility are not clearly described in the paper, nor in the supplemental materials (e.g., the online appendix). Simply looking at the 12 articles selected, the authors appear to have used the following filter: 1. The study fielded a measure of problem gambling in a survey (either SOGS, CPGI, PGSI, or DSM-5, using the original scale, not a scale adapted to measure gambling in financial markets specifically). 2. The study also included some data about the financial investments or financial trading behavior of the respondents. I recommend to state this clearly in the paper.\n- When the authors refer to problem gambling, it is not clear what precisely their definitions of gambling and problem gambling are. For example, does problem gambling also encompass problematic financial trading behavior that is similar to traditional forms of gambling? A similar question can be asked about the 12 selected studies: when measures like SOGS, CPGI, PGSI, or DSM-5 are fielded to ask about gambling behavior, does this also include gambling-like speculative trading behavior, or are those questions clearly limited to traditional forms of gambling (sports betting, slot machines, poker, etc.)?\n- Given that the 12 selected studies vary quite widely in their research design as well as in their results, can the authors provide some more recommendations on what type of study design would be especially useful to provide more evidence on the relation between problem gambling and financial trading? What are the key knowledge gaps in this literature? For example, one question that comes to my mind is the direction of causality. Do problem gamblers mainly start to gamble in traditional ways (e.g., sports betting, slot machines, poker etc.) and then shift to speculative financial trading, such as betting on crypto-currencies and day-trading stocks? Or did widespread access to online trading of stocks and crypto-currencies in recent years create a new group of problem gamblers who mainly gamble in financial markets?\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? Yes",
"responses": []
},
{
"id": "176369",
"date": "13 Jul 2023",
"name": "Matthew Rockloff",
"expertise": [
"Reviewer Expertise gambling studies"
],
"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 examines the relationship between participation in financial trading activities and the experience of gambling-related problems. It also discusses the underlying features of behavioural addiction that can be associated with using gambling products and financial trading products.\nI endorse and take no issue with the comments of Clark and Kouwenberg. Consequently, I will not repeat those same issues here.\nHere are some additional observations that I think should be addressed:\nUnder the section, \"Is investing gambling?\" there is a statement on speculating on day-trading, \"Because of the short duration it is not investing but it is also not gambling.\" For gambling-studies researchers, day-trading is generally accepted as a form of gambling. It would be helpful to note that investing and hedging are activities that can produce positive net benefits to market participants. Gambling, in contrast, is a zero-sum game, where someone loses and someone wins. Of course, the house always wins, but stockbrokers or market-makers also always win. Arguably, the entertainment value is also an important component of gambling, whereas an improvement in financial position is presumably the only purpose of financial markets. In short, you should recognise that a few criteria might be used, although not definitively, to identify what is gambling and what is not.\n\nI was confused by the term \"neutral attribute\" in the last paragraph of the section, \"Psychological characteristics of traders versus gamblers\". Can you clarify this sentence?\n\nImmediately before the methods, you say, \"thus the present study aims to review the literature on the financial trading and gambling, by examining the prevalence of participation in both...\" Similar to the comments of the other reviewer, I think you are instead comparing the relative prevalence of gambling problems (generally) between people who either do or do not engage in financial trading. Thus, the absolute prevalence of either gambling or trading in each sample is not at issue. You should make this point clearer.\n\nIn the second line of the results, you say, \"Many articles were published in 2021, with a significant increase after 2019, demonstrating a steady interest in this topic. Are 12 articles an adequate sample size for assessing interest? Also, wouldn't this interest qualify as \"increasing interest\" or more-probably \"recent interest\" given the bump in 2021?\n\nThe K-CPGI is likely a Korean version of the PGSI rather than the full CPGI. The CPGI is a very long survey instrument, and cannot be scored to reveal an index of gambling problems. The PGSI is a subset of 9 scorable items from the larger survey. You should make this clear.\n\nUnder the subsection on \"stock trading\" there is an incomplete sentence, \"Additionally, a significantly higher gambling frequency for high-risk traders WERE reported by Arthur et al. (2015).\"\n\nIn the discussion, you should note that your findings may reflect, in part, that the kind of people who trade in financial instruments are the same kind of people who gamble and experience gambling-problems as a result. That is, the gambling problems may not emanate from financial trading itself, but rather from the concomitant likelihood of engaging in both products.\n\nRelatedly, it is important for you to recognise in the discussion that the gambling-problem scales that you review (PGSI, SOGS) are filled with language that measures problems related to how people \"bet\" and \"win\" money. That is, the scales are only sensitive to measuring problems regarding people losing money on gambling and not necessarily on financial products. Thus, it is likely that some or most of the \"problems\" identified are due to concomitant gambling and not trading.\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",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-111
|
https://f1000research.com/articles/12-110/v1
|
30 Jan 23
|
{
"type": "Research Article",
"title": "Investigating the influence of artificial intelligence on quality management in healthcare centers",
"authors": [
"Nasser Ali AlJarallah"
],
"abstract": "Background: New emerging technologies enable healthcare centers to enhance their information technology (IT) infrastructure, which offers an opportunity to provide adequate services to patients. In Saudi Arabia, the government has initiated artificial intelligence-based technologies to increase productivity in organizations. However, recent studies demand innovative approaches for quality management in healthcare centers. In addition, there is a scarcity of techniques for evaluating the performance of healthcare professionals. Methods: The study intended to investigate the role of IT in quality management in Saudi Arabian healthcare centers. A set of hypotheses were proposed to identify the relationship between IT and quality management. A web-based questionnaire was used and interviews were conducted in the healthcare centers of Riyadh and Eastern provinces. A total of 233 healthcare professionals and management employees participated in the survey. A mixed-method approach was applied to evaluate the responses. Furthermore, exploratory and confirmatory factor analyses were used to draw insights from the data. Results: The outcome reveals a positive relationship between IT and quality management. Moreover, the thematic findings outline the importance of IT competence in healthcare centers. Conclusions: The study's findings can support healthcare centers to deploy valuable tools and techniques to improve the quality of service.",
"keywords": [
"healthcare",
"information technology",
"IT infrastructure",
"healthcare professionals",
"quality management."
],
"content": "Introduction\n\nThe exponential growth of information technology (IT) has enabled a wide range of facilities in healthcare organizations.1 Quality management (QM) governs the overall activities of a healthcare center (HC) to provide sophisticated patient care services.2,3 The existing literature suggests that healthcare IT can improve the service quality and the efficiency of healthcare. The lack of IT knowledge and infrastructure are barriers to deploying IT applications. Saudi Arabia's Vision 2030 encourages an organization to automate its activities to satisfy the patients' demands. However, the automation processes are in the infancy stage and require training sessions to educate employees and other healthcare professionals (HCPs) to adopt the new working environment.4\n\nOn the other hand, recent research reveals that HCPs are reluctant to accept and utilize the latest technologies. A robust pre-assessment model for gauging the expectations and perceptions of HCPs should be developed before deploying newer technologies.5 A better understanding of HCPs’ level of technology awareness can support IT designers in building a user-friendly system.6\n\nThe essence of healthcare IT is communication. It enables an opportunity for HCPs to share critical information. These communication channels are supported by hardware solutions that have been carefully selected and installed, and timely and effective maintenance services.7 The healthcare industry relies heavily on the IT sector. The primary purpose of IT implementation is to enhance the population's health status by offering patients higher levels of comfort and confidence.8 The exponential increase in the population has led to HCPs handling more patients. Also, routine responsibilities must be completed on schedule and without delays. IT makes patient treatment more accessible, faster, and more convenient.9,10 In recent times, patients can access more medical facilities.\n\nAdditionally, the use of technology mitigates the risks of healthcare management. IT has also made it easier for healthcare practitioners, including physicians, nurses, researchers, and physicians, to access patient information and data quickly and easily. There are several types of health IT.11,12 The Electronic Medical Record (EMR) is among the most prevalent and highly discussed. Patients' medical information, such as medical history, medication, laboratory test results, and other clinical data, may be found here in a digital format. It is expected that EMRs will eventually displace paper-based medical records, making it easier to read and maintain track of patients' medical histories.13,14 Furthermore, transmitting a patient's digital records between healthcare providers is easier and faster. They have access to their patient's EMRs from any location. Patients may also access their medical records and reports using an IT application, which benefits physicians and their patients.\n\nThe newer technologies, including machine learning (ML) tools and artificial intelligence (AI) based key performance indicators (KPIs), are being introduced in HCs to improve the quality of service.15,16 The relationship between IT and QM has been investigated in several studies. Few studies have attempted to examine the role of recent technologies in governing the crucial activities of healthcare.\n\nThere is a correlation between aging and medical care, which might result in unplanned and frequent visits to the hospital.17 Healthcare systems for the elderly can benefit significantly from advances in Internet-of-things (IoT) technology.12 Many countries strive to manage people's demands because of the strain on public health care and the lack of necessary resources. In the past, the healthcare system was physician-centric; now, it is patient-centric. Health and other ambient assisted-living technologies are integrated into smart homes, enabling older adults to interact with HCs.12,18 Nonetheless, older adults are reluctant to use the technology due to the complex infrastructure. Thus, HCs are not deploying advanced technology to treat people in remote places and older adults. Recent studies on IoT and smart homes indicate the advantages of such a system for the elderly and a significant push toward developing new underlying technologies and service offerings. On the other hand, there are a lack of data demonstrating how the perception of HCPs might influence healthcare systems. In addition, there is limited information about the association between current IT technologies and QM.\n\nWith its ability to minimize costs, and monitor and reduce medical mistakes, IT is a significant health care innovation. Increasing numbers of experts and policymakers are becoming increasingly concerned about this issue of a low adoption rate.\n\nAlthough health IT systems have been supported for a long time, it is crucial to understand why certain hospitals or care providers are hesitant to embrace such technology.19 Research in this area frequently incorporates case studies, surveys, or interviews. Two of the most significant impediments to healthcare providers adopting health IT is the cost and a lack of available IT skills.8 There is a demand for identifying the factors affecting HCPs adopting the new technologies, and how these technologies could support an HC to enhance its QM dimensions. Therefore, the researcher intends to examine this study's relationship between IT and QM dimensions. In addition, the study identifies HCPs’ perception of IT applications in maintaining HCs. According to the existing literature, no studies examine the role of advanced IT applications in HCs.\n\nThe contributions of the proposed study are as follows:\n\ni. Develop a theoretical framework for investigating the relationship between IT and QM dimensions.\n\nii. Identifying the HCP perception of the role of IT in quality of service.\n\niii. Presenting the empirical evidence about the influence of recent technologies in HCs.\n\nThe rest of the study is structured as follows: The Literature review outlines the existing literature and proposed hypotheses. The research methodology is presented in the Methods. The Results and Discussion highlight the study's outcome. The Limitations section offers the study's limitations. Finally, the Conclusions concludes the study with its future implications.\n\n\nLiterature review\n\nThe lack of global health IT standards is one of the factors affecting QM.1,20 IT vendors present their own set of technical documentation, which causes complexity in training HCPs. Many research studies reported the challenges a healthcare organization faces in automating its core activities. Patients' EMRs should include a single overview of their treatment, including a standard reporting format, content, and language to ensure access to all care team members.21,22 Healthcare providers should not be burdened by this centralization, which may not necessitate more financial resources. Instead, it necessitates more time to properly teach patients how to use EMRs.\n\nMine et al.23 proposed a theoretical framework for evaluating the existing IT tools and their ability to apply QM principles successfully. Aggarwal et al.,24 reported that there is no statistically significant evidence between IT and QM. They focused on the technical aspects of IT. According to Hsu et al.,25 future research should investigate the association between QM and IT tools and techniques. Kraus et al.,26 discussed the digital transformation in healthcare and its outcome.\n\nThe current literature revealed that insufficient consideration had been devoted to developing accurate and relevant assessment instruments to evaluate hospital QM aspects. Mosadeghrad27 discussed the 10 dimensions: management and leadership, strategic quality planning, quality culture, training and education, employee management, customer management, supplier management, resource management, information management, and process management.\n\nSun & Medaglia2 developed a technique for monitoring QM procedures in Chinese hospitals. It comprises eight different QM dimensions: senior management, quality policy, training, process management, customer focus, staff relations, and quality and analysis information. Quality management approaches were shown to be the most effective in various situations. Managers of healthcare facilities may use the tool to understand QM procedures to provide a better service to patients. Algunmeeyn et al.28 carried out a qualitative study at Jordan's two private hospitals and revealed that the top management's teamwork, communication, training, commitment, and support were primary facilitators of total quality management (TQM) adoption. Kumar et al.29 studied Indian manufacturing sectors using an analytical hierarchy method. They determined that QM's dimensions were customer focus, leadership and people management, supplier focus, and continuous improvement. Figure 1 reflects the widely discussed QM dimensions. Most studies emphasized the QM dimension and its relationship with IT.\n\nThe present studies describe the necessity of IT knowledge in the business area.30 defines IT knowledge as a tool to utilize the available resources in the work environment. It is a technique to manage information. In other words, it covers IT knowledge management, IT operation, and resources based on IT tools. Algunmeeyn et al.28 and Pérez-Aróstegui et al.31 proposed a method to examine an organization's IT competence and strategic management. In addition, studies have suggested IT technical knowledge, IT management knowledge, IT integrated functional strategy and human resource management as the dimensions of IT knowledge.28,30,31 Authors31 have argued that IT knowledge is one of the primary factors of successful QM.\n\nIT infrastructure covers software application, hardware, and other resources governing HCs. It supports the organization in enabling a flexible working environment and neutralizes possible threats. Rahman et al.32 discussed the importance of IT infrastructure in treating patients with high care. On the other hand, ALOmari & Jenkins33 stated that the lack of IT infrastructure causes a delay in providing a better service. Likewise, Al-Samarraie et al.34 emphasized that HCs should implement an adequate IT infrastructure in order to deploy recent IT technologies.\n\nIn recent times, big data applications have been widely used in HCs. They provide multiple KPIs to evaluate the performance of individual units and employees accordingly. For instance, managers can view the overall performance of HCs in a dashboard. Furthermore, interfaces including hospital-wide or disease-specific quality, nursing performance, and safety diagnostic dashboards cover a wide range of HC activities. Mukherjee35 presented the applications of KPIs in HCs and how they assess managers to improve the quality of HC services.\n\nAmann et al.36 presented a survey on different ML approaches in HCs. ML is a subset of AI, which automate complex HC processes. Pallathadka et al.37 argued that the ML tools and techniques provide knowledge for decision-making and finding solutions to the problems. They presented some ML tools for monitoring HCs.\n\nHCs focus on healthcare IoT (HIoT) devices to collect patients' data and store it into the cloud-assisted remote servers. Across the globe, data scientists invest their time in discovering new technologies for HCs. In addition, IoT devices are employed in detecting dangerous diseases from computed tomography and X-ray images. Khatoon12 suggested that the IoT device supports the physician in treating disorders. Marrella38 proposed a framework for identifying the IoT influence in HC applications. They discussed that HCPs demand adequate training to handle advanced devices and applications. In addition, the lack of IT knowledge leads to improper information management. Table 1 presents the recent literature on IT and its relationship with QM dimensions.\n\nBased on the existing literature, the researcher framed the theoretical framework to investigate the relationship between IT and QM dimensions. Figure 2 outlines the proposed framework. QM is a dependent variable, whereas IT knowledge, IT infrastructure, KPIs, ML tools, and HIoT are independent variables.\n\nHypothesis 1 (H1): There is a significant relationship between IT knowledge and QM.\n\nHypothesis 2 (H2): There is a significant relationship between IT infrastructure and QM.\n\nHypothesis 3 (H3): There is a significant relationship between KPIs and QM.\n\nHypothesis 4 (H4): There is a significant relationship between ML tools and QM.\n\nHypothesis 5 (H5): There is a significant relationship between HIoT and QM.\n\n\nMethods\n\nIn this study, the researcher follows a mixed-method approach to achieve the study's goal. Figure 3 highlights the research methodology for identifying the perception of HCPs on the role of IT in maintaining a quality of service in HCs. According to the hypotheses, a questionnaire is prepared to receive the participants' responses based on the dependent and independent variables. A total of 57 questions are presented in the questionnaire. The quantitative section contains 44 questions, whereas the qualitative section includes 13 questions. The researcher adopts a number of measures from the critical studies to ensure content validity. A 5-point Likert scale ranges from 1—strongly disagree to 5—strongly agree. Initially, the questions on IT knowledge are adapted from.31 The questions investigate the participants' perception on IT knowledge, and cover IT competence, technical and managerial knowledge, and training sessions.\n\nTo evaluate the relationship between IT infrastructure and QM, five questions are adapted from.33 The topics such as software, hardware, and other resources are presented in the section. Likewise, six questions are included in the KPI section. The first three questions are adapted from Ref. 47 and the remaining questions are developed according to the current work environment of Saudi Arabian HCs. ML tools and HIoT are the current concepts in HCs. Amann et al.36 discussed the role of ML tools and HIoT in HCs. The researcher asked two IT experts to suggest some questions. Based on the existing literature36,37 and expert suggestions, six and five questions are included in ML tools and HIoT sections, respectively.\n\nFinally, to measure QM dimensions, six questions are adopted from Ref. 31. The questions cover QM dimensions and their relationship with IT in HCs.\n\nThe details of the HCPs were extracted from the Ministry of Health, Saudi Arabia website (www.moh.gov.sa). HCPs and administrative staff were the target population of the study. The researcher conducted a pilot study in order to validate the questions. In addition, two experts were involved in the study to develop and validate the questions. A total of 45 individuals (managers and HCPs) participated in the pilot study. The questions were revised according to the outcome.\n\nThe researcher obtained the Institutional Research Board approval (IRB07-12052022-42) from Almaarefa University, Saudi Arabia, for conducting the study in the HC. A consent form was attached with the web-based questionnaire in order to inform the participants about the study's objectives. In addition, the participants were informed that their data would not be disclosed to any external entities. The researcher clarified to the participants that they would not gain any monetary benefits. Moreover, participation was voluntary; at any stage, the participants could leave the survey.\n\nThe researcher contacted the HCs through emails and Zoom meetings. The questionnaire was sent to the HR manager or person in charge to circulate among the HCPs. A total of 286 individuals were requested to participate in the survey. Participants responded to the questions between November 2021 and December 2021. Finally, a total of 233 responses were received, with a response rate of 81.4%.\n\nA maximum of 75% of HCs had implemented ISO 9000 standards and deployed recent IT technologies. In addition, the HCs facilitated 100 and above beds, with approximately 75 HCPs. A total of 95% of HCs had enabled access to web-based services for the patients to interact with HCPs, and 72% had deployed EMR for data interchange. Confirmatory factor analysis was conducted to ensure reliability and validity. IBM SPSS 18.0 with AMOS package (RRID:SCR_022686) was employed for analyzing the data. The metrics were applied to measure the study's findings, including chisq/df, GFI, CFI, MFI, and RMSEA. Moreover, exploratory factor analysis was used to evaluate the responses' internal correlation. Internal consistency was ensured using Cronbach's Alpha coefficients and composite reliability (CR) with a value greater than 0.7 and average variance extracted (AVE) greater than 0.6.\n\nFinally, correlation and regression were applied to test the proposed hypotheses. Content analysis was used for qualitative findings to identify the key terms from the participants' responses.\n\n\nResults\n\nA total of 233 participants recorded their responses. Table 2 represents the demographic information of the participants. It classifies the participants into multiple categories to support the study's goal. The findings outline that the number of male participants (53.65%) is higher than the number of female participants (45.92%). The majority of participants are managers (57, 24.46%), whereas physicians are the smallest group of participants (37, 15.88%). However, the total number of HCPs is 77, representing more than 30% of participants. In addition, most participants have more than six years of experience, supporting the research to draw a meaningful insight.\n\nFigure 4 highlights the Pareto chart of the mean value of the dependent and independent variables. For instance, the ML tools variables obtained a mean value of 4.3. This denotes that a more significant number of participants believe that ML tools and techniques could support the HCPs to identify a disease at earlier stages.\n\nTable 3 presents the item loadings of the variables. It is evident from the outcome that each variable has achieved reasonable item loading and communality. For instance, IT knowledge items are loaded with values ranging from 0.90 to 0.91. The items achieved the communality ranges from 0.81 to 0.84, Eigenvalue of 3.31, and Cronbach's alpha of 0.93.\n\nTable 4 reflects the values of AVE and CR of the dependent and independent variables. The outcome ensures that the importance of variables is significant and greater than the minimum AVE and CR. In addition, the Goodness of fit index is 0.924, representing the proposed model's effectiveness.\n\nTable 5 highlights the correlation analysis outcome of the variables. There is a positive correlation between each variable. In addition, the prior results ensure a significant inter-correlation between items in each variable.\n\nFinally, Table 6 denotes the regression outcome for each hypothesis. It is evident that R2 and standardized parameters support the proposed hypotheses. For context, H1 is supported by R2 = 0.54 and remaining H2, H3, H4, and H5 are by 0.56, 0.69, 0.67, and 0.85, respectively.\n\nThe findings of the qualitative analysis reveals the importance of IT in healthcare QM. Many participants share their experiences in healthcare management. Table 7 presents the themes and elements emerging from the thematic analysis.\n\nDrivers for change\n\nIn order to provide patients with effective treatment, medical personnel need to acquire or refine new skills. Medical professionals' competence and expertise are crucial to delivering high-quality treatment. In order to ensure that the healthcare industry has competent and well-trained personnel, medical schools play a pivotal role. Organizational structure and culture, staff competency, infrastructure, leadership and management, and the collaborative care approach are all internal variables that contribute to quality care. An organizational structure is a method of coordinating its operations to achieve its goals. It defines everyone's functions, norms, and obligations. The structure is critical in providing high-quality healthcare because it determines how the treatment is delivered and who makes the decisions. In a horizontal or flat organizational structure, all employees have a voice in the decisions that are made, leading to better outcomes. Employees' beliefs, conventions, assumptions, and values are the foundation of a company's culture. Values that are effective and supportive of excellent practice are defining characteristics of healthcare delivery that meet or exceeds expectations.\n\nFurthermore, one of the respondents expressed their view on the association between IT and QM. The outcome suggests that HCPs' present IT knowledge is insufficient for handling complex tasks. There is a demand for training programs and documentation (Arabic and English) to learn recent technologies.\n\n“Initially, I thought that IT would not cause any major impact on QM and patient satisfaction. However, in the long term, IT has supported us in improving the routine task's quality.”\n\nThe participants' expression denotes the advantage of the IT infrastructure in healthcare. Moreover, it is evident that IT positively influences QM in healthcare practices. IT infrastructure enables healthcare management to analyze past and present data to enhance crucial processes.\n\nFurthermore, IT infrastructure is one of the factors for the successful implementation of advanced technologies. Some HCPs perceived the current IT infrastructure as unsuitable for emerging IT applications. On the other hand, few HCPs appreciated their management for providing adequate IT infrastructure.\n\n“ … our management is implemented a high standard infrastructure for IT application. My previous employment was with a foreign-based HC; however, this HC has a better infrastructure.”\n\nUse of emerging technologies\n\nLeaders in the healthcare industry recognize that new technologies have the potential to significantly affect the future of healthcare by boosting care delivery systems, lowering costs, and increasing revenue. It is necessary to consider the aspects of motivation that affect everyone. One consistent trend in the healthcare industry is the shift away from in-house health information systems and towards electronic medical care delivery.\n\nDissatisfaction with using the EHR, electronic claim processing, payment variations, remittances, and the company's scale may also be contributing issues. Each of these challenges necessitates implementing digitally updated information and communication systems. There is still a lot of interest in how new technologies might facilitate digital transformation and modernization. However, most top-level executives are still clueless about the time and energy required to realize the technology's potential advantages fully. It is important to note that there is more to deploying cutting-edge technology than just hardware, infrastructure, system customization, digitization of physical assets, algorithms, automation, data collecting, accessibility, analysis, and augmentation of established management practices. To effectively utilize new technologies, businesses must develop a long-term technology plan that will reshape how they do business and enable them to offer clients more valuable services and goods.\n\nKPIs are widely applied in HCs to govern HCPs and overall activities of HCs. They support the managers in monitoring routine activities and HC performance. In addition, other HCPs can visualize their performance through dashboard applications. Nonetheless, some participants suggest that there is a possibility of privacy issues. They demand a protected environment to ensure the data privacy of both employees and patients. One of the managers shared their perception of KPIs.\n\n“It reduces our turn-around time for each task. I can view each activity of HC with an interactive dashboard application.”\n\nML tools and techniques are being introduced in the HCs to identify tumors and other malicious diseases using images. In Saudi Arabia, HCs apply ML techniques for treating patients. Physicians believe that ML tools and processes support them in diagnosing diseases and satisfying patient demands.\n\nLastly, participants perceive HIoT devices as a critical resource in HCs. The deployment of the ML tools and HIoT is in the initial stages and requires further study for successful implementation. Thus, many participants are not aware of the newer technologies. However, few HCs have started the deployment of HIoT devices. Physicians agreed that emerging technologies could be used to provide a better service. Emerging technologies have a positive influence on QM.\n\n\nDiscussion\n\nThe study's findings outline the influence of IT on leadership, information and analysis, and other dimensions of QM. First, the demographic information shows a higher number of male than female participants. However, there is no impact of sex differences in the proposed study. In addition, more than 100 participants have more than six years work experience, supporting this study's extract relevant responses for QM. The findings also confirm the findings of,1,16 and,48 which emphasize the importance of experienced employees in a survey. The studies,9,24 and49 suggest that the employee's knowledge and experience support an organization in improving the quality of service.\n\nSecond, the outcome indicates the association between IT knowledge and QM dimensions. It follows the findings of,24,25,37 and50 that reflect the significant positive influence of HCPs’ IT knowledge in treating patients. The qualitative findings highlight that the participants perceive IT knowledge as a tool for identifying the shortcomings of the work environment. On the other hand, some participants demanded a training session to improve their IT knowledge. They argued that the recent technologies are challenging to learn in a limited duration.\n\nThird, the significant relationship between IT infrastructure and QM denotes the crucial part of IT in HCs. The results follow the outcome of the studies that described the benefits of IT infrastructure. In contrast, studies11,20 argued that the IT infrastructure is not a significant factor in quality practices. However, the participants accepted that a better IT infrastructure could support HCs in serving the patients with a high-quality service. Few participants indicated that the lack of IT infrastructure inhibited the management from deploying recent technologies.\n\nFourth, the mixed-method approach identifies the association of KPIs and information and analysis, which is one of the dimensions of QM. HCs managers shared their experience in evaluating HCP performance using KPIs. Studies51,52 confirm the importance of KPIs. Similarly, The authors proposed a useful KPI and method to apply in HCs.8 However, this study finding suggests a thorough evaluation of the KPI to ensure its accuracy.\n\nFifth, the findings outline the role of ML tools and techniques in HC applications. Saudi Arabian HCs started experimenting with ML tools in diagnosing patients. The participants' attitude highlights that the ML tools positively influence QM practices. Some physicians require a set of training programs and seminars to learn emerging technologies. It follows the findings of the studies36,37 in which the authors emphasize the importance of training sessions.\n\nFinally, the results indicate that the introduction of HIoT mitigates the risks in HC management. Mainly older adults can access treatment through IoT devices from their residences. On the one hand, the technology is not entirely functional in a significant number of HCs in Saudi Arabia. On the other hand, physicians and managers emphasized that the HIoT can support them in identifying dangerous diseases. The results also favor the findings of studies8,12 that discuss the advantages of emerging technologies.\n\n\nLimitations\n\nThis research study has some shortcomings, all of which need to be taken into account to assess the possibilities for more research in the future. This study employed a survey questionnaire to collect data in a cross-sectional design. It should be highlighted that future studies could use longitudinal research designs to remove supporting evidence between variables over time. In the context of Saudi Arabian Hospitals, a more extensive investigation is needed to determine the barriers to implementing QM. In addition, this research was only conducted in Saudi Arabia's healthcare service sector. Future research should expand its scope to include other service industries, such as education and banking. It should focus on the influence of QM implementation on other possible performance metrics, such as strategy performance, rather than just focusing on this study's QM dimensions. Finally, the study's findings are based on HCPs. As a result, the subsequent research should be gathered using data methodologies such as interviews and surveys with patients.\n\n\nConclusions\n\nThe study intends to identify the influence of IT on the QM dimensions. The recent literature discusses the role of emerging technologies in HCs and how they support management to render effective service to patients. A mixed-method approach is followed in this study in order to achieve the study's goal. The findings reveal a significant relationship between IT knowledge, IT infrastructure, KPIs, ML tools and techniques, HIoT, and QM dimensions. For instance, IT knowledge and infrastructure support HCs to monitor overall activities and improve productivity. In addition, HCPs believe that the emergence of ML tools and techniques could offer a protective environment for patients and older adults. This study's contribution is an investigation of the influence that IT has had on QM techniques. This collection of management best practices has gained widespread attention and adoption in recent years. Researchers and management may benefit from the relationship between IT and QM. However, a literature review reveals two fundamental shortcomings in studying the link between IT and QM. As a result of the absence of empirical data, IT is frequently characterized solely in terms of its technological aspects. For this reason, the researcher establishes a multidimensional IT definition and uses a structural model to test the assumptions about the relationships between variables. Managers must understand that IT may influence competitive performance without having a direct impact; it can enhance QM practices. IT-related skills and QM practices prevalent in the significant QM projects are described in depth in this research.\n\n\nEthical approval\n\nThe author obtained ethical approval (IRB07-12052022-42) from the Institution Research Board, Almaarefa University.\n\n\nConsent\n\nPrior to the survey, the author explained the objective of the study to the participants and gained their informed written consent.\n\n\nAuthor profile\n\nDr Nasser Ali Aljarallah is working as an Assistant Professor at AlMajmaah University, Kingdom of Saudi Arabia. In addition, he leads various scientific committees and has received patents and awards. He completed his PhD in business administration and quality management at University of Hull, UK. He has published many research articles in the field of quality management and business administration.",
"appendix": "Data availability\n\nFigshare: Quality management in the healthcare centers. https://doi.org/10.6084/m9.figshare.21678977.v1. 53\n\nThis project contains the following underlying data:\n\n- Complete_dataset.xlsx (numerical data of the responses collected from the HCPs. Each column represents the items of the dependent and independent variables).\n\nFigshare: Quality management in the healthcare centers. https://doi.org/10.6084/m9.figshare.21678977.v1. 53\n\nThis project contains the following extended data:\n\n- Questionnaire.docx (original 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\nØygarden O, Olsen E, Mikkelsen A:Changing to improve? Organizational change and change-oriented leadership in hospitals. J. Health Organ. Manag. Sep. 2020; 34(6): 687–706. 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Manag. 2021; 14(4): 1422–1428. Publisher Full Text\n\nKumar P, Dwivedi YK, Anand A:Responsible Artificial Intelligence (AI) for Value Formation and Market Performance in Healthcare: the Mediating Role of Patient’s Cognitive Engagement. Inf. Syst. Front. 2021; 1–24. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAgarwal R, Gao GG, DesRoches C, et al.:The digital transformation of healthcare: Current status and the road ahead. Inf. Syst. Res. 2010; 21(4): 796–809. Publisher Full Text\n\nPérez-Aróstegui MN, Bustinza-Sánchez F, Barrales-Molina V:Exploring the Relationship between Information Technology Competence and Quality Management.Mar. 2020; 18(1): 4–17. Publisher Full Text\n\nRahman M, Ming TH, Baigh TA, et al.:Adoption of artificial intelligence in banking services: an empirical analysis. Int. J. Emerg. Mark. Dec. 2021; ahead-of-print. Publisher Full Text\n\nALOmari MO, Jenkins J:Exploring the Attitudes of Patients towards using the Seha Application (Telehealth) in Saudi Arabia during the Coronavirus Epidemic. ABC J. Adv. Res. Apr. 2021; 10(1): 9–22. Publisher Full Text\n\nAl-Samarraie H, Ghazal S, Alzahrani AI, et al.:Telemedicine in Middle Eastern countries: Progress, barriers, and policy recommendations. Int. J. Med. Inform. Sep. 2020; 141: 104232. PubMed Abstract | Publisher Full Text\n\nMukherjee S:How IT allows E-Participation in Policy-Making Process. arXiv:1903.00831. Mar. 2019. Publisher Full Text\n\nAmann J, Blasimme A, Vayena E, et al.:Explainability for artificial intelligence in healthcare: a multidisciplinary perspective. BMC Med. Inform. Decis. Mak. Dec. 2020; 20(1): 1–9. Publisher Full Text\n\nPallathadka H, Mustafa M, Sanchez DT, et al.:Impact of machine learning on management, healthcare and agriculture. Mater. Today Proc. Jul. 2021. Publisher Full Text\n\nMarrella A:Automated planning for business process management. J. Data Semant. Jun. 2019; 8(2): 79–98. Publisher Full Text\n\nPalanica A, Flaschner P, Thommandram A, et al.:Physicians’ perceptions of chatbots in health care: cross-sectional web-based survey. J. Med. Internet Res. Apr. 2019; 21(4): e12887. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKisekka V, Giboney JS:The effectiveness of health care information technologies: evaluation of trust, security beliefs, and privacy as determinants of health care outcomes. J. Med. Internet Res. Apr. 2018; 20(4): e107. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOwusu Kwateng K, Appiah C, Atiemo KAO:Adoption of health information systems: Health professionals perspective.2019; 14(2): 517–533. Publisher Full Text\n\nHeyer A, Granberg RE, Rising KL, et al.:Medical Oncology Professionals’ Perceptions of Telehealth Video Visits. JAMA Netw. Open. Jan. 2021; 4(1): e2033967–e2033967. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMahajan S, Lu Y, Spatz ES, et al.:Trends and Predictors of Use of Digital Health Technology in the United States. Am. J. Med. Jan. 2021; 134(1): 129–134. PubMed Abstract | Publisher Full Text\n\nAlrahbi D, Khan M, Hussain M:Exploring the motivators of technology adoption in healthcare. Int. J. Healthc. Manag. 2019; 14(1): 50–63. Accessed: Jun. 12, 2022. Publisher Full Text\n\nAhmed S, Manaf NHA, Islam R:Assessing top management commitment, workforce management, and quality performance of Malaysian hospitals. Int. J. Healthc. Manag. 2021; 14(1): 236–244. Publisher Full Text\n\nJiang F, Liu Y, Hu J, et al.:Understanding Health Empowerment From the Perspective of Information Processing: Questionnaire Study. J. Med. Internet Res. Jan. 2022; 24(1): e27178. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBadawy M, El-Aziz AAA, Idress AM, et al.:A survey on exploring key performance indicators. Futur. Comput. Informatics J. Dec. 2016; 1(1–2): 47–52. Publisher Full Text\n\nWang T, Wang Y, McLeod A:Do health information technology investments impact hospital financial performance and productivity? Int. J. Account. Inf. Syst. Mar. 2018; 28: 1–13. Publisher Full Text\n\nAlrubaiee L, Alkaa’ida F:The Mediating Effect of Patient Satisfaction in the Patients’ Perceptions of Healthcare Quality – Patient Trust Relationship. Int. J. Mark. Stud. Jan. 2011; 3(1): 103. Publisher Full Text\n\nBabu F, Thomas S:The relationship between total quality management practices and organisational image in the hospital industry: An empirical examination. Int. J. Product. Qual. Manag. 2020; 29(1): 1–23. Publisher Full Text\n\nBishop DA:Key Performance Indicators: Ideation to Creation. IEEE Eng. Manag. Rev. Mar. 2018; 46(1): 13–15. Publisher Full Text\n\nAgostino D, Arnaboldi M:Rational and ritualistic use of key performance indicators in hybrid organizations. Public Money Manag. Sep. 2017; 37(6): 409–416. Publisher Full Text\n\nFigshare: Quality management in the healthcare centers. DOI: 10.6084/m9.figshare.21678977.v1"
}
|
[
{
"id": "178595",
"date": "03 Jul 2023",
"name": "Karin Ahlin",
"expertise": [
"Reviewer Expertise e-health",
"welfare technology",
"health data"
],
"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 title reveals that artificial intelligence (AI) should be the article's focus. As such, I expect a distinct focus on AI throughout the article. The author must include AI in the keywords, contributions, and literature review. There is a general presentation on IT, ML, EMR, HIoT, and other IT-related concepts, confusing the reader about the focus. Even more confusing is that the first contribution is said to be a theoretical framework for investigating the relationship between IT and QM dimensions. The same goes for QM. The author needs to include several interesting sources regarding QM and a definition of what is viewed as QM.\nIt is hard to understand how the framework is designed and what the design is based on. It is just presented.\nThe presented method is a mixed method, using a survey with ended questions and interviews with open-ended questions. Despite this, no research question is related to the study, and I would like to know how the interview questions are related to the hypothesis.\nQualitative data must be governed by a research question to fulfil a goal. There is a need to present the interview guide and the survey to understand the study fully.\nAre there more findings in the qualitative data than just two themes?\nThe discussion is more of a presentation of quantitative data than qualitative and quantitative data. I expect more of a discussion since qualitative data is included.\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? 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? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "178603",
"date": "03 Aug 2023",
"name": "Anthony Bokolo",
"expertise": [
"Reviewer Expertise Telemedicine",
"Telehealth",
"Digital 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\nInvestigating the influence of artificial intelligence on quality management in healthcare centers\nBelow are notes to improve the manuscript\nThe abstract is not well written. The key findings and conclusion can be improved. Also, which tool was used to analyze the collected data in the mixed-method approach.\nThe introduction section needs to be improved to include the main research problems and research aim.\nNo research questions were examined. Do provide research questions in the introduction section.\nA section on related works needs to be well written. Include prior studies on artificial intelligence on quality management in healthcare.\nHow does your work differ from these studies already published related to prior studies related to artificial intelligence on quality management in healthcare (provide justification)\nThe methodology looks well written. But provide justification for methodology employed.\nThe results are not well presented. How was reliability and validity measured in the study to ensure that the findings are validated. This should be well discussed based on existing scales or benchmark from the literature.\nWhat sampling was employed in the study.\nImprove the results section and related back to the literature. What are the main discoveries from the study.\nThe discussion section needs to map back to the literature. This is not well presented. Possibly you can improve this section. Include implication for theory and implication for practice related to artificial intelligence on quality management in healthcare. The conclusion should include the significance of the study.\nAlso, the limitations and future works needs to be described in detail\nGood 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": []
}
] | 1
|
https://f1000research.com/articles/12-110
|
https://f1000research.com/articles/11-350/v1
|
23 Mar 22
|
{
"type": "Review",
"title": "Cefotaxime: A reappraisal for use in lower respiratory tract infections",
"authors": [
"Nikhilesh Jain"
],
"abstract": "Lower respiratory tract infections (LRTIs) are documented to cause significant morbidity and mortality in patients worldwide. During the ongoing pandemic, LRTIs like pneumonia are posing a major health concern for patients and the healthcare system. In COVID-19-related pneumonia bacterial co-infection is not uncommon and remains a leading cause of mortality in affected cases. Cefotaxime, a third-generation parenteral cephalosporin, has a broader spectrum of antimicrobial activity with a high-level of stability against β-lactamases. Despite many years of clinical usage for cefotaxime in LRTIs, resistance to this drug does not seem to be a major concern, and it is still one of the cornerstones in the choice effective antimicrobial therapy. This paper attempts to delineate available evidence for cefotaxime usage in various clinical situations like community acquired pneumonia (CAP), nosocomial pneumonia, acute exacerbations of chronic bronchitis (AECB) and acute bronchitis. This may be of help for a clinician to develop a thorough viewpoint on the rational use of this time-tested antimicrobial agent and to take an apt clinical decision towards the optimum patient care.",
"keywords": [
"Cefotaxime",
"LRTI",
"Community acquired pneumonia"
],
"content": "Introduction\n\nIn late 2019, a pneumonia of unknown cause was diagnosed in a few patients in Wuhan, China and on 7 January 2020; the organism responsible for this pneumonia was identified as a new coronavirus which was named as the 2019 novel coronavirus (2019-nCoV).1 Subsequently, the coronavirus disease 2019 (COVID-19), and subsequent lower respiratory tract infection (LRTI) like pneumonia have remained troublesome buzzwords for all components of a healthcare system.\n\nLower respiratory tract infections (LRTIs) are considered to be comprised of acute bronchitis, bronchiolitis, influenza. They are a substantial cause of morbidity and death in patients globally.2 The Global Burden of Disease Study assessed evidence for the global, regional and national morbidity and mortality of LRTIs which revealed that, during 2016, LRTIs remained a significant contributor to infectious disease-related mortality and the fourth most common cause of death on the whole.3\n\nThe surge in infections acquired from the community and hospital caused by multidrug-resistant (MDR) bacterial pathogens is constraining choices for effective antibiotic therapy. To add to the worrying spread of antimicrobial resistance, newer antimicrobial agents are not being developed to balance it.4 Resistance to even novel antimicrobials has been documented.4 In the aforementioned scenario, judicious and rational use of conventional antimicrobial agents may serve as a possible option for the treatment of MDR bacterial pathogens. It can give therapeutic optimization choices to widen the spectrum of antibiotics, with the aim to preserve newer antimicrobial agents and counter drug resistance.4\n\nCefotaxime, one of the most clinically utilized cephalosporins, has been in clinical usage for a long time and is still deemed to be effective if used appropriately.\n\nFollowing on this background, the present narrative review aims to revisit the basic science behind cefotaxime and its clinical applicability in one of the most common bacterial infections, lower respiratory tract infection (LRTI). This reappraisal can be of use to clinicians for developing a scientific rationale and subsequent clinical decision for utilizing the right drug for the right patient.\n\n\nLRTI\n\nIn this world of competing health priorities, respiratory tract infections have always posed a huge burden in terms of morbidity and mortality. Based on the site of infection, they are broadly classified into upper and lower respiratory infections.5 LRTI is an umbrella term including different diseases like acute bronchitis, pneumonia, acute exacerbation of chronic lung diseases such as chronic obstructive pulmonary disease (COPD) or bronchiectasis. The European Respiratory Society defines various terms related to LRTIs, as described in Table 1.6\n\n\nDisease burden in various age groups\n\nLRTI has been reported to be the fourth most common cause of death across the globe. According to the Global Burden of Disease study, in 2016, LRTIs led to 23,77,697 deaths worldwide. Among them, 6,52,572 deaths were documented in children less than five years of age. The study also reported 10,80,958 deaths in adults older than 70 years.3 LRTIs are one of the leading cause of mortality in children under five years of age and account for approximately four million deaths per year.7 These account for 13.1% of all deaths in the under-five age group. However, these infections are not limited to childhood and predispose the individual to chronic respiratory diseases later in life.7\n\nAs per the GBD-2016 study, the maximum number of LRTI episodes among children younger than five years across the globe were reported in south Asia (18.76 million).3\n\nPneumonia has been reported to be the single largest cause of mortality among children worldwide.8 Pneumonia is reported to have an incidence of 24.8 per 10,000 adults in a year. Extremes of age (less than five years and elderly population more than 65 years) are predominant contributors to the quantum of pneumonia cases overall.9\n\n\nMicrobial spectrum\n\nPneumococcal pneumonia remains a leading cause of LRTI incidence and mortality in both children and adults. The infection episodes caused by Streptococcus pneumoniae outnumber the cumulative number of infections caused by all other pathogens. The incidence of LRTI attributable to S. pneumoniae across all ages was 26.7 per 1,000 people between 1995 and 2016.3 This incidence is disproportionately higher in children <5 years (70.7/1000 people) and elderly people >70 years of age (72.8/1000 people).3 There is suggestive evidence that S. pneumoniae may occur as a coinfection with viral infections or may follow a viral infection.10\n\nApart from S. pneumoniae, other Gram-positive bacteria responsible for LRTI include Staphylococcus aureus, as well as Gram-negative organisms such as Pseudomonas aeruginosa, Haemophilus influenzae, Klebsiella pneumoniae, and Escherichia coli.11\n\nCommon viral pathogens implicated in LRTI include human rhinovirus, influenza viruses and human coronavirus, human parainfluenza viruses, human respiratory syncytial virus and human metapneumovirus (Table 2).12\n\n\nRisk factors for LRTI\n\nApart from age extremes, other risk factors which predispose to LRTIs include poor sanitization owing to crowded living conditions, severe malnutrition, lack of breast feeding for infants, HIV infection, lack of immunization, chronic illness, family history of LRTIs and exposure to tobacco smoke and air pollutants.15,16\n\nLRTIs are a major issue in critically ill patients, being associated with prolonged hospitalization, higher costs, and possibly, an increase in mortality.17\n\n\nCefotaxime: molecular profile\n\nCephalosporins have a broad spectrum of antimicrobial activity, good clinical efficacy, favorable pharmacokinetics and tolerability profile in clinical use, making them frequently utilized antimicrobial agents.18 Like penicillin, they belong to the β-lactam class of drugs.19\n\nOn the basis of chronological order of drug discovery and antimicrobial properties, these antibiotic agents have been grouped into various generations, from first to fifth,20 as shown in Table 3.\n\nThird-generation cephalosporins are usually efficacious against Gram-negative as well as Gram-positive organisms.20 Normally, as we move from first to third, the microbicidal activity of cephalosporins decreases against Gram-positive organisms but increases against Gram-negative bacilli.18 Furthermore, the resistance against β -lactamases increases from first to fifth generations.18\n\nCefotaxime is a β-lactam antibiotic, first produced in 1976, belonging to third-generation cephalosporins and is therapeutically approved for the treatment of various Gram-positive, Gram-negative, and anaerobic bacteria.22 It has been widely available for decades and still holds a vital place in the management of various serious infections.23\n\n\nMolecular structure\n\nCefotaxime sodium is the generally available formulation of cefotaxime which is semisynthetic in nature.24 It comprises an acetyl side chain of an aminothiazoyl ring, along with an a-syn-methoxyimino group.\n\n\nIntrinsic activity and spectrum of action\n\nCefotaxime is active in vitro against a broad range of Gram-positive, Gram-negative and anaerobic organisms (Table 4). It retains a high level of stability in the presence of both the β-lactamases including penicillinases and cephalosporinases produced by Gram-negative as well as Gram-positive bacteria.24\n\n\n\n✓ Enterococcus spp.\n\n✓ Staphylococcus aureus\n\n✓ Staphylococcus epidermidis\n\n✓ Streptococcus pneumoniae\n\n✓ Streptococcus pyogenes\n\n✓ Streptococcus viridans spp.\n\n\n\n✓ Acinetobacter spp.\n\n✓ Citrobacter spp.\n\n✓ Enterobacter spp.\n\n✓ Escherichia coli\n\n✓ Haemophilus influenzae\n\n✓ Haemophilus parainfluenzae\n\n✓ Klebsiella spp.\n\n✓ Morganella morganii\n\n✓ Neisseria gonorrhoeae\n\n✓ Neisseria meningitidis\n\n✓ Proteus mirabilis\n\n✓ Proteus vulgaris\n\n✓ Providencia rettgeri\n\n✓ Providencia stuartii\n\n✓ Serratia marcescens\n\n\n\n✓ Bacteroides spp.\n\n✓ Clostridium spp.\n\n✓ Fusobacterium spp.\n\n✓ Peptococcus spp.\n\n✓ Peptostreptococcus spp.\n\n\nClinical pharmacology\n\nLike other cephalosporins, cefotaxime inhibits bacterial cell wall synthesis in a way equivalent to penicillin. Its β-lactam rings bind to penicillin-binding proteins (PBPs) and inhibits transpeptidation in peptidoglycan cell wall synthesis of susceptible bacteria. This leads to autolysis of the bacteria.25 Inhibition experiments have demonstrated high affinity of cefotaxime for PBPs Ib and III, which results in a high bactericidal activity.\n\nThe resistance developed by various bacteria against β-lactam antibiotics is mainly due to their β-lactamase-producing capability. Similar to other β-lactam group of antibiotics, β-lactamases can cause hydrolysis of cefotaxime, which reduces its bactericidal efficacy despite the molecule being stable against the activity of most β-lactamases.25\n\nOnce administered, it is metabolized in the liver26 where cefotaxime converts its primary metabolite, desacetyl cefotaxime (des-CTX), followed by desacetyl cefotaxime lactone and subsequently to M metabolites.26 Most of the cefotaxime (>80%) and its metabolites are excreted through the renal route. The antimicrobial activity of des-CTX has been reported to be eight-fold lower than cefotaxime.27 Usually, cefotaxime and des-CTX act synergistically with antagonism documented in strains of Morganella and Proteus vulgaris, and presence of des-CTX has been shown to enhance the efficacy of cefotaxime.28\n\n\nAdministration and dose\n\nCefotaxime formulations are available as powder (500 mg, 1 g, 2 g, and 10 g vials) or premixed solutions (1gm and 2gm) to be administered through intramuscular and intravenous routes. The powder form is available in 500 mg, 1 g, 2 g, and 10 g vials while the premixed solution is available as 1gm and 2gm for injection.25 Cefotaxime is used as as therapeutic agent of lower respiratory infections, meningitis, urinary tract infections, pelvic inflammatory disease, skin and skin structure infections, and gonorrhea (Table 5).29\n\n\nKey advantages\n\nCefotaxime has a broader spectrum of activity against Gram-positive, Gram-negative aerobic and anaerobic bacteria, and has a better efficacy against Gram-negative bacteria compared to previous generations of cephalosporins.30\n\nIt is generally well-tolerated and hypersensitivity reactions such as rash, fever, and pruritus are relatively infrequent. Cefotaxime has not been reported to cause hypoprothrombinemia or disulfiram-like reactions, as has been noted with other cephalosporins. One more favorable characteristic of cefotaxime is that its usage is not found to be associated with significant occurrence of coagulopathies and pseudocholelithiasis.25\n\nCefotaxime therapy is simple, generally economical and has a relatively broad spectrum of activity compared to many other antimicrobial agents used for postoperative nosocomial pneumonia.31\n\n\nCefotaxime: clinical evidence in LRTI\n\nQuite a good amount of published evidence prevails when the use of cefotaxime in CAP is considered. Cefotaxime in combination with Gentamycin has been recommended as one of the first line agent in management of severely ill hospitalized patients with community acquired pneumonia by Norwegian guidelines.32 In a retrospective observational study conducted by the University Hospital of North Norway, Cefotaxime was one of the most commonly prescribed antibiotics, in combination with other antimicrobials, among hospitalized CAP patients.33\n\nAnother study documents the successful use of cefotaxime among pediatric patients with necrotizing pneumonia (NN). NN is a complication of pneumonia with very limited data in pediatric patients. Retrospective-prospective data of 51 NN patients admitted to pediatric intensive care units between 2010 and 2018 were reported. Out of 34 patients with a definite etiologic diagnosis, 29 patients were infected with pneumococci. Other microbes involved were Streptococcus pyogenes, Streptococcus anginosus and Haemophilus influenza. Cefotaxime was used in 49 patients (in combination with clindamycin in 44 patients). Antibiotics with pleural effusion was sufficient in 48 patients. Only three patients required a surgical intervention. All patients recovered and were discharged successfully.34\n\nA study conducted by the Infectious Disease Surveillance of Pediatrics (ISPED) collaboration group in China found that H. Influenzae, which is one of the common pathogens behind CAP in children, has developed phenomenal resistance against antibiotics.35 More than two thirds of H. influenzae strains have been reported to be ampicillin-resistant and almost one third of strains were resistant to common antibiotics like azithromycin and cefuroxime. Cefotaxime retained activity against 94% of strains.35 Based on above, Cefotaxime was proposed as a first-choice therapy for treating ampicillin-resistant H. influenzae strains.35 Similar results were documented by another study from China in which 90% H. influenzae samples from children suffering with CAP were Cefotaxime-sensitive.36 The same samples reported 100% resistance to ampicillin and more than 60% resistance to trimethoprim, cefaclor and cefuroxime.36 Another study conducted in rural Vietnam, which studied the antimicrobial susceptibility of S. pneumoniae in children under five years reported high resistance to oral antibiotics like co-trimoxazole (78%), tetracycline (75%), phenoxymethylpenicillin (75%), erythromycin (70%) and ciprofloxacin (28%) along with minimal resistance to cefotaxime (2%), benzylpenicillin (4%) and amoxycillin (4%).37\n\nA meta-analysis was conducted in Africa to evaluate the susceptibility of CAP-causing S. pneumoniae, among patients having invasive pneumonia from 1978 to 2011.38 Results revealed that S. pneumoniae isolated from the nasopharynx/oropharynx were often resistant to ampicillin (26.4%), penicillin (25.4%), sulfamethoxazole (47.5%) and tetracycline (33.9%). On the contrary, 98.3% samples were sensitive to ceftriaxone/cefotaxime.38\n\nAnother paper evaluated the resistance pattern of S. pneumoniae strains among organ transplant patients. Susceptibility to azithromycin, erythromycin, clarithromycin, levofloxacin and a trimethoprim-sulfamethoxazole combination was seen in 53%, 67%, 71%, 75% and 53% strains respectively, with no resistance detected against cefotaxime, vancomycin and intravenous penicillin in the above cohorts.39\n\nOne study conducted in Yuying Children’s Hospital, Wenzhou, China specifically looked at antimicrobial resistance patterns in children under 12 years suffering from invasive pneumococcal disease. Penicillin-intermediate S. pneumoniae (PISP) and penicillin-resistant S. pneumoniae (PRSP) incidences were noted to be 30% and 41%, respectively. Reported resistance against erythromycin (94%) and lincomycin (88%) was high and the lowest resistance rate was seen for cefotaxime (22%).40 A similar study conducted in Spain reported less resistance against cefotaxime as compared to other antibiotics viz. penicillin, erythromycin and tetracycline, in S. pneumoniae strains responsible for causing CAP, meningitis in adults and acute otitis media in children.41\n\nA study conducted in the department of Microbiology, Vardhman Mahaveer Medical College, in Safdarjung Hospital, India, compared BacT/Alert 3D with conventional culture for diagnosing CAP. This study also reported antimicrobial susceptibility using the disk diffusion technique.42 The studied microbes included S. pneumoniae, S. aureus, K. pneumoniae, H. influenzae, Streptococcus Group A and G. Out of a total of 34 isolates of the above-mentioned microbes, all except two isolates of K. pneumoniae were sensitive to cefotaxime.42\n\nAs per the SENTRY study conducted in Latin America during 1997-2001 on pneumococcal isolates from mainly community-acquired respiratory tract infections, resistance rates were very low (0.4%) for cefotaxime vis-à-vis other antibiotics, including penicillin (11.9%), azithromycin (88.5%), clarithromycin (87.5%), tetracycline (79.5%) and trimethoprim + sulphamethoxazole (60.5%).43\n\nCurrently, viruses have become the predominant causative etiology for respiratory infections; owing to the availability of effective vaccination with pneumococcal conjugate vaccines, bacterial etiologies remain the leading cause of mortality among CAP patients.44 Among patients with COVID-19-related pneumonia, co-infection with bacteria is also a major concern. Common bacteria implicated in these infections include S. pneumoniae, H. influenzae, Chlamydia pneumoniae, and S aureus. Empirical treatment with antibacterial agents can be useful to reduce mortality in such cases.44 The latest CAP guidelines released by the American Thoracic Society and the Infectious Diseases Society of America recommend cefotaxime in combination with macrolides or doxycycline as one of the empiric antibiotics for management of such infections.45\n\nSeveral noncomparative and comparative studies have assessed the efficacy of cefotaxime as treatment for nosocomial or hospital-acquired pneumonia. Nosocomial pneumonia is associated with significant increase in duration of hospital stay, greater expenses as well as a higher incidence of morbidity and mortality.46\n\nIn an Indian study by M. Merchant et al., incidence of nosocomial infection was documented at 1.8% in patients of general wards, against 16.7% in ICU patients. It reported cefotaxime (34%) as a commonly utilized antibiotic, followed by amikacin and gentamicin.47\n\nA German study group by HP Bruch48 evaluated twice a day dosing of cefotaxime in patients with postoperative pneumonia. A total of 515 postoperative pneumonia patients were given 1 or 2 g cefotaxime twice a day. Patients without serious underlying diseases (n=88), receiving 1 g every 12 hours dosage regimen in this study, got clinically cured along with eradication of all pathogens.48 In the cohort with severe infection/severe underlying disease who were given 2 g every 12 hours cefotaxime, the overall clinical success rate (cumulated cured and improved) was 98.4%. The above-mentioned findings support the use of cefotaxime as a feasible option instead of empiric monotherapy to manage nosocomial pneumonia, in surgical-service patients on long-term artificial ventilation who do not have neutropenia.48 A similar study which evaluated a twice-a-day dosing of cefotaxime (2 g every 12 hours) in patients with severe nosocomial pneumonia documented this regimen of cefotaxime as adequate and appropriate. Authors of the above study also suggested a combination of cefotaxime with aminoglycosides to be reserved for cases with suspected multi-resistant Gram-negative bacterial infections.49\n\nAn open, controlled, randomized and multicentric study which evaluated the use of cefotaxime and ceftriaxone in adult patients with nosocomial pneumonia, showed 80% clinical and 93% bacteriologic success rate with cefotaxime, comparable to ceftriaxone.46 In terms of adverse events, a higher incidence of gall bladder sludge and diarrhea was reported for the ceftriaxone group.\n\nOne Canadian multicentric, open labeled, randomized trial compared the effects of cefotaxime and ceftriaxone in 57 patients with nosocomial LRTI. In this study, 28 out of 30 patients in the cefotaxime group showed cure/improvement after seven to 10 days of therapy, which was relatively similar to the ceftriaxone group (25 out of 27). G.E. Garber et al., the investigators of the aforementioned study, inferred that cefotaxime at 1 g intravenous (I.V.) every eight hours was non-inferior to ceftriaxone at 1 g I.V. every 12 hours, with a trend for less likely side effects, reinfections, and superinfections.50\n\nA multicentric study was conducted in 32 hospitals on 588 nosocomial pneumonia patients not on mechanical ventilation. The patients were randomized to receive either cefotaxime or routinely used antibiotic combination. The cure rate was significantly more in the cefotaxime arm (79%) compared to the comparator arm (71%). Moreover, the seriously adverse events were significantly more common in the comparator arm as compared to the cefotaxime arm.51 These results hint at superiority of cefotaxime as an empirical therapy for nosocomial pneumonia.51\n\nA study was conducted on 46 adults hospitalized with pneumococcal pneumonia in Spain. The common underlying diseases in these patients included heart disease, COPD/asthma and diabetes mellitus. When the resistance pattern to antibiotics of the pneumococci were studied, it was reported to be 15%, 11% and 6% with penicillin, erythromycin and cefotaxime respectively.52\n\nA double-blind prospective study from The Netherlands evaluated a total of 180 hospitalized patients with acute purulent exacerbations of chronic bronchitis. The patients received 1 g intramuscular injection of either cefodizime or cefotaxime two times a day for seven days. In this study, F. P. V. Maesen et al. found statistically non-significant difference between both study molecules in terms of overall efficacy and bacterial eradication. Authors pointed out an interesting fact in the discussion that in spite of wide and long-term usage of cefotaxime in this hospital set up, there was no fear of widespread increase in resistance.53\n\nThe same study group evaluated cefotaxime use in hospital in-patients with acute purulent exacerbations of chronic bronchitis. In this study, 30 patients were given 1 g cefotaxime intramuscularly two times a day for a longer duration (10 days).53 Additionally, 10 patients who received a higher dose of cefotaxime (2 g twice daily) were also included in this particular study. The clinical results were excellent in 21 patients out of 30 patients who received 1 g daily, and all patients given twice 2 g reported excellent cure rates.53\n\nAnother randomized, controlled, prospective nonblinded study was performed for 93 hospitalized patients requiring antibiotics for acute exacerbations of chronic obstructive pulmonary disease. This study compared continuous versus intermittent administration of cefotaxime, where forty-seven patients received 2 g of cefotaxime intravenously over 24 hours plus a loading dose of 1 g, and 46 patients were given the drug intermittently (1 g three times daily). The study concluded that continuous administration of cefotaxime at a lower dose was equally effective pharmacodynamically and microbiologically, maybe more cost-effective, and offered at least a similar clinical efficacy.54\n\nAcute bronchitis is characterized by extensive airway inflammation and presents with cough (productive/non-productive) in absence of any chronic lung illness. For the majority, the etiology includes viruses like influenza A and B, parainfluenza and respiratory syncytial virus.55 Bacterial infections may also cause bronchitis in people with underlying health issues/prior co-morbidities. Bacterial infections associated with bronchitis include Mycoplasma pneumoniae, H. influenzae, Moraxella catarrhalis and Bordetella pertussis.56 Though the role of antibiotics in management of acute bronchitis remains controversial,56 there is some evidence supporting use of cefotaxime to treat this disease.\n\nM Rylski et al. conducted a study on 100 patients with respiratory infections like bronchopneumonia, acute bronchitis and chronic bronchitis who underwent fiberoptic bronchoscopy. A total of 48% of these patients tested positive for bacterial flora (aerobic, anaerobic and mixed bacterial flora). Pneumococci and Bacteroides melaningogenicus were commonly isolated. From antibacterial susceptibility reports, cefotaxime was one of the antibiotics to which high sensitivity was reported.57\n\nIn another publication, K Konishi et al. reported 129 cases of respiratory tract and other infections which were treated with cefotaxime. Out of 129 cases, the majority presented pneumonia, 20 cases each of bronchopneumonia and acute bronchitis, 14 of chronic bronchitis and 17 AECB. These patients received 0.5 to 8 mg of cefotaxime daily through the intravenous route for two to 61 days. Cefotaxime was documented to be efficacious in 87.1% (108/124) cases. The study concluded that cefotaxime is quite effective against LRTIs.58\n\n\nConclusions\n\nLRTIs are responsible for substantial morbidity and mortality across the globe. LRTIs caused by various organisms can often be complicated by emerging antimicrobial resistance. Strategies to promote timely and appropriate use of effective antibiotics should be implemented to reduce symptom duration, complications and mortality associated with LRTIs. Cefotaxime, a third-generation injectable antibiotic, has demonstrated good efficacy and safety in the management of LRTIs including CAP, hospital-acquired/nosocomial-acquired pneumonia, acute exacerbation of pneumonia and acute bronchitis caused by both Gram-positive and Gram-negative bacteria. Despite the usage of cefotaxime against LRTIs for several decades, significant resistance has not been reported and the drug remains a reasonable option in managing these infections in present times.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "References\n\nWang M, Zhou Y, Zong Z, et al.: A precision medicine approach to managing 2019 novel coronavirus pneumonia. Precis. Clin. Med. 2020 Mar 25; 3(1): 14–21. PubMed Abstract | Publisher Full Text\n\nFeldman C, Richards G: Appropriate antibiotic management of bacterial lower respiratory tract infections. F1000Research. 2018 Jul 23; 7: 1121. PubMed Abstract | Publisher Full Text\n\nTroeger C, Blacker B, Khalil IA, et al.: Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect. Dis. 2018 Nov 1; 18(11): 1191–1210. PubMed Abstract | Publisher Full Text\n\nCassir N, Rolain J-M, Brouqui P: A new strategy to fight antimicrobial resistance: the revival of old antibiotics. Front. Microbiol. 2014 [cited 2021 Apr 5]; 5. PubMed Abstract | Publisher Full Text\n\nDasaraju PV, Liu C: Infections of the Respiratory System. Baron S, editor. Medical Microbiology. 4th ed.Galveston (TX): University of Texas Medical Branch at Galveston; 1996 [cited 2021 Apr 6]. Reference Source\n\nWoodhead M, Blasi F, Ewig S, et al.: Guidelines for the management of adult lower respiratory tract infections - Summary. Clin. Microbiol. Infect. 2011 Nov 1; 17: 1–24. PubMed Abstract | Publisher Full Text\n\nWHO|Pneumonia: the forgotten killer of children: WHO. World Health Organization. [cited 2021 Apr 6]. Reference Source\n\nPneumonia: [cited 2021 Apr 6]. Reference Source\n\nMahashur A: Management of lower respiratory tract infection in outpatient settings: Focus on clarithromycin. Lung India Off. Organ Indian Chest Soc. 2018 Apr; 35(2): 143–149. PubMed Abstract | Publisher Full Text\n\nMalosh RE, Martin ET, Ortiz JR, et al.: The risk of lower respiratory tract infection following influenza virus infection: A systematic and narrative review. Vaccine. 2018 Jan 2; 36(1): 141–147. PubMed Abstract | Publisher Full Text\n\nKhan S, Priti S, Ankit S: Bacteria Etiological Agents Causing Lower Respiratory Tract Infections and Their Resistance Patterns. Iran. Biomed. J. 2015 Oct; 19(4): 240–246. PubMed Abstract\n\nIeven M, Coenen S, Loens K, et al.: Aetiology of lower respiratory tract infection in adults in primary care: a prospective study in 11 European countries. Clin. Microbiol. Infect. 2018 Nov 1; 24(11): 1158–1163. PubMed Abstract | Publisher Full Text\n\nAbdullah FE, Ahuja KR, Kumar H: Prevalence and emerging resistance of Moraxella catarrhalis in lower respiratory tract infections in Karachi. JPMA J. Pak. Med. Assoc. 2013 Nov; 63(11): 1342–1344.\n\nThiem U, Heppner H-J, Pientka L: Elderly patients with community-acquired pneumonia: optimal treatment strategies. Drugs Aging. 2011 Jul 1; 28(7): 519–537. Publisher Full Text\n\nForum of International Respiratory Societies, European Respiratory Society: The global impact of respiratory disease.2017.\n\nIndian Pediatrics - Editorial: [cited 2021 Apr 6]. Reference Source\n\nZampieri FG, Póvoa P, Salluh JI, et al.: Lower Respiratory Tract Infection and Short-Term Outcome in Patients With Acute Respiratory Distress Syndrome. J. Intensive Care Med. 2018 Apr 26; 35(6): 588–594. Publisher Full Text\n\nKlein NC, Cunha BA: The selection and use of cephalosporins: a review. Adv. Ther. 1995 Apr; 12(2): 83–101.\n\nArumugham VB, Cascella M: Third Generation Cephalosporins. StatPearls. Treasure Island (FL): StatPearls Publishing; 2021 [cited 2021 Apr 1]. Reference Source\n\nEl-Shaboury SR, Saleh GA, Mohamed FA, et al.: Analysis of cephalosporin antibiotics. J. Pharm. Biomed. Anal. 2007 Sep 21; 45(1): 1–19. Publisher Full Text\n\nClassification of Cephalosporin Antibiotics. MediMoon. 2013 [cited 2021 Apr 5]. Reference Source\n\nDudley MN, Barriere SL: Cefotaxime: microbiology, pharmacology, and clinical use. Clin. Pharm. 1982 Apr; 1(2): 114–124. PubMed Abstract\n\nPlosker GL, Foster RH, Benfield P: Cefotaxime. A pharmacoeconomic review of its use in the treatment of infections. PharmacoEconomics. 1998 Jan; 13(1 Pt 1): 91–106. Publisher Full Text\n\nCefotaxime (Cefotaxime for Injection): Uses, Dosage, Side Effects, Interactions, Warning: RxList. [cited 2021 Apr 4]. Reference Source\n\nPadda IS, Nagalli S: Cefotaxime. StatPearls. Treasure Island (FL): StatPearls Publishing; 2021 [cited 2021 Apr 3]. Reference Source\n\nCoombes JD: Metabolism of cefotaxime in animals and humans. Rev. Infect. Dis. 1982 Oct; 4 Suppl: S325–S332. PubMed Abstract | Publisher Full Text\n\nChin NX, Neu HC: Cefotaxime and desacetylcefotaxime: an example of advantageous antimicrobial metabolism. Diagn. Microbiol. Infect. Dis. 1984 Jun; 2(3 Suppl): 21S–31S. PubMed Abstract\n\nAntibacterial Activity of Desacetylcefotaxime alone and in combination with Cefotaxime by Harold C. Neu Reviews of Infectious diseases. September-October 1982; 4(Supplement _2): S374–S378. Publisher Full Text\n\nCastle SS: Cefotaxime. Enna SJ, Bylund DB, editors. xPharm: The Comprehensive Pharmacology Reference. New York: Elsevier; 2007 [cited 2021 Apr 11]; p. 1–4. Reference Source\n\nCarmine AA, Brogden RN, Heel RC, et al.: Cefotaxime. A review of its antibacterial activity, pharmacological properties and therapeutic use. Drugs. 1983 Mar; 25(3): 223–289. PubMed Abstract | Publisher Full Text\n\nWittmann DH, Jones RN, Malledant J, et al.: Cefotaxime in the treatment of prophylaxis of surgical infections. J. Chemother. Florence Italy. 1997 May; 9 Suppl 2: 19–33.\n\nPneumoni, samfunnservervet: Helsedirektoratet.[cited 2021 Apr 8]. Reference Source\n\nHøgli JU, Garcia BH, Svendsen K, et al.: Empirical prescribing of penicillin G/V reduces risk of readmission of hospitalized patients with community-acquired pneumonia in Norway: a retrospective observational study. BMC Pulm. Med. 2020 Jun 15 [cited 2021 Apr 8]; 20: 169. PubMed Abstract | Publisher Full Text Reference Source\n\nBlanco-Iglesias E, Oñoro G, Almodovar-Martín JL, et al.: Retrospective Study in Children With Necrotizing Pneumonia: Nine Years of Intensive Care Experience. Pediatr. Infect. Dis. J. 2020 Jul; 39(7): 571–575. Publisher Full Text\n\nAntibiotic Resistance Profiles of Haemophilus influenzae Isolates from Children in 2016: A Multicenter Study in China - PubMed.[cited 2021 Apr 10]. Reference Source\n\nLu Y-Y, Luo R, Fu Z: Pathogen distribution and bacterial resistance in children with severe community-acquired pneumonia. Zhongguo Dang Dai Er Ke Za Zhi Chin J Contemp Pediatr. 2017 Sep; 19(9): 983–988.\n\nHoa NQ, Trung NV, Larsson M, et al.: Decreased Streptococcus pneumoniae susceptibility to oral antibiotics among children in rural Vietnam: a community study. BMC Infect. Dis. 2010 Mar 31; 10: 85. PubMed Abstract | Publisher Full Text\n\nGinsburg AS, Tinkham L, Riley K, et al.: Antibiotic non-susceptibility among Streptococcus pneumoniae and Haemophilus influenzae isolates identified in African cohorts: a meta-analysis of three decades of published studies. Int. J. Antimicrob. Agents. 2013 Dec; 42(6): 482–491. PubMed Abstract | Publisher Full Text\n\nRoca-Oporto C, Cebrero-Cangueiro T, Gil-Marqués ML, et al.: Prevalence and clinical impact of Streptococcus pneumoniae nasopharyngeal carriage in solid organ transplant recipients. BMC Infect. Dis. 2019 Aug 6 [cited 2021 Apr 10]; 19: 697. PubMed Abstract | Publisher Full Text Reference Source\n\nLiu S, Dong L, Yang J: Clinical characteristics and antimicrobial resistance of invasive pneumococcal disease in children. Zhonghua Er Ke Za Zhi Chin. J. Pediatr. 2010 Feb; 48(2): 95–99.\n\nFranco-Alvarez de Luna F, Causse del Río M, Ibarra González A, et al.: Streptococcus pneumoniae: antibiotic resistance and serotypes in a two-year period. Rev Espanola Quimioter Publicacion of Soc Espanola Quimioter. 2005 Sep; 18(3): 217–221.\n\nCapoor MR, Nair D, Aggarwal P, et al.: Rapid diagnosis of community-acquired pneumonia using the BacT/Alert 3D system. Braz. J. Infect. Dis. Off. Publ. Braz. Soc. Infect. Dis. 2006 Oct; 10(5): 352–356. Publisher Full Text\n\nCastanheira M, Gales AC, Mendes RE, et al.: Antimicrobial susceptibility of Streptococcus pneumoniae in Latin America: results from five years of the SENTRY Antimicrobial Surveillance Program. Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 2004 Jul; 10(7): 645–651. Publisher Full Text\n\nMetlay JP, Waterer GW: Treatment of Community-Acquired Pneumonia During the Coronavirus Disease 2019 (COVID-19) Pandemic. Ann. Intern. Med. 2020 Aug 18; 173(4): 304–305. PubMed Abstract | Publisher Full Text\n\nMetlay JP, Waterer GW, Long AC, et al.: Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am. J. Respir. Crit. Care Med. 2019 Oct 1; 200(7): e45–e67. PubMed Abstract | Publisher Full Text\n\nShah PM, Stille W: Cefotaxime versus ceftriaxone for the treatment of nosocomial pneumonia results of a multicenter study. Diagn. Microbiol. Infect. Dis. 1995 May; 22(1–2): 171–172. PubMed Abstract | Publisher Full Text\n\nMerchant M, Karnad DR, Kanbur AA: Incidence of nosocomial pneumonia in a medical intensive care unit and general medical ward patients in a public hospital in Bombay, India. J. Hosp. Infect. 1998 Jun; 39(2): 143–148. Publisher Full Text\n\nBruch H-P, Kujath P: Study of cefotaxime twice daily for the therapy of postoperative pneumonia. Diagn. Microbiol. Infect. Dis. 1995 May; 22(1–2): 203–207. Publisher Full Text\n\nKeller C: Prospective evaluation of twice-daily cefotaxime in the treatment of hospitalized patients with severe infections. Diagn. Microbiol. Infect. Dis. 1995 Jun; 22(1–2): 159–161. Publisher Full Text\n\nGarber GE, Auger P, Chan RMT, et al.: A multicenter, open comparative study of parenteral cefotaxime and ceftriaxone in the treatment of nosocomial lower respiratory tract infections. Diagn. Microbiol. Infect. Dis. 1992 Jan; 15(1): 85–88. PubMed Abstract | Publisher Full Text\n\nFernández-Guerrero M, Arnau C, Valdés L, et al.: Nosocomial pneumonia: Comparative multicentre trial between monotherapy with cefotaxime and treatment with antibiotic combinations. Infection. 1991 Jun; 19(S6): S320–S325. PubMed Abstract | Publisher Full Text\n\nDíaz A, Torres C, Flores LJ, et al.: Community acquired pneumococcal pneumonia in hospitalized adult patients. Rev. Med. Chil. 2003 May; 131(5): 505–514. PubMed Abstract\n\nMaesen FPV, Davies BI, Drenth BMH, et al.: Treatment of acute exacerbations of chronic bronchitis with cefotaxime: a controlled clinical trial. J. Antimicrob. Chemother. 1980 Jan 1; 6(suppl A): 187–192. PubMed Abstract | Publisher Full Text\n\nvan Zanten ARH , Oudijk M, Nohlmans-Paulssen MKE, et al.: Continuous vs. intermittent cefotaxime administration in patients with chronic obstructive pulmonary disease and respiratory tract infections: pharmacokinetics/pharmacodynamics, bacterial susceptibility and clinical efficacy. Br. J. Clin. Pharmacol. 2007 Jan; 63(1): 100–109. PubMed Abstract | Publisher Full Text\n\nTackett KL, Atkins A: Evidence-Based Acute Bronchitis Therapy. J. Pharm. Pract. 2012 Dec 1; 25(6): 586–590. Publisher Full Text\n\nWorrall G: Acute bronchitis. Can. Fam. Physician. 2008 Feb; 54(2): 238–239.\n\nRylski M, Stelmaska-Dworak E, Andrzejewski K: Aerobic and anaerobic bacterial flora as a cause of lower respiratory tract infection. Pneumonol. Alergol. Pol. 1993; 61(3–4): 144–147. PubMed Abstract\n\nKonishi K, Takishima T, Honda I, et al.: Clinical evaluation of cefotaxime in internal medicine. Jpn. J. Antibiot. 1983 Jul; 36(7): 1653–1675. PubMed Abstract"
}
|
[
{
"id": "138030",
"date": "13 Jun 2022",
"name": "Wojciech Feleszko",
"expertise": [
"Reviewer Expertise pediatric pulmonology",
"LTRI",
"immunology",
"respiratory viruses",
"bronchiolitis",
"pneumonia"
],
"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 started reading Nikhilesh Jain's article with great enthusiasm, which is an extensive discussion of the properties of cefotaxime. It is a complete discussion of this drug's pharmacological, antimicrobial, and clinical properties. The author has included several tables showing, for example, the spectrum of antibacterial activity of this antibiotic that we have known for years.\nIt is an antibiotic known as an effective weapon in lower respiratory tract infections, effective and readily used for years. It has a particularly high therapeutic potential in lower respiratory tract infections, as shown by the author of this paper. However, I cannot help feeling that I am reading a package insert or a chapter in a pharmacology textbook.\nWhy?\nFirst of all, the scientific article lacks a critical and balanced view of this drug, especially compared to its biggest competitor - ceftriaxone. Both drugs have an identical antimicrobial spectrum, similar indications, and clinical use. So why is one of them used more often? Why would cefotaxime be better? Such comparisons are sorely lacking in this article.\nSimilarly, I miss figures, for example, illustrating the mechanism of action or the diseases in which it is used. In particular, I also miss such a figure which would compare both drugs.\nThe article is a good compendium about one well-known drug, but I did not get the impression that there was anything particularly cutting-edge in the research on this drug in the last two to three years.\nPerhaps it is worth examining the databases for the last five years to see these new perspectives? Perhaps it is worth placing more emphasis on the position of this drug in the context of growing antibiotic resistance (e.g., 1,2, also on cefotaxime3, or show the geographical differences in the use of drugs of this group in different countries and continents 3.\nSuch an analysis would significantly improve the quality of this paper. However, I do not recommend it for indexing in its current form.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? No\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? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-350
|
https://f1000research.com/articles/11-1298/v1
|
14 Nov 22
|
{
"type": "Research Article",
"title": "The Frontline War: A Case-control study of risk factors for COVID-19 among health care workers",
"authors": [
"Cynthia Amrutha Sukumar",
"Nandakrishna Bolanthakodi",
"Aarthi Venkatramanan",
"Ravishankar Nagraj",
"Sudha Vidyasagar",
"Cynthia Amrutha Sukumar",
"Nandakrishna Bolanthakodi",
"Aarthi Venkatramanan",
"Ravishankar Nagraj"
],
"abstract": "Purpose: The global pandemic of COVID-19 has infected several people worldwide. World Health Organization(WHO) has reported that an alarming number of health care workers (HCWs) have been affected and have also succumbed to this disease. Though health infrastructure can be boosted in a short period, the number of HCWs cannot. Hence understanding the risk factors that the HCWs are exposed to and strategically protecting them is of paramount importance. Methods: A case-control retrospective study was carried out on 116 HCWs at a tertiary care hospital treating COVID-19 patients in South India. We attempted to investigate and stratify the specific risk factors for COVID-19 transmission among HCWs. Data was collected regarding their exposure to COVID-19 patients, infection control precautions used, possible breaches in the protocol, and details of Hydroxychloroquine (HCQ) prophylaxis. Results: The demographics were equally distributed among the cases and controls. Exposure to surgical procedures on suspected/positive COVID patients was also found to affect contracting the COVID-19 illness. HCWs who wore face shields instead of eye goggles along with the use of scrubs and hospital gowns were found to have a lesser incidence of COVID-19 illness. Conclusion: This study helped us understand the varied risk factors that health care workers are exposed to while treating COVID-19 patients. It helped us contextualize and strategize our infection control practices to prevent further morbidity and mortality due to COVID-19.",
"keywords": [
"COVID-19",
"SARS-CoV-2",
"Infection control",
"prevention",
"health care workers",
"coronavirus",
"risk factors"
],
"content": "Introduction\n\nFrom a cluster of patients with viral pneumonia at a wet market of Wuhan, China, emerged one of the biggest pandemics of our era, the coronavirus disease 2019 (COVID-19) virus. From its origin in December 2019, this virus has rapidly encircled the globe, infecting over 110 million people and claiming up to 2.5 million lives worldwide to date. The most affected countries include the USA, Brazil, and India. India accounts for 2.5 crore total cases and 2.7 lakh deaths due to COVID-19.1\n\nWHO reported that over 14% of the total COVID-19 cases account for HCWs and has reached even 35% in some countries.\n\nIn India, more than 15,000 HCWs have been affected and over 800 health care workers have succumbed to COVID-19 according to the Indian Medical Association (IMA) records.\n\nIndia’s health infrastructure has only 76 doctors for every 1 lakh population, which adds to the health care burden in the face of this pandemic.2\n\nWhile health care systems and equipment can be boosted in a pandemic, the same cannot be done for health care personnel, which makes them a precious resource. Thus, protecting the health care personnel becomes paramount. However, with the increasing patient burden, the second wave of cases, shortage of staff, limited isolation facilities, and personal protective equipment we found more and more HCWs being ensnared by this disease. This posed a difficult problem for the health care community and society as a whole. The only protection that the HCWs have is infection control measures to prevent them from contracting this virus. A rapid review also confirmed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), like other coronavirus infections, is a burden on the HCW, and the use of personal protective equipment (PPE) and infection control training is associated with decreased risk.3\n\nWe conducted a case-control retrospective study, to assess the risk factors that HCWs were exposed to in a tertiary care hospital treating COVID-19 patients. We attempted to assess why some HCWs contracted COVID-19 while others did not. We intended to investigate specific risk factors for COVID-19 transmission among HCWs in a tertiary care university hospital. We also decided to stratify risk factors among Heath care workers based on their exposure, precautions taken, breach in infection control precautions, and prophylaxis used.\n\nWe found that despite using the conventional infection control precautions as per the Ministry of Health and Family Welfare (MoHFW), there were some interesting findings in the study that helped us review and contextualize the infection control policies based on available resources. These factors could also aid in shielding the HCWs from the next wave of the pandemic by refining and strengthening the infection control policies in individual health care facilities.\n\n\nMethods\n\nFor this case-control study, a total of 116 HCWs working in Kasturba Hospital, Manipal (South India) were recruited from all clinical departments involved in the care of COVID-19 patients between July 2020 to September 2020 (3 months). Among these 50% were cases and 50% were controls in 1:1 ratio. Both cases and controls were between the age of 20 to 60 years.\n\nCases were defined as symptomatic HCWs working in our hospital who tested positive for COVID-19 by real time reverse transcription polymerase chain reaction (RT-PCR) using the TRU PCR kit by KILPEST’s [Blackbio]. Controls were defined as HCWs who did not develop symptoms and did not test positive for COVID-19.\n\nAll 116 patients (57 cases and 59 controls) filled up a detailed questionnaire (after consenting) regarding demographics, details of their work profile, exposure details, details of precautions used, breach of infection control precautions, and Hydroxychloroquine (HCQs) prophylaxis.5,6 Cases were asked for details of their COVID illness as well.\n\nThe details of work profile included the areas that the participants were exposed to in the hospital as frontline HCWs, the duration of exposure as number of days per week and number of hours per day and exposure to high-risk COVID areas such as the COVID intensive care units (ICU). The exposure details included details of COVID-19 exposure during collection of throat swab, intubation, handling and transport of respiratory secretions and exposure to high-risk activities such as surgical procedures on COVID-19 patients. Details of personal protective equipment used by HCWs such as face mask, gloves, face shield, hospital gown, scrubs, shoe covers and practise of hand hygiene were collected. Breach of these precautions in terms of omission of use or improper/intermittent use were also included. During data collection, the participants were asked to provide accurate information and assured of their anonymity. Hence potential bias such as improper reporting of breach in infection control precautions were also minimized.\n\nThe collected data was analysed using the SPSS for Windows version 22.0, RRID: SCR_002865 (SPSS, Inc., Chicago, IL). The variables were summarized using frequency and percentage. A Chi-square test was used to determine the association between the risk factors for COVID-19 transmission among healthcare workers (HCWs) and the dependant variable (case/control). The variables which were found to be significantly associated were subjected to multivariable logistic regression. Adjusted odds ratio with 95% confidence interval is reported. p-value <0.05 represents statistical significance.\n\n\nResults\n\nThe recruited HCWs (n = 116) were equally distributed into cases and controls in a 1:1 ratio. All the 116 participants who were approached for the study were found to be eligible and consented to participate in the study. All the participants completed the entire questionnaire required for the study. Table 1 shows the baseline characteristic of all the recruits.\n\n* COPD - chronic obstructive pulmonary disease.\n\n# ICU - intensive care unit.\n\nThe maximum representation was between the age of 20–30 years (74%) followed by recruits between 31–40 years (26%). There were 64 males and 52 females among the study population. The HCWsincluded in the study were medical interns (46%), post-graduates (22%), medical staff (21%), and nurses (11%) who were involved in treating patients with COVID-19. Only 10% of the recruits had associated co-morbidities.\n\nThe areas of work among both cases and controls were the emergency area (28%), COVID intensive care (51%), and COVID ward (21%). The duration of exposure was mostly more than 6 hours (66%) followed by 3-6 hours (39%). A majority of the recruits also reported working for 7 days of the week (49% cases and 59% controls) while 40% of all recruits clocked 3-6 days a week.\n\nExposure to patients in the COVID intensive care was equal (50%) among both cases and controls. Table 2 indicates the comparison between cases and controls based on their exposure to COVID-19 infection at work.\n\nInvolvement in taking a throat swab for the COVID test also was almost similar among the cases and the controls. Though they had a similar exposure of work in an intensive care setting, only around 10% of cases and controls were involved in intubating a COVID suspect or a COVID positive patient. None of the recruits were involved in endotracheal sample collection for a COVID suspect/COVID positive patient. Only 12% of cases and controls were involved in the collection/transportation of blood/urine for a COVID suspect or COVID positive patient.\n\nSurgical procedures including tracheostomy, emergency orthopedic and general surgery procedures, cesarean sections on a COVID suspect/positive patient saw a significant 28% cases in attendance compared to only 13% among controls (p=0.05). Table 3 compares the cases and controls based on the infection control precautions used. It was noted that an equal number of cases and controls wore a mask at all times during patient contact.\n\nHowever, only 15% of the cases and controls were non-compliant with the use of gloves during patient contact. In addition to masks and gloves, HCWswere provided with face shields during patient contact. However, only 56% of the cases wore the face shield compared to 71% among the controls (p=0.09). Also, hospital gowns were provided toHCWs. Interestingly, only 47% of cases used this provision compared to 71% of the control population (p=0.009). Similarly, only 49% of cases wore scrubs compared to 67% controls (p=0.04). The use of shoe covers was similar among cases and controls with only half of the recruits regularly making use of them. All recruits performed hand hygiene following doffing after patient contact. There was no significant difference in the breach of infection control precautions among cases and controls. Table 4 compares the breach in infection control precautions and prophylaxis used between cases and controls.\n\nA majority of the recruits did not report improper use of PPE or making mistakes while implementing infection control precautions. Though some of the recruits (38% cases and 34% controls) stayed in the same duty room with another HCW without masks, this data was similar among both cases and controls. Consumption of food within a meter of another health care worker also did not show a significant difference among cases (64%) and controls (50%). Half of the cases and controls reported failure to maintain safe social distance from another healthcare worker.\n\nHydroxychloroquine prophylaxis was taken by 17% cases and 25% controls. However, only 5 cases and 7 controls took the HCQ prophylaxis for the entire 8 weeks.\n\nAmong the cases, most of the recruits tested positive in July 2020 and had mild severity of COVID illness. Ten cases reported the spread of the COVID illness to their primary contacts.\n\n\nDiscussion\n\nThe COVID pandemic that broke out from the confines of China reached our district in South India by February 2020. However, the first HCW contracted COVID only in July 2020 with medical intern testing positive for COVID by RT-PCR. This five-month delay could be attributed to the stringent infection control precautions in place at our hospital. However, when the first case was detected among a HCW despite all the precautions, the initial question was whether it was a hospital-acquired or a community-acquired infection. Over the subsequent weeks, several other HCW contracted COVID thereby confirming the possibility of a hospital-acquired spread. This led us to revisit the infection control policies and re-evaluate the risk factors that the HCW are exposed to while treating COVID patients.\n\nThe volunteers in the study had a male: female ratio of 1.2:1 with 64 men and 52 women participants. This correlated with the findings in other Indian studies as well.4 The age distribution among the cases and controls showed a predominant population between the age of 20–30 years (74%) followed by 30–40 years (23%). The age distribution did not follow a Gaussian pattern. This could be due to the hospital policy to protect older individuals with co-morbidities from COVID exposure by not allowing them on the front line. The age distribution is reflected in the type of health care worker included in the study as well. A majority of the recruits were interns and post-graduates followed by staff doctors and nurses. As the study population leaned towards the younger age group, 90% of them did not have associated co-morbidities. Table 1 shows the demographic profile of the cases and controls in the study.\n\nIn a large Indian study done on 18,000 HCW, it was noted that the median age was in the range of 18–40 years.4 A case-control study done on HCW in North India, using a data portal to obtain exposure details among HCW fighting COVID-19, showed a mean age of 34 years with cases being slightly older than controls.5 This younger age group resonates with the similar finding in our study and the trend of the younger HCWs manning the front lines was likely a strategy to deter increased morbidity and mortality among HCWs.\n\nEvaluation of the details of their work profile showed a significant association between duration of exposure and contracting the COVID illness. The HCW who had >6 hours of work in the COVID area seemed more likely to contract the disease as shown among the 67% cases vs the 46% controls (p=0.02). However, the number of days at work did not seem to have a significant bearing on contracting the COVID disease.\n\nIn a study done in Turkey on over 50 HCWs involved in COVID care, it was found that the positivity rates among the HCWs who worked in frontline positions were higher (RR=2.449, CI=1.06, p=0.027) than those who were not in frontline positions.6 At this point, it is important to note that it is difficult to ascertain whether COVID infection in a HCW is hospital-acquired or community-acquired. However, owing to the cluster of cases following the index case among HCWs in our facility, the infection is more likely to be hospital-acquired rather than acquired from the community. A modeling study by Temime et al. found that R0 for Covid-19 (i.e. ability to transmit the infection to other people) was higher for HCWs compared to the general public as they have prolonged contact with infected individuals.7 This further corroborates the assumption that the COVID-19 illness in the HCWscould be hospital-acquired rather than community-acquired.\n\nThe study showed similar exposure of both cases and controls to the COVID intensive care facility. Though only a few of the cases and controls were involved in high-risk procedures like the collection of throat swabs or intubation of a COVID suspect/positive patient, it did not predispose them to develop the disease. This could be because all precautions are taken stringently for high-risk procedures such as these and the risk of breach of infection control precautions is low. Though there is conflicting literature regarding the risk of transmission during high-risk procedures like intubation, most of the evidence suggested no or low rates of transmission during these procedures. A study by Van Doremalen also implicated aerosols generated during high-risk procedures as an important factor in the mode of virus transmission among HCWs.8 An international registry study (INTUBATE COVID), included over 1700 clinicians who performed intubation on COVID patients, and only a mere 3% developed COVID.6 Another study from Wuhan, China on 420 HCWs who were involved in intubation reported no transmission at all.9\n\nIncidentally, exposure in the operating room to a COVID suspect/positive patient during surgical procedures indicated a significant risk for cases (28%) compared to controls (13%). SARS-CoV-2 shows high infectivity in the hospital setting as it has been isolated from sputum, nasopharynx, oropharynx, stool, blood, & conjunctiva.10–12 This could be attributed to prolonged duration of exposure in closed spaces of an operation theatre, aerosol generation during intubation/airway suctioning during the administration of anesthesia, or even surgical smoke produced during laparoscopy.13\n\nUsage of face shields was found to offer significant protection against COVID to HCWs. It was noted that only 56% of cases used face shields compared to 71% controls (p=0.09). WHO has included face shields as a part of standard PPE for COVID, to protect against aerosol generation.14 However, some HCWs prefer using eye goggles over face shields. This has shown an increased risk of COVID transmission in our study. It is possible that using a face shield decreases accidental touching of the face compared to eye goggles.\n\nOur study also noted a significant association between the use of gowns and protection against COVID. Gowns or coveralls are provided as a part of the standard PPE in keeping with the WHO guidelines.14 However, our study noted less transmission risk among HCWs who used gowns compared to coveralls. Almost 71% of controls used gowns compared to 47% of cases who used coveralls instead. No study has compared the effectiveness of gowns and coveralls in reducing the transmission of the virus to HCWs. The only difference between the gown and the coverall is their design. Coveralls are designed to cover the entire body including the back and the legs. They also allow ease of movement. However, the zipper of the coverall may pose a risk if it is not covered by a flap as it can compromise barrier protection. They also generate more heat stress compared to gowns making it uncomfortable for HCWs to spend long hours in the PPE (especially during hot and humid months in South India). Also, coveralls are harder to don/doff and most HCWs are not familiar with its usage as gowns were more commonly used during the pre-COVID times. Gowns, on the other hand, offer complete protection to the front of the body which is more exposed to infection during patient care. Though it allows limited movement, it is comfortable during long duty hours and is also easy to doff carefully.15\n\nIt was also noted that the use of scrubs decreased the risk of transmission of COVID. Scrubs were used in only 49% of cases compared to 67% of the controls (p=0.04). Scrubs are beneficial compared to regular clothes as they allow for adequate microbial decontamination. Domestic laundering of regular clothes worn to the hospital is of concern due to lack of control and monitoring of decontamination thereby providing a route for pathogens to enter the clinical environment. This minor but significant association is of importance during this pandemic to prevent transmission via clothes as fomites.16\n\nThe Turkish study on HCWs reported an increased risk of transmission due to a breach of infection control precautions such as staying in a duty room without a mask with another HCW or eating meals together.6 However, our study did not show an increased risk of transmission due to these breaches in protocol. It should be noted that our study did not evaluate other possible avenues of infection among HCWs like commuting in a vehicle together or social interaction, etc.\n\nThe use of HCQs as prophylaxis was also evaluated in our study but it did not show any significant difference in the outcome. This could be because most of the recruits who took the HCQ prophylaxis were not compliant with it and less than 10% completed the entire course for 8 weeks. This is in conjunction with the results of a Cochrane database review17 done on randomized control trials which showed no efficacy of HCQ in the prevention of COVID-19 infection. In another Indian study, it was noted that HCQ prophylaxis played no role in the prevention of COVID-19.4 Multiple systematic reviews also concluded that there is no pertinent data to support the use of HCQ outside that of research.18,19 Also, there is lack of clinical data to support its efficacy and adverse effects like prolongation of QTc. Further, the use of HCQ seems to be counter-productive as it tends to instil a false sense of protection.\n\n\nStudy limitations\n\nA major limitation in our study was that it was a voluntary questionnaire-based study. Though the study was performed on health workers who included doctors, interns, nurses, and residents, there was a poor representation among the nurses as reflected in the limited number of nurses who participated in the study. This resulted in a skewed representation of theHCWs. Also, details of vaccination could not be collected from all the participants as many of them regarded sharing this detail as an invasion of their privacy. This detail could have helped us better understand the interplay between the risk factors that HCWsare exposed to and the benefit offered by vaccination.\n\n\nConclusion\n\nWe found that, in the face of this unprecedented pandemic, prevention is the goal to avert a health care crisis. In this regard, the frontline workers must be protected and equipped in every way to fight the battle ahead. With the recent increase in COVID cases, it becomes important to consolidate our resources and refine our infection control policies to shield us from the impending wave of pandemics. Small steps like shorter shifts and rotating HCWsthrough various areas of exposure with lesser risk may reduce the risk of contracting the infection. The provision of scrubs, which undergo industrial cleaning should be advocated for all HCWs. Use of gowns and face shields over the coveralls and eye goggles as a part of the PPE may also contribute to the mitigation of COVID-19 infection amongHCWs. Such changes as these will go a long way in strengthening our defenses at the frontline.\n\n\nConsent\n\nAn informed written consent was obtained from all participants.\n\n\nAuthor contributions\n\nCAS and SV conceptualized the study. NB was involved in drafting the protocol and ethical clearance. AV and RN were involved with the initial planning data collection and data analysis. NB also contributed to the data processing and analysis. CAS, SV and NB were involved in preparing the draft and editing the final manuscript.",
"appendix": "Data availability\n\nFigshare: The Frontline War: A Case-control study of risk factors for COVID-19 among health care workers\n\n1. This project contains the Baseline characteristics of the participants including their demographics, co-morbidities, COVID exposure and duration of work. (raw)\n\nhttps://figshare.com/s/df9fc1ad42c71d0498cc\n\nhttps://doi.org/10.6084/m9.figshare.19249670\n\n2. This project contains the comparison between details of exposure among cases and controls in the study (raw)\n\nhttps://figshare.com/s/4043be187ba173e733dd\n\nhttps://doi.org/10.6084/m9.figshare.19249694\n\n3. This project contains the comparison between details of precautions taken among cases and controls (raw)\n\nhttps://figshare.com/s/6722f26025cd0acbc5f5\n\nhttps://doi.org/10.6084/m9.figshare.19249697\n\n4. This project contains the comparison between breach in infection control precautions and prophylaxis among cases and controls\n\nhttps://figshare.com/s/95e4d1cd29aa8c6f0ebd\n\nhttps://doi.org/10.6084/m9.figshare.19249721\n\n\nReferences\n\nDong E, Du H, Gardner L: An interactive web-based dashboard to track COVID-19 in real-time. Lancet Infect. Dis. 2020; 20: 533–534. PubMed Abstract | Publisher Full Text\n\nDeo MG: Doctor population ratio for India-The reality. Indian J. Med. Res. 2013; 137: 632–635. PubMed Abstract\n\nChou R, Dana T, Buckley DI, et al.: Epidemiology of and Risk Factors for Coronavirus Infection in Health Care Workers. Ann. Intern. Med. 2020; 173: 120–136. PubMed Abstract | Publisher Full Text\n\nJha S, Soni A, Siddiqui S, et al.: Prevalence of flu-like symptoms and COVID-19 in healthcare workers from India. J. Assoc. Physicians India. 2020 Jul 1; 68(7): 27–29. PubMed Abstract\n\nChatterjee P, Anand T, Singh KJ, et al.: Healthcare workers & SARS-CoV-2 infection in India: A case-control investigation in the time of COVID-19. Indian J. Med. Res. 2020; 151: 459. Publisher Full Text\n\nÇelebi G, Pişkin N, Bekleviç AÇ, et al.: Specific risk factors for SARS-CoV-2 transmission among health care workers in a university hospital. Am. J. Infect. Control. 2020; 48: 1225–1230. PubMed Abstract | Publisher Full Text\n\nTemime L, Gustin MP, Duval A, et al.: Estimating R0 of SARS-COV-2 in Health care settings. medRxiv. 2020. Publisher Full Text\n\nVan Doremalen N, Bushmaker T, Morris DH, et al.: Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N. Engl. J. Med. 2020; 382: 1564–1567. PubMed Abstract | Publisher Full Text\n\nEl-Boghdadly K, Wong DJ, Owen R, et al.: Risks to healthcare workers following tracheal intubation of patients with COVID-19: a prospective international multicentre cohort study. Anaesthesia. 2020; 75: 1437–1447. PubMed Abstract | Publisher Full Text\n\nLiu M, Cheng SZ, Xu KW, et al.: Use of personal protective equipment against coronavirus disease 2019 by healthcare professionals in Wuhan, China: a cross-sectional study. Brit. Med. J. 2020; 10: 369. Publisher Full Text\n\nZou L, Ruan F, Huang M, et al.: SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N. Engl. J. Med. 2020; 382: 1177–1179. PubMed Abstract | Publisher Full Text\n\nWang W, Xu Y, Gao R, et al.: Detection of SARS-CoV-2 in different types of clinical specimens. J. Am. Med. Assoc. 2020; 323: 1843–1844. PubMed Abstract | Publisher Full Text\n\nBlouhos K, Boulas KA, Paraskeva A, et al.: Understanding surgical risk during COVID-19 pandemic: the rationale behind the decisions. Front. Surg. 2020; 7: 33. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization (WHO): Infection prevention and control during health care when novel coronavirus (nCoV) infection is suspected: interim guidance.2020. Accessed 10 May 2021.Reference Source\n\nPark SH: Personal protective equipment for healthcare workers during the COVID-19 pandemic. J. Infect. Chemother. 2020; 52: 165–182. PubMed Abstract | Publisher Full Text\n\nOwen L, Laird K: The role of textiles as fomites in the healthcare environment: a review of the infection control risk. Peer J. 2020; 8: e9790. PubMed Abstract | Publisher Full Text\n\nSingh B, Ryan H, Kredo T, et al.: Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19. Cochrane Database Syst. Rev. 2021. Publisher Full Text\n\nKucharski AJ, Russell TW, Diamond C, et al.: Early dynamics of transmission and control of COVID-19: a mathematical modelling study. Lancet Infect. Dis. 2020; 20: 553–558. PubMed Abstract | Publisher Full Text\n\nGbinigie K, Frie K: Should chloroquine and hydroxychloroquine be used to treat COVID-19? A rapid review. Br. J. Gen. Pract. open. 2020; 4: 20. Publisher Full Text"
}
|
[
{
"id": "155727",
"date": "24 Nov 2022",
"name": "Biji Thomas",
"expertise": [
"Reviewer Expertise I am a clinical practitioner and am not qualified to comment on statistical analysis."
],
"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 is an interesting study and the premise is good. However, there are some important flaws in the methodology and conclusions.\nHow did you reach the sample size for the case and controls? No mention of sample size calculation based on the confidence level, the power of the study etc.\n\nThere is no mention or raw data provided about the time between exposure and the development of symptoms or positive testing in the case group. Instead, there is a vague statement that 'most' of the recruits tested positive in July 2020.\n\nThis is important because you state that there was a \"cluster of cases following the index case among HCWs\" in your facility.\nThis indicates that the mode of transmission was not probably patient-HCW, rather it was from HCW-HCW. The only way to exclude this is by meticulous contact tracing from the index case and then onwards through the cluster as cases appear.\nWhether some of the cases are community acquired or hospital acquired, can only be determined by citing the time interval between the exposure and the onset of symptoms or testing positive.\n\nThe duration of exposure is also very limited (between 3-6 hours over a week). There is no breakup of the time of exposure and whether the exposure occurred at the beginning of the study for both case and control groups or, instead, the exposure occurred throughout the study period.\nIf it occurred throughout, the possibility that some of the control recruits may have developed symptoms or become positive after the study concluded cannot be excluded from the provided data.\n\n\"Surgical procedures including tracheostomy, emergency orthopedic and general surgery procedures, cesarean sections on a COVID suspect/positive patient saw a significant 28% cases in attendance compared to only 13% among controls\".\nIf the index patient of the cluster was working in the surgical setting, this would account for increased number of cases in this subgroup, irrespective of the other factors. Unless, this factor is ruled out with data, this conclusion is unsupported.\n\n\"The HCW who had >6 hours of work in the COVID area seemed more likely to contract the disease as shown among the 67% cases vs the 46% controls (p=0.02).\" How many of these recruits had contact with the positive cases among the recruits and for what duration?\n\"However, the number of days at work did not seem to have a significant bearing on contracting the COVID disease.\" How is this compatible with the above conclusion?\n\n\"However, our study noted less transmission risk among HCWs who used gowns compared to coveralls. Almost 71% of controls used gowns compared to 47% of cases who used coveralls instead.\" Could the reason be that HCWs who wore gowns were most likely to be in a surgical setting where the patient has already been tested negative for COVID in the pre-operative assessment period?\nMy recommendation is that the data be retaken from the individuals with the missing parameters stated above and the article rewritten to remove the flaws.\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?\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": [
{
"c_id": "9253",
"date": "25 Jan 2023",
"name": "Cynthia Sukumar",
"role": "Author Response",
"response": "1. Size for the case and controls? No mention of sample size calculation based on the confidence level, the power of the study etc. The sample size of 116 (57 cases and 59 controls) was calculated for a confidence interval of 95% and power of 90%. 2. There is no mention or raw data provided about the time between exposure and the development of symptoms or positive testing in the case group. Instead, there is a vague statement that 'most' of the recruits tested positive in July 2020. This is important because you state that there was a \"cluster of cases following the index case among HCWs\" in your facility. This indicates that the mode of transmission was not probably patient-HCW, rather it was from HCW-HCW. The only way to exclude this is by meticulous contact tracing from the index case and then onwards through the cluster as cases appear. Whether some of the cases are community acquired or hospital acquired, can only be determined by citing the time interval between the exposure and the onset of symptoms or testing positive. Time of exposure could not be ascertained as all the HCW were working in the COVID exposure area in the preceding weeks. We surmised that the mode of transmission was not HCW-HCW as most of the HCWs who contracted the infection soon after the index case were from different areas of the hospital and did not have any contact with the index case. The index case underwent extensive line tracing and only 2 patients contracted the infection from exposure to the index case. Both were the intern’s room-mates. 3. The duration of exposure is also very limited (between 3-6 hours over a week). There is no breakup of the time of exposure and whether the exposure occurred at the beginning of the study for both case and control groups or, instead, the exposure occurred throughout the study period. If it occurred throughout, the possibility that some of the control recruits may have developed symptoms or become positive after the study concluded cannot be excluded from the provided data. The duration of exposure has been considered as days per week and not hours per week. The exposure has occurred at the beginning of the study for both the cases and controls. 4. \"Surgical procedures including tracheostomy, emergency orthopedic and general surgery procedures, cesarean sections on a COVID suspect/positive patient saw a significant 28% cases in attendance compared to only 13% among controls\". If the index patient of the cluster was working in the surgical setting, this would account for increased number of cases in this subgroup, irrespective of the other factors. Unless, this factor is ruled out with data, this conclusion is unsupported. The index case was working in the medicine wards at the time of contracting the illness in July 2020. 5. \"The HCW who had >6 hours of work in the COVID area seemed more likely to contract the disease as shown among the 67% cases vs the 46% controls (p=0.02).\" How many of these recruits had contact with the positive cases among the recruits and for what duration? \"However, the number of days at work did not seem to have a significant bearing on contracting the COVID disease.\" How is this compatible with the above conclusion? The HCW who had >6 hours of work continuously in the COVID area seemed more likely to contract the disease as shown among the 67% cases vs the 46% controls (p=0.02), when compared to the HCWs who worked in the COVID areas for 3-6 or <3 hours. However, the number of days at work did not seem to have a significant bearing on contracting the COVID disease, as most of the HCWs were rotated through different areas of work through the week. 6. \"However, our study noted less transmission risk among HCWs who used gowns compared to coveralls. Almost 71% of controls used gowns compared to 47% of cases who used coveralls instead.\" Could the reason be that HCWs who wore gowns were most likely to be in a surgical setting where the patient has already been tested negative for COVID in the pre-operative assessment period? Both coveralls and gowns were used in surgical and non-surgical settings."
}
]
},
{
"id": "157177",
"date": "19 Dec 2022",
"name": "Smitha Bhat",
"expertise": [
"Reviewer Expertise Infectious diseases and diabetes"
],
"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\nReview of article on risk factors for COVID-19 among HCWs\nThe authors have written a well-researched article on a topic which may be relevant to future pandemics of air borne pathogens as well. Especially appreciable are certain valid points which may be used to inform policy - namely the fact that duration of exposure > 6 hours increases the risk of the disease, and that gowns (not coveralls) and face shields were protective.\nCertain points may be looked in to:\nWas the impact of asymptomatic episodes of COVID-19 and the immunity that they would confer considered – were COVID-19 antibodies measured to find out whether the control population did not have previous asymptomatic infection?\n\nDid the lack of data from older individuals and those with comorbidities influence the results?\n\nAuthors may consider explaining the greater risk associated with intubation in the operation theatre compared to the intensive care unit, when in fact both are closed, air-conditioned environments.\n\nIn the discussion , the point on vaccination may be omitted. COVID-19 vaccination in India started from January 2021, after the conclusion of the study period.\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": "9254",
"date": "25 Jan 2023",
"name": "Cynthia Sukumar",
"role": "Author Response",
"response": "1. Was the impact of asymptomatic episodes of COVID-19 and the immunity that they would confer considered – were COVID-19 antibodies measured to find out whether the control population did not have previous asymptomatic infection? The testing for COVID-19 antibodies was not done due to the cost constraint in this study. This has been included as a limitation of the study. 2. Did the lack of data from older individuals and those with comorbidities influence the results? Yes. The lack of data from older individuals could have possibly influenced the results. HCWs above the age of 50 years were discouraged from frontline work in our institution. 3. Authors may consider explaining the greater risk associated with intubation in the operation theatre compared to the intensive care unit, when in fact both are closed, air-conditioned environments. This could be attributed to the prolonged proximity to the intubated patients in the surgical setting compared to the intensive care units. 4. In the discussion, the point on vaccination may be omitted. COVID-19 vaccination in India started from January 2021, after the conclusion of the study period. Vaccination details omitted from the discussion as advised."
}
]
}
] | 1
|
https://f1000research.com/articles/11-1298
|
https://f1000research.com/articles/12-108/v1
|
30 Jan 23
|
{
"type": "Research Article",
"title": "Effect of arsenic exposure on MDA, SOD, H2O2 and TNF-α levels of uterus homogenate of female Sparague-Dawleys rats",
"authors": [
"Irnawati Irnawati",
"Rinaldi Idroes",
"Muslim Akmal",
"Eko Suhartono",
"Irma Seriana",
"Rinaldi Idroes",
"Muslim Akmal",
"Eko Suhartono",
"Irma Seriana"
],
"abstract": "Background and Aim: Arsenic exposure to the body through the oral, dermal, and inhalation routes have a detrimental impact on health, including women’s reproductive health. However, the effect of arsenic exposure through the vulva of women is unclear. The present study therefore examined the effects of long-term arsenic exposure of vulva on uterus inflammation mediated by oxidative stress and inflammatory mechanism. Materials and Methods: Female Rattus norvegicus L was used as the animal model and the arsenic were exposed through vulvar immersion. The arsenic solution was made into four concentrations while the duration of exposure was made in four-time combinations. Uterus inflammation was assessed through histopathological observation of uterus tissue through hematoxylin and eosin (H&E) staining. Oxidative stress was assessed using malondialdehyde (MDA), superoxide dismutase (SOD), and hydrogen peroxide (H2O2); while inflammatory profile was assessed by measuring using tumor necrosis factor α (TNFα). Results: Our data suggested that inflammation could occur at the permissible quality standard concentrations when arsenic was exposed for more than two weeks. At higher concentrations and a longer exposure time, arsenic exposure could lead to chronic inflammation. Arsenic exposure was able to increase the levels of MDA and H2O2 and reduced the SOD suggesting stress oxidative of the organ. Arsenic also could increase the level of TNFα at any concentration after 6 and 8 weeks of exposure suggesting the inflammation process in the uterus. Conclusion: Continuous exposure of vulva with arsenic could induce oxidative stress and chronic inflammation of the uterus. Further study to investigate this finding in human is critical as basic to propose health campaign program to the community in the high arsenic regions.",
"keywords": [
"Arsenic exposure",
"uterus inflammatory",
"vulva absorption",
"vulva exposure"
],
"content": "Introduction\n\nHeavy metal exposure is still often found in humans.1 Heavy metals in the environment come not from industrial pollution as well as nature itself.2 Hot springs,3,4 water blowouts,5 volcanic eruptions, and abrasion are examples of the natural activities that produce and supply the heavy metal into environment.6 This makes heavy metal exposure to the organisms difficult to avoid. Therefore, assessing potential pollution, heavy metal exposure mechanisms, and their health effects are important.7 The effects of heavy metal exposure on an organism are significant, since it could easily interact with many organs.8,9 Frequent exposure can also deposit the metal inside the body.10 Although the organism has its own outer protective barrier,11,12 it still has some open organs, which can be the heavy metals’ point of entry into the body.13\n\nThe female external genital organs are open14 and they could become the entrance for toxic agents into the body. The tissue structure of the vulva and vagina is more permeable than the skin because vulvar tissue has the ability to hydrate and reduce water barrier function.15 In addition, most of the vaginal wall is covered by blood and lymphatic vessels, and therefore chemical exposure might be directly absorbed into the circulatory system.16 It is also very easy for the vulva and vagina to absorb toxic chemicals, and absorbed chemicals can be easily and effectively distributed through the body.17\n\nThe entry of harmful chemicals into the body through the female reproductive organs can be caused by many activities. Most are linked to the use of feminine hygiene or feminine care products.18 These various products are used by attaching them to the vulva, smearing, douching, and evaporating into the vagina or through immersion. The basic ingredients of these products can contain dioxin, chlorine, pesticide residues, methyldibromo glutaronitrile, methylchloroisothiazolinone, methylisothiazolinone, parabens, quaternium-15, DMDM hydantoin, and other hazardous substances.17 Apart from these various products, other activities that allow the entry of harmful chemicals into the body through the genital organs can occur while bathing, wiping, swimming, and soaking.\n\nWomen in Aceh Province, Indonesia use river estuaries for their daily livelihoods. They collect various estuarine biota such as oysters and shellfish at the bottom of the estuary by sitting or squatting in the estuary. During work, estuary water containing hazardous substances wet the genital organs. A study found that the work is performed for 2–3 h/day without using personal protective equipment.13 The north zone of the geothermal area around Seulawah Agam volcano of Aceh Province has a hot spring feature.19,20 This hot water flows and joins the nearest river21 such as Ie Seu Um geothermal river that crosses a residential area in Mesjid Raya Sub-District, in the Aceh Besar District.22 This river contains various levels of arsenic: the highest level found in water sources was 5478 μg/L (5 mg/L); the arsenic level in local wells was 800 μg/L (0.6 mg/L), and those at river estuaries was 300 μg/L (0.3 mg/L).23 Meanwhile, the quality standard concentration for arsenic level in water set by the World Health Organization (WHO) and the Ministry of Health of the Republic of Indonesia is only 10 μg/L (0.01 mg/L).24,25\n\nThe effects of arsenic on the female reproductive system not only cause toxicity to the reproductive organs, decreases libido, and teratogenic disorders, but it could also affect the well-being of a fetus, for example through congenital malformation.26–28 Arsenic exposure to the body causes metabolic toxicity in cells as well as oxidative stress and as a result, causes lipid peroxidation, membrane damage, membrane peroxidation and destruction, which might lead to cell death.29 Many studies assessed the effects of arsenic exposure through oral, ingestion, inhalation, parenteral, and dermal on damages to the reproductive system. However, research assessing the effect of arsenic exposure through the vulva and vagina on uterus damages is limited.\n\nThe present study aimed to assess the effects and damages of arsenic exposure through the vulva on the uterus using animal model. The concentration was adjusted to the arsenic levels in the geothermal area of Ie Seu Um, Aceh Besar Regency (5, 0.8, 0.3, and 0.01 mg/L) and the exposure was applied for 2, 4, 6, and 8 weeks. The oxidative effect was examined through the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and hydrogen peroxide (H2O2) of the uterus tissue. Uterus inflammation was studied by measuring the level of tumor necrosis factor α (TNFα) and examining the histopathology of the uterine tissue.\n\n\nMethods\n\nFemale Sprague-Dawley rats (Rattus norvegicus L.) aged 6–24 months and weighing 200–300 g were used in this study. The model animals were purchased from the Abadi Jaya Farm in Yogyakarta, Indonesia. All animals were healthy confirmed with active movements, ate well, hair did not dull or fall out, with bright eyes, and were not blemished. All animals were reared in a controlled temperature environment (25°C±2°C) at a 12-hour dark/light cycle. All efforts were taken to minimize animal suffering during the study: the animal facility was cleaned and disinfected regularly, the animal facility was kept quiet with controlled environmental conditions, and the animals were supplied with c-05 pellets (Citra Ina Feedmill, Jakarta, Indonesia) and water from the national water utility company ad libitum. Before treatment, all rats were acclimatized for seven days.\n\nThe animals were divided into five groups, consisting of group K0 (control group), K1, K2, K3 and K4 with arsenic concentration of 5 mg/L, 0.8 mg/L, 0.3 mg/L and 0.01 mg/L, respectively. The control group did not receive any exposure but was placed in the same condition as the treatment groups. Each group (K0-K4) consisted of six rats; during the arsenic exposure process, the animals in each treatment group were placed in separate plastic tub covered with woven iron wire with the same room conditions. All treatment groups were exposed to arsenic over four durations: 2, 4, 6 and 8 weeks (i.e., 14, 28, 42 and 56 consecutive days, respectively).\n\nThe study was conducted from September to December 2020 in the Laboratory of Chemistry/Biochemistry, Faculty of Medicine, Universitas Lambung Mangkurat, Banjarmasin, Indonesia. The protocol of the study was reviewed and approved by the Ethics Committee of the Medical Research, Universitas Lambung Mangkurat (No. 259/KEPK-FK UNLAM/EC/VII/2020, dated 30 July 2020).\n\nArsenic trioxide with a purity of 99%, purchased from Loba Chemie Laboratory Reagents and Fine Chemicals (Loba Chemie Pvt Ltd, Maharashtra, India), was used to make the arsenic solution. The solution was made by dissolving 5 mg, 0.8 mg, 0.3 mg, and 0.01 mg of arsenic in 1 L of water to produce concentrations of 5 mg/L, 0.8 mg/L, 0.3 mg/L and 0.01 mg/L, respectively. These arsenic levels correspond to the arsenic levels in the geothermal river flow of Ie Seu Um, Aceh Besar District, Aceh Province, Indonesia.30\n\nThe arsenic exposure was carried out by immersing the vulva of animals. Soaking was done in a 39 × 42 × 15 cm plastic tub covered with woven iron wire. One soaking tub contained one rat; the immersion limit was as high as the tail until the entire vulva was submerged. The arsenic exposure was conducted over 2, 4, 6, and 8 weeks (i.e., each treatment group had four different exposure times). The exposure was conducted 2.5 h/day. This duration was based on the average length of time that female workers forage for oysters in the estuary of the Ie Seu Um geothermal river.13\n\nOne day after the end of exposure periods (2, 4, 6 or 8 weeks for K1, K2, K3 and K4, respectively) the animals were euthanized by injecting ketamine 150 mg/kg-xylazine 10 mg/kg intraperitoneally following the guideline of Animal Euthanasia Policy from the Institutional Animal Care and Use Committee.31 The uterus was removed during surgery, cut into small pieces and fixed using a phosphate buffer solution with a pH of 7. The small pieces of uterus were mashed to form 5 mL of liquid and centrifuged for 10 min at 3500 rpm.32 The supernatant fraction was collected and used directly to measure the levels of MDA, SOD, H2O2, and TNFα.\n\nA total of 100 μL of uterus homogenate was mixed with 550 μL of distilled water, 100 μL of 10% trichloroacetic acid (TCA), 250 μL of 1 N HCl, and 100 μL of 1% Na-Thio (EMD Millipore Corporation, Billerica, USA). The mixture was then homogenized and centrifuged for 10 min at 500 rpm. Then, the top layer was collected and heated in a water bath at 100°C for 30 min and then cooled at room temperature (25±2°C). The absorbance was measured with a UV–Vis spectrophotometer at a maximum wavelength of 532 nm.33\n\nA total of 100 μL uterus homogenate to be measured for SOD levels was incubated for 5 min using 3 mL of 0.05 M Na2CO3 and 3 mL of 0.1 M EDTA with a pH of 10.2 and added with 100 μL of adrenaline. The initial absorption was measured (A0) using a spectrophotometer (λ = 480 nm). The solution then incubated again at 30°C for 5 min before determining the final absorption (A1).34\n\nA total of 1 mL of uterus homogenate was added to 5 mL of phosphate buffer and slowly homogenized. Then 1 mL of the product of this reaction was taken and 2 mL of dichromate/glacial acetate was added. Heating was done if blue precipitates were formed by heating the tube in a water bath for 10 min until a green color from chromic acetate was formed. The tube was then cooled to room temperature (25 ± 2°C), and H2O was added to a volume of 3 mL. Next, the solution was placed in a cuvette, and its absorbance was measured by UV–Vis spectrophotometer (λ = 570 nm).35,36\n\nThe level of TNFα was measured using the enzyme-linked immunosorbent assay (ELISA) method. The Rat TNFα ELISA kit was used following the manufacture’ protocol (NB-E30635, Novatein Biosciences, Massachusetts, USA). The ELISA was conducted according to the manufacturer’s instructions and the absorbance was read at a wavelength of 450 nm within 30 min.\n\nThe uterus tissue was immersed in 10% formalin, cut to a size of 10–15 mm × 10–15 mm × 5 mm, and then proceeded with dehydration, clearing, impregnation, and embedding following standard protocol in Anatomy Pathology.34 Briefly, the tissues were sliced with a thickness of 3–5 μm using a microtome before hematoxylin-eosin (HE) staining. The slices were placed on a slide, immersed in xylol (2 min), absolute ethanol (1 min), and 95% ethanol (1 min) sequentially, then added with water for 10–15 min, and immersed four times in water. The slices were then soaked for 3 min with a hypo solution, rinsed with water for 10 min, then soaked for another 5 min in Mayer’s hematoxylin solution, and watered for approximately 20 min. The preparation was then covered with a coverslip and glued with adhesive.\n\nThe uterus histopathology assessment was performed by counting the average number of cells involved in inflammation (macrophages, neutrophils, and lymphocytes). Observations were made using a Meiji Techno microscope with a Sigma HDMI digital photo, 400× magnification. Observation of inflammatory cells was conducted using TopView software through 10 fields of view by paying attention to the histological zone structure of the three preparations found on the slide. The number of inflammatory cells was obtained from the average number of macrophages, neutrophils, and lymphocytes.37 To reduce bias in the study, two pathologists did the observation.\n\nData were presented as mean ± standard deviation (SD). To compare the levels MDA, SOD, H2O2, TNFα and inflammatory cell counts among groups, ANOVA test was used. Duncan’s multiple range tests were used to compare MDA, SOD, H2O2, TNFα and inflammatory cell counts between exposure times. All analyses were conducted using a Statistical Analysis System (SAS) version 9.4 (SAS Institute Inc., NC, USA).\n\n\nResults\n\nAmong treatment groups, the highest MDA level was found in the K1 group (5 mg/L) exposed for eight weeks (224.33 ± 1.75 μM) while the lowest concentration was seen for K4 group (0.01 mg/L) exposed for two weeks (174.33 ± 0.51 μM) (Table 1). In the control group, the average MDA levels for the four different exposure times was approximately the same (174 μM). Our data indicated that the higher the arsenic concentration and the longer the exposure time, the higher the uterus MDA levels.\n\nThe ANOVA test indicated a significant difference in MDA levels in all groups (p < 0.0001) (Table 1). Duncan’s multiple range tests were used to compare the MDA level between exposure times in each concentration group. The significant difference between exposure time is indicated by different superscript letters (Table 1). There were significant differences in MDA levels between exposure times in all arsenic concentration groups, except for the concentration of 0.01 mg/L exposed for 2 weeks, for whichthere was no difference between control and the 0.01 mg/L group.\n\nThe SOD levels in the uterus after exposure to arsenic at different concentrations and exposure times are presented in Table 2. The highest SOD level observed in K4 (0.01 mg/L) group exposed for two weeks while the lowest SOD level was in the K1 (5 mg/L) group exposed for eight weeks. The levels of SOD were significantly different between groups (treatment and control group) with p < 0.0001.\n\nOur data suggest that the longer the exposure time, the lower the levels of SOD. There was a decreasing trend with the length of exposure time. In the K1 group for example, exposure to arsenic at a concentration of 5 mg/L for two weeks produced a SOD of 1.47 ± 0.34 U/mL, and this decreased to 0.36 ± 0.08 U/mL after eight weeks. Duncan’s multiple range test in this group found that there were differences in SOD levels at two, four, six, and eight weeks; however, there was no difference between four and six weeks, nor between six and eight weeks (Table 2).\n\nA similar result was also found in concentrations of 0.8 (K2 group) and 0.3 mg/L (K3 group), for which there was a decrease in SOD levels as the duration of exposure increased (Table 2). The SOD levels were significantly higher for two weeks of exposure compared to the longer exposure time: after the second week, the SOD levels did not change significantly. At the lowest arsenic concentration in accordance with the permissible quality standard concentration (0.01 mg/L), SOD levels in the first two weeks were found at the highest level (2.50 ± 0.46 U/mL) then decreased afterward.\n\nH2O2 is one of the oxidative compounds observed in this study, and the levels of uterus H2O2 after exposure to arsenic at various concentrations and durations are presented in Table 3. Our data suggested an increase in H2O2 levels at each additional exposure time in every arsenic concentration group. The mean H2O2 level in the control group after eight weeks was 2.33 ± 0.07 μM. This figure was significantly different from the other treatment groups (p < 0.0001). The multivariate test also showed a significant difference in the mean H2O2 levels between each treatment group (Table 3).\n\nTable 4 presents the TNFα levels after exposure to arsenic in all treatment groups. Drastic spikes in all concentration groups were observed in the six- and eight-week exposure groups. These data suggest that the uterus inflammatory response to arsenic exposure through the vulva increased rapidly when arsenic exposure lasted more than 4 weeks. Overall, there were significant differences between the treatment and control groups (p < 0.0001). Post-hoc tests in all concentration groups also showed significant difference between the two- and four-week groups and the six- and eight-week groups (Table 4).\n\nThe uterus tissues from all animals were stained with HE and observed with 400×magnification. The total number of inflammatory cells in each group and statistical analysis test results are presented in Table 5. There was a significant difference of the number of inflammatory cells in arsenic exposure between length of exposures in all concentration groups (p < 0.0001). A further test using Duncan’s multiple range test found that there was no difference in inflammation at 5 mg/L arsenic exposure between two, four, and six weeks. The difference was only seen after eight weeks exposure. The arsenic concentration of 0.8 mg/L exposed through the vulva did not significantly differ between two, four, six, and eight weeks of treatment duration. At a concentration of 0.3 mg/L, there was a difference between two and four weeks of exposure and six and eight weeks of exposure. The 0.01 mg/L concentration group did not show any significant differences in any exposure time.\n\nH&E staining on the uterus tissue suggested that inflammation occurred in the lining of the endometrium, myometrium, and perimetrium (Figure 1). Inflammatory cells were also found in the uterus fatty tissue. The representation of the histopathology of inflammatory cells in the uterus lining from all groups are presented in Figure 1.\n\n(A) infiltration of inflammatory cells occurred in all treatment groups. Inflammatory cells were found in the endometrium, myometrium, and perimetrium and reached the fat tissue. (B) Infiltration of N, M, and L occurred in all treatment groups (2, 4, 6, and 8 weeks). The inflammatory cells reached the myometrium layer, perimetrium layer, and fat tissue. (C) Infiltration of inflammatory cells in the control group was dominated by N. In the treatment group, the inflammatory cell infiltration contained N and M and also L. Inflammatory cells occurred in the lining of the endometrium, myometrium, and perimetrium. (D) Infiltration of inflammatory cells was found in all treatment and control groups. Most M and L were found in the treatment at 4 and 8 weeks. The inflammatory cells also reached the perimetrial lining. N: neutrophils, M: macrophages, L: lymphocytes.\n\n\nDiscussion\n\nOnce absorbed by the vulva and vagina, arsenic seemed to increase its oxidative effect in the uterus. This is supported by increasing MDA and H2O2 levels and decreasing SOD levels in the uterus of experimental animals. Arsenic exposure rapidly stimulates the formation of intracellular reactive oxygen species (ROS). The ROS formed causes changes in how cells work. The contaminated cells might carry epigenetic modifications and changes in signaling pathways. ROS are even capable of causing direct oxidative damage to molecules. The induction of ROS production by arsenic in cells occurs via the mitochondrial electron transport chain and exerts a toxic effect on the mitochondria by inhibiting the activity of succinate dehydrogenase and releasing the oxidative phosphorylation pair through the production of superoxide anions to form other ROS.38,39 Another mechanism occurs through the deployment of nicotinamide adenine dinucleotide phosphate, which is oxidized (Nox). Nox is a membrane enzyme that produces ROS as a result of arsenic exposure. Nox accelerates the formation of superoxide anions. Another factor is that the metabolism of arsenic itself triggers the formation of ROS in cells, such as singlet oxygen, H2O2, superoxide anions, and SOD.38,39\n\nOur data also suggested that the arsenic exposure at all concentrations induced the uterus MDA levels from a two-week exposure except for the 0.01 mg/L concentration. At this standard concentration, when exposed for two weeks, it did not cause oxidative effects. However, when the exposure lasted more than two weeks, the oxidative effect could still be observed. Arsenic exposure caused oxidative stress to the uterus in experimental animals after two weeks, indicated by the oxidative biomarker of MDA. MDA is a marker of oxidative stress derived from the end product of lipid peroxidation produced by free radicals.40 Our data suggests that the longer the exposure time and the higher arsenic concentration, the higher the ROS levels.\n\nSlightly different from MDA, arsenic exposure induced H2O2 production even for the lowest concentration (0.01 mg/L). The permissible quality standard concentration of arsenic could increase the H2O2 level after two weeks exposure. The results also showed a decrease in SOD levels. SOD is an antioxidant defense enzyme, being the first line of defense against the occurrence of OS. SOD also acts as an enzyme detoxifying ROS and eliminating free radicals.41,42 Our data suggested arsenic exposure increased ROS and decrease the level of SOD. This condition could increase lipid peroxidation, endometrial cell growth and adhesion, and increase the formation of macrophages leading to an imbalance between antioxidants, especially SOD and ROS.43 This imbalance disrupts angiogenesis and blood supply, and causes persistent inflammation.43\n\nOur present study also found that arsenic at the quality standard limit, when exposed continuously for more than two weeks, could cause oxidative effects. This caused the emergence of more ROS in the uterus, leading to infiltration of more macrophages. The higher the arsenic level and the longer the exposure, the higher the number of macrophages in the uterus tissues. Macrophages are part of the innate immune system, coordinate the process of the adaptive immune responses, restoring tissue homeostasis, inflammatory processes, and repair activities, and are also considered to be pro-inflammatory immune cells.44 The presence of macrophages could activate TNFα, a pro-inflammatory agent capable of regulating many aspects of macrophage function. TNFα can be released rapidly following toxicity, infection, or exposure to lipopolysaccharides and is considered to be a major regulator of pro-inflammatory cytokine production. Apart from pro-inflammatory cytokines, TNFα also enhances lipid signal transduction mediators such as prostaglandins and platelet-activating factors.45 Therefore, TNFα is considered to be the main cause of the activation and recruitment of inflammatory cells and plays an important role in chronic inflammation.45 Arsenic induces ROS production by changing antioxidant enzymes such as catalase and SOD to trigger the appearance of lymphocytes in inflamed tissues.46\n\nInflammation is a protective response that aims to protect tissues from becoming necrotic, eliminate the causes of infection, and stimulate tissue healing and repair processes. When inflammation occurs, neutrophils will appear as the body’s first defense cells against injury or infection. Macrophages will help the process of eliminating infection and damaged tissue through the process of phagocytosis. Lymphocytes play a role in chronic inflammation.47,48 Chronic inflammation occurred in the arsenic exposure groups with 0.5, 0.8, and 0.3 mg/L concentrations. This chronic inflammation was characterized by the appearance of abundant lymphocytes. The appearance of this accumulation of leukocytes is due to tissue injury resulting from a long-term inflammatory response.49 Although macrophages and lymphocytes were found in animal exposed to 0.01 mg/L arsenic, the number was significancy smaller. However, exposure for more than two weeks also could present inflammation responses. Our data also found that neutrophils were present in the uterus in all treatment groups. Inflammatory cells were also present in the control group in very small numbers and only neutrophils and macrophages were present. Neutrophils are the first cells present when there is tissue injury and infection and are associated with the body’s defense against infection and other inflammatory processes and it is also known as the first responder and constant defender.47\n\n\nConclusions\n\nOur data suggest that continuous and long-term immersion of animal vulva with water containing arsenic even at the permissible concentration (0.01 mg/L) could cause inflammation of the uterus tissues. Arsenic at 0.3, 0.8, and 5 mg/L could cause chronic inflammation of the uterus after a two-week exposure. Arsenic exposure was able to increase the uterus MDA levels even at 0.01 mg/L when exposed for more than two weeks. Arsenic increased the levels of H2O2 at all concentrations after a two-week exposure. In contrast, arsenic also induced the ROS by reducing the levels of SOD in uterus. Arsenic could increase the level of TNFα at any concentration after six and eight weeks of exposure.",
"appendix": "Data availability\n\nFigshare: ‘Damage to the uterus due to arsenic exposure to the vulva via oxidative stress (MDA, SOD and H2O2) and inflammatory (TNF-α) pathways of female Sprague-Dawley rats’. DOI: https://doi.org/10.6084/m9.figshare.21774989. 50\n\nThis project contains the following underlying data:\n\nMaster Table.xlsx [Table containing the raw data of the study].\n\nFigshare: ARRIVE checklist for ‘Damage to the uterus due to vulva exposure to arsenic via oxidative stress (MDA, SOD and H2O2) and inflammatory (TNF-α) pathways of female Sprague-Dawley rats’. https://doi.org/10.6084/m9.figshare.21774989. 50\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 would like to thank the Indonesian Ministry of Health for providing the fund for this study.\n\n\nReferences\n\nPark J-D: Heavy metal poisoning. Hanyang Med. Rev. 2010; 30(4): 319–325. 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}
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[
{
"id": "162541",
"date": "14 Feb 2023",
"name": "Izabela Michalak",
"expertise": [
"Reviewer Expertise Environment pollution",
"heavy metal ions",
"Biomonitoring",
"Multielemental analysis of biological samples"
],
"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 raises the important issue of women's exposure to arsenic. The results obtained in this publication may be helpful in raising public awareness of the dangers of staying in water contaminated with arsenic or other heavy metals. Generally this manuscript is well written. In my opinion, manuscript in the present form can be accepted after minor revision.\nSome specific comments on this paper: Abstract:\n\nMaterials and Methods: should be “Female rat Rattus norvegicus L.” Not arsenic was exposed “the arsenic were exposed through vulvar immersion” but for example “exposure to arsenic occurred by immersing the vulva in water solutions of this heavy metal” “…into four concentrations…” – I think it will be beneficial to add here in the bracket these concentrations “…made in four-time combinations” – I think it will be beneficial to add here in the bracket these exposure periods “…At higher concentrations and a longer exposure time…” – please indicate these results Change the order of Keywords and add “rat”: Rat, arsenic exposure, vulva exposure, vulva absorption, uterus inflammatory. Keywords should be arranged in a logical manner, in the order in which the research is conducted\nIntroduction:\n“The basic ingredients of these products can contain dioxin…” – it looks like all hygiene products are very polluted/contaminated. I would advise caution. What's more, this data comes from a 2013 report published a decade ago. It's better to cite a current source\nMethods:\n“…made by dissolving 5 mg, 0.8 mg, 0.3 mg, and 0.01 mg of arsenic in 1 L” – it is not clear for me. Did you dissolve in water salt – arsenic trioxide? Was the concentration calculated to arsenic alone or to an arsenic salt? Then we have two different output concentrations “..measure the levels of MDA, SOD, H2O2, and TNFα” – should be: TNF-α – please standardize in the whole manuscript “..10% trichloroacetic acid” – please add the name of the Producer, city and country for all chemicals you used in this study how was the MDA, SOD, H2O2, TNF-α level calculated from absorbance? This should be added to the manuscript a model of UV–Vis spectrophotometer (Producer) should be added Data analysis: you present your data as a mean and standard deviation. Did you check normality of distribution of your results? Only for normal distribution we can apply mean\nResults:\nhere, before the section “MDA levels”, it is worth adding an introductory sentence unify the number of significant digits in all tables H2O2 levels and TNF-α level: lack of a more detailed interpretation of the results, such as for MDA and SOD level – please add In Table 2: SOD levels Figure 1 – the inscriptions in the picture are very hard to see, please increase the font size and its color\nDiscussion:\nShould be “…and decreased the level of SOD” “by changing antioxidant enzymes such as catalase and SOD to trigger…” – why the level of catalase was not studied in this study?\nConclusions:\nconclusions should be supported by research results in the future, it is worth examining the accumulation of arsenic in the examined tissues\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? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "183681",
"date": "25 Aug 2023",
"name": "Aqeel Ahmad",
"expertise": [
"Reviewer Expertise Life 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\nGeneral evaluation: The content of the manuscript is interesting and important for a wide range of readership in this research field. The article is well organized. The abstract of the paper is compressed, realistic, and understandable.\nThe manuscript contains original data. The innovation of the paper is strongly connected to the journal. The introduction and discussion sections look good, summarize the current state of the problem with the elaboration of the theme, and provide scientific key information about the work. The introduction should briefly show what is already known and then focus more on what is not known and why it is worth studying. The philosophy of this work is good, and applicable in the next research.\nPlease include the missing information (research gaps and the significance of your research). Why is it required to run such an investigation?\n\nTitle: It is realistic and attractive.\n\nAbstract: Abstract is integral and can serve as a stand-alone document that succinctly describes both procedures and conclusions.\n\nIntroduction: The literary structure of the Introduction section is good, with a simple but scientific objective, containing essential information about the work and critical information on the problem under study.\n\nThe presentation of the results in the form of graphs and tables is clear, and the results are well described. All results are comprehensive. However, the Discussion section could be improved to make the manuscript more attractive. I have made a suggestion about the Discussion section. But overall, the discussion is sufficient.\n\nThe conclusions are well formulated and justified. The research meets all applicable standards for research integrity. The presentation of the results and figures facilitated the understanding of the experimental results. A deeper mechanistic understanding of the measured parameters is missing.\n\nReferences - include more recent references throughout the manuscript, specifically in the discussion, to increase the value of the paper. I don’t put much stress at this point, but in my suggestion, some new references can be added to show the complexity of the topic.\n\nFinal comments: The manuscript is interesting, associated with actual plant science trends. My opinion is in support of the manuscript to be indexed. I propose acceptance of this manuscript, with recommended minor revisions.\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/12-108
|
https://f1000research.com/articles/11-359/v1
|
28 Mar 22
|
{
"type": "Research Article",
"title": "Ensemble of multimodal deep learning autoencoder for infant cry and pain detection",
"authors": [
"Yosi Kristian",
"Natanael Simogiarto",
"Mahendra Tri Arif Sampurna",
"Elizeus Hanindito",
"Yosi Kristian",
"Natanael Simogiarto",
"Elizeus Hanindito"
],
"abstract": "Background: Babies cannot communicate their pain properly. Several pain scores are developed, but they are subjective and have high variability inter-observer agreement. The aim of this study was to construct models that use both facial expression and infant voice in classifying pain levels and cry detection.\n\nMethods: The study included a total of 23 infants below 12-months who were treated at Dr Soetomo General Hospital. The the Face Leg Activity Cry and Consolability (FLACC) pain scale and recordings of the baby's cries were taken in the video format. A machine-learning-based system was created to detect infant cries and pain levels. Spectrograms with the Short-Time Fourier Transform were used to convert the audio data into a time-frequency representation. Facial features combined with voice features extracted by using the Deep Learning Autoencoders was used for the classification of infant pain levels. Two types of autoencoders: Convolutional Autoencoder and Variational Autoencoder were used for both faces and voices.\n\nResult: The goal of the autoencoder was to produce a latent-vector with much smaller dimensions that was still able to recreate the data with minor losses. From the latent-vectors, a multimodal data representation for Convolutional Neural Network (CNN) was used for producing a relatively high F1 score, higher than single data modal such as the voice or facial expressions alone. Two major parts of the experiment were: 1. Building the three autoencoder models, which were autoencoder for the infant’s face, amplitude spectrogram, and dB-scaled spectrogram of infant’s voices. 2. Utilising the latent-vector result from the autoencoders to build the cry detection and pain classification models.\n\nConclusion: In this paper, four pain classifier models with a relatively good F1 score was developed. These models were combined by using ensemble methods to improve performance, which resulted in a better F1 score.",
"keywords": [
"Infant facial pain classification",
"infant cry detection",
"autoencoder",
"audio frequency features",
"deep learning."
],
"content": "List of abbreviations\n\nANN: Artificial Neural Networks\n\nASM: Active Shape Model\n\nBCE: binary cross-entropy\n\nCAE: convolutional autoencoder\n\nFACS: Facial Action Coding System\n\nFLACC: Face, Legs, Activity, Cry, Consolability\n\nIFPaLVD: Infant FLACC Pain Level Video Dataset\n\nLSTM: Long-Short Term Memory\n\nMFCCs: Mel-Frequency Cepstrum Coefficients\n\nMSE: Mean Squared Error\n\nNIPS: Neonatal Infant Pain Scale\n\nROI: region of interest\n\nSSIM: Structural Similarity\n\nSTFT: Short-Time Fourier Transform\n\nVAE: Variational Autoencoder\n\n\nBackground\n\nBabies cannot communicate their feelings properly, as such they cry to show hunger, discomfort (wet diaper and itchy skin), and pain. Methods such as Face, Legs, Activity, Cry, Consolability (FLACC),1 Neonatal Infant Pain Scale (NIPS),2 Wong-Baker FACES Rating Scale,3 and others,4 are used to detect pain experienced by a baby. Based on these methods, the main factors for detecting pain are the baby’s facial expression, sound of crying, and body movements. Most of the pain scores are subjective, and they have high variability inter-observer agreement. Therefore, there is a need for a pain measurement tool to objectively measure and classify the pain.\n\nHospitals mainly have more patients than medical staff, therefore, manually monitoring all their patients would be very time consuming and difficult. Normally, neonates are kept inside incubators, which can reduce the volume of their voice, resulting in difficulty for the medical staff to notice their discomfort. Therefore, an automation program with an artificial intelligence system that can identify the baby’s condition is needed. It can also be used to recognize and monitor the infant’s pain scale’s progress and increase or reduce pain medication. Automatization will allow a doctor to monitor infant conditions remotely with input from the nurses. This invention can significantly improve the health care services, especially in developing countries where doctors are not always on-site.\n\nM. Petroni et al.5 used Artificial Neural Networks (ANN) to classify infant voices to assess whether they’re in pain, fear, or anger. J. O. Garcia and C. A. R. Garcia6 also used infant voices to classify a normal or a pathological cry. This research used Mel-Frequency Cepstrum Coefficients (MFCCs)7 to encode speech signals before the signals were forwarded into the neural network. One study8 also used infant voices with MFCC representation to predict respiratory diseases such as wheeze, asthma, and crackles. Besides pain classification, MFCC has also been used to detect cries using audio features.9 This research divided an audio sequence into segments with 10 seconds duration. Instead of using infant voices, some studies also used facial expression features. K. Sikka et al.10 used facial expression feature to classify pain by using a Facial Action Coding System (FACS). Y. Kristian et al.11 tried hand-crafted extraction of facial expression features by using the Active Shape Model (ASM), based on the infant facial landmark detection and cry detection results from their previous research.12 These studies were further developed by using the deep learning autoencoder method to build a cry detection and pain classifier system.13 The deep learning extracts facial expression features automatically with the help of facial landmark detection as demonstrated by Kristian et al.11 J. Egede et al.13 utilized facial expression by trying to combine hand-crafted feature extraction and deep learning feature extraction. All these studies applied a facial expression as the only feature for classifying pain levels and crying detection. P. Werner et al.14 used a facial expression as a feature for one of their models. However, this research built other models by using the Biomedical Signals features while applying the Random Forest algorithm to combine these features.\n\nThe aim of this paper was to use both facial expression and infant voice as features for classifying pain levels and cry detection. As such deep learning autoencoders to automatically extract features for both facial and audio features were used. Additionally, the results for three features: only facial expression, only voice, and both facial expression and voice were compared in this study.\n\nThe key contributions of this paper are:\n\n1) Automated three frame selection from videos dataset. Since several frames consist of an infant’s face, it was not possible to use all the frames. However, automated frame selection can also be a step to building an automated system.\n\n2) Autoencoders were constructed to build a latent-vector with a smaller dimension than the original dimension but capable of representing the original data for both facial and audio data.\n\n3) Introduction of the classifier models using the Convolutional Neural Network (CNN) for the classification of pain level and cry detection.\n\n4) Combination of the best four pain classifier models that uses the ensemble methods to produce a higher F1 score.\n\n\nMethods\n\nIn this paper, the facial expression and infant’s voice to build a cry detection and pain classifier system was used. From the video frames, face detection and face landmarks were applied to gain the face region. From the audio frames, the wave signal was transformed into amplitude spectrograms and dB-scaled spectrograms by using the Short-Time Fourier Transform (STFT). To gain the features from the infant’s face and voices spectrograms, autoencoders were used for the production of the latent-vector. These latent-vectors were used for CNN classifiers to ultimately predict crying condition and pain level. Four pain classifier models were used to form an Ensemble model. An overview of the system is shown in Figure 1.\n\nThe face region will be extracted from the selected frames using face landmark. The amplitude and dB-scaled spectrograms are obtained from STFT process. These data are forwarded into autoencoders resulting five latent-vector which will be the input for the cry detection and pain classifier system.\n\nThis study was an observational study enrolled at Dr. Soetomo General Hospital (Surabaya City, East Java Province, Indonesia). The study included 23 infants below 12-months who were treated at Dr Soetomo General Hospital from November 2011 until December 2012. These infants were selected using a consecutive sampling. The FLACC pain scale and recordings of the baby's cries were taken in the video format and then analyzed using the software.\n\nThis study was approved by Clinical Research Unit at Dr. Soetomo General Hospital (248/Panke.KKE/III/2016). Due to the nature of the research, the visual data documenting facial expressions of observed infants will not be disclosed under the ethical considerations and regulations. Informed written consent was obtained from all patient’s parents, confirming that the results and any accompanying images including direct or indirect identifiers can be published.\n\nHanindito15 has taken 46 videos from 23 infants. Those videos were obtained before and after surgery (mostly hernia surgery) for each infant. The videos were labeled using FLACC measurement methods which took place in Dr Soetomo General Hospital. From this scoring method, all the data were concluded into three classification labels, which were no pain, moderate pain, and severe pain (See Underlying data).16 In 2017, Kristian et al.11 added ten more videos using the same FLACC ground truth labels and method.\n\nFor this research, these videos were divided into smaller segments with a 10 second duration to generate more data. At the same time, it provided the opportunity to avoid videos with high noise for both video frames and audio waves. Some videos could only be divided into one segment, while others into more than ten segments, depending on the number of frames that contain an extractable infant frontal face. After this process, 253 videos with an average of 10 second duration was obtained. Unfortunately, 64 videos were discarded as they did not contain any extractable frontal face frames. This dataset is called Infant FLACC Pain Level Video Dataset (IFPaLVD), which can be downloaded.17\n\nThe 189 videos were used to apply the data augmentation process to increase the number of data collection. The augmentation process included both image and audio augmentation. For image data, horizontal flip and image rotation was used. The angles used for image rotation were -10°, 10°, -20°, 20°, and 15°. The output example of this face augmentation can be seen in Figure 2.\n\nThere is the time-shifting process (0.25 seconds) during spectrogram conversion. Therefore, the duration of 9.75 seconds was used to obtain 10 seconds for audio data. Further audio augmentation process was tuning the volume 2×, 3×, and 4× higher or 2× and 3× lower. Therefore, each video was generated into 12 unique videos, resulting in the final data to consist of 2,668 videos. Visually, the augmentation result for the audio data did not look any different.\n\nEvery 10 second video had approximately 259 frames depending on the Frames Per Second (FPS) from each video. Therefore, in order to save resources, instead of using all the frames three selected frames were chosen. The first frame was at the time which the baby cried the loudest. This was made possible by selecting the highest value of audio frames along with mapping the index value from audio frames to match the video frames’ index value. Following this, two more frames were chosen from one second before and after the first selected frame. However, there was a possibility that the chosen frame might have not had an extractable frontal face. Therefore, with the selected frame as the starting point, each frame was evaluated until a frame with an extractable frontal face was reached.\n\nUpon selecting three desired frames, the remaining frames which included the non-face region was discarded. Since grayscale images were used in this process it was important to convert the image color. The region of interest (ROI), which is the face region was selected in the grayscale images. This process used the face detection model from a previous study.18 In this model, a rectangle area that consisted of the baby’s face was selected, and facial mapping (landmark) with the use of DLIB library was applied. This technique resulted in 64 points for the face landmarks. These points were used to draw a filled convex polygon and eliminate all the values outside the polygon. Finally, the frame was resized into the shape of 200×200 to uniform all the data dimensions.\n\nSounds are continuous analog signals, and their waveforms can take any value.19 Therefore, to digitalize and homogenize an audio signal, computers convert the value into specific sample rate. Similar to FPS for video, audio has a variety of sample rates. The sample rates needed to be uniform in the dataset. The sample rate used was 22,050 Hz, resulting in an array with the length of 21,500 for 9.75 seconds of audio, which represented the audio wave. However, it was not possible to extract any information from this audio wave. Therefore, the wave representation was changed into the time-frequency representation. The method to change the audio representation was by STFT18 (Equation 1). This equation contains two parameters, hop counter (h) and frequency index (f).\n\nIn the STFT process a 2,048 length “Hann” window with 512 hops was used. The total of 215000 samples, produced 420 hop iterations, with each iteration having a 2,048 window size (N). The result was a two-dimensional array with the shape of 1025×420. The two-dimensional array still had a complex number (i), therefore an absolute function to remove that complex number was done (Amplitude spectrogram). This amplitude spectrogram has many near-zero values as babies cry for a certain frequency range. Therefore, row 50 until 350 for this spectrogram was used and the rest was discarded, resulting in the final shape of 300 × 420. The amplitude spectrogram in its linear scale was transformed into its power log scale or dB scale20 (Equation 2), and the result was called dB-scaled spectrogram. The value of 1.0 was used for the power reference (P0), and A represented the amplitude spectrogram.\n\nIn 1986, D. E. Rumelhart et al.21 introduced a method called autoencoder. Autoencoder is a neural network consisting of two parts, encoder, and decoder. The encoder maps the input to the latent-vector with a smaller dimension, while the decoder maps the latent-vector back into the original input.21 An autoencoder for image representation with the use of deep networks was used by Vincent et al.22 for denoising images. That research inspired S. Gao et al.23 to use a deep autoencoder for extracting features from human faces, which showed promising results.\n\nVariational Autoencoder (VAE) is a new variation of an autoencoder that was proposed in 2013.24 The VAE can control the latent-vector distribution, due to its structure that contains two latent-vectors (Figure 3). As shown in previous research,24 VAE can generate new data from its latent-vector, and build a face generation model to create a completely new face image. As shown in Figure 3, the two latent-vectors are combined into a single latent-vector using a reparameterization trick (Equation 3). The combination of latent-vector is important as it enables the backpropagation process for VAE. In this equation, μ represents mean (first latent-vector), σ represents variance (second latent-vector), and ϵ represents random normal. Moreover, VAE also adds the reconstruction loss with its latent-loss, which is usually called KL Divergence Loss (Equation 4) with N representing the size of the latent-neuron.\n\nThese latent-vector were combined using reparameterization trick.\n\nApart from autoencoders for image data, a study in 201725 applied autoencoder for denoising a single-channel audio source. The autoencoder type used in this study was a convolutional autoencoder (CAE). They attempted to recreate the magnitude spectrograms. The spectrogram was a time-frequency representation of an audio signal. Figure 4 shows the example of dB-scaled spectrograms from this study data. This research indicates that using CAE from denoising audio produced promising results.\n\nAutoencoders are unsupervised learning neural network algorithm with a backpropagation process.26 This algorithm is unsupervised learning because it will try to produce an output that has a close similarity to the input, which can lead to both the output and the input to have similar shapes. Therefore, eliminating the use of data labels.\n\nAfter being forwarded into several hidden layers, autoencoders will reduce the data dimension. At a certain point, the layers will start to increase the data dimension. Finally, the last layer will have the same size as the input. The main idea of autoencoders is to reduce the original data dimension without losing important details so that it can be reconstructed back into the original data.27\n\nBased on this explanation, autoencoders consist of four main parts. The first part is the encoder, where the model will keep reducing the data dimension. The second part is called bottle-neck, or latent-vector. Latent-vector is the result of the encoder, which has the smallest size in the model. The third part is the decoder, which will try to recreate the original data from the latent-vector. The last part is the reconstruction loss, which is a function to measure the similarity between input and output.28 From all these parts, the encoder and latent-vector is needed. The purpose of the decoder and the reconstruction are to make sure there is an excellent encoder and latent-vector. Finally, only the encoder is used to get the latent-vector, and this latent-vector will be forwarded into the classifier.\n\nIn this paper, the autoencoders were used as the feature learning process. As mentioned, this paper has used autoencoders for both face and audio data. Both CAE and VAE were used, and the results were compared. Additionally, the results were analyzed with and without using a dense latent-vector. Mostly, the autoencoders consist of three kinds of layers, which were convolutional, max pooling, and upsampling layer. For the models that used a dense latent-vector, a fully connected layer was added. Rectified Linear Unit (ReLU) was used29 (Equation 5) as the activation function of the convolutional layers and the sigmoid function30 (Equation 6) for the fully connected layers. Other activation functions did not increase the performances.\n\nBoth amplitude and dB-scaled spectrograms used the same structure, but they were trained separately. Although layers with variant parameters were used, all convolutional layers only used one stride and the same padding so that the convolutional layers don’t reduce the dimension. The max-pooling layer for the dimensionality reduction task used 2×2 kernels to minimize the detail loss. The structure for the best model for CAE without dense latent-vector can be seen in Table 1 for face autoencoder, and Table 2 for spectrogram autoencoder. For the models that used dense latent-vector, a similar architecture was used with a different bottle-neck part (yellow color). The bottle-neck part was changed into a fully connected layer with 1,250 neurons, and the next layer with 8,250 neurons for the face autoencoder. For the spectrogram autoencoder layers were not changed, however, a convolutional layer with ten filters and a 3×3 kernel before the bottle-neck, and a fully connected layer with 7,875 neurons after the bottle-neck part was added. For the VAE models, the same architecture for both with and without dense latent-vector was used with the difference that the bottle-neck parts were duplicated, and an extra layer was added to implement the combination of the two latent-vector by using the reparameterization trick.\n\nBased on the autoencoders structure without dense latent-vector, the latent features will have the shape of 25×25×2 for the face data and the shape of 75×105×1 for spectrograms data. This shape is the smallest that could be produced which still gave a good reconstruction result. In the next part, we’ll present that autoencoders without dense latent-vector provide a better reconstruction result.\n\nAutoencoders need a loss function to measure their performance. The most common and simple function is the Mean Squared Error (MSE) function.31 However, using this function won’t produce the best result for this study therefore, Structural Similarity index (SSIM)32 was used as the loss function for the face autoencoder. In addition, binary cross-entropy (BCE) instead of MSE was used in the spectrogram autoencoder. The benefits of using SSIM and BCE compared to MSE has been shown in in Figures 5 and 6.\n\n(a) Original spectrogram, (b) BCE reconstruction, and (c) MSE reconstruction. MSE can’t reconstruct the original data.\n\n(a) Original image, (b) SSIM reconstruction, and (c) MSE reconstruction.\n\nEquations 7 and 8 for SSIM and BCE loss functions were used with h representing model prediction, and y representing the desired output. For the SSIM loss function, 0.01 for k1 and 0.03 for k2, while L represents the maximum value was used (This value is one since the image has already been normalized).\n\nIn 2018, T. Baltrušaitis et al.33 summarized methods that have been used for multimodal data representation. At present, there are only two methods for co-learning multimodal data at the same time: joint and coordinated representations. The basic concept of the joint representation method is to fuse the data representation by concatenating its individual features. On the other hand, the coordinated representation let each representation to be learned separately while still in coordination. Joint representation was used in the present study as it is the most used method. However, limited labeled data has been the main obstacle faced in this case. The solution to this problem was to use a pre-train representation of unsupervised learning, such as autoencoders. The method of using autoencoder for unsupervised learning has been used previously by another study.34\n\nIn 2011, M. A. Nicolaou et al.35 used a multimodal data without deep learning methods. Since the features were hand-crafted, autoencoders were not used. The same joint representation method along with three fusion methods were used by that study. The methods were feature-level (used in this study), model-level, and output-level fusion. The feature-level fusion is combining the feature to be predicted using one model. While model-level and output-level fusions predict each representation individually, and combine them using another model.36\n\nIn both studies by Y. Kristian et al.11,12 a cry detection and pain classification system was created. This study used 46 videos taken by E. Hanindito et al.15 and added ten more videos with multiple duration. These studies introduced an ASM for landmarking infant’s face. The ASM was built using the frontal face on the videos as their data to extract hand-crafted geometric features. From these features, they’re able to achieve high accuracy for the infant facial cry detection and pain classifier.\n\nIn 2018, while deep learning had already been widely used as a feature learning method, Y. Kristian, et al.37 removed all the hand-crafted feature extraction, and switched to deep learning by using autoencoders. This research still used the same ASM from their previous research12 to crop the face region and discarded unimportant data. This paper transforms the ASM model into Kazemi et al. face landmark algorithm38 (Figure 7). DLIB library supports this algorithm. The extracted features were forwarded into the Long-Short Term Memory (LSTM) model to classify pain and for cry detection from a sequence of video frames. This research reported a high accuracy for both cry detection and pain classification. The face landmark algorithm from this research was used in this paper by using the DLIB library.\n\nApart from studies using facial expression, several studies tried to classify infant pain using acoustic features from the infant voices data. In 1995, Petroni et al.5 tried to classify the infant’s cry by using the Mel-cepstrum coefficients representation and filter-band energies with the help of ANN. This research used three classification targets: anger, fear, and pain. The results provided good accuracy for predicting anger and pain. However, this research had many prediction errors for the fear label.\n\nIn 2003, J. O. Garcia and C. A. R. Garcia6 set out to classify normal and pathological infant’s cries. This research provided a high accuracy by using 506 data to classify two target classes. Instead of using the audio wave signal, MFCC as the audio representation was used in this study, which is the same as the spectrogram but adapted to resemble the human ear. This research also used the help of a neural network to classify their final prediction. In addition, the study also included experiments with feature selection methods such as PCA.\n\nIn the present study classifiers for both cry detection and pain classifier were used. Throughout this study, from all the autoencoders tested, both CAE and VAE without dense latent-vector had better performances (Results shown in the next section). Therefore, the latent-vector from autoencoders without a dense-latent vector was used as the input for the classifiers. Following this, it was noticed that autoencoder models with similar performances may have completely different latent features from each other. Some latent features may be able to provide good classification results while this might not be possible for others. Due to this reason, the use of a neural network classifier consisting of just fully connected layers and dropout layers could not be used in this study. Therefore, at least one convolutional layer to boost the classifier performances was needed. In addition to the convolutional layer, dropout layers to prevent overfitting were used considering the small amount of data in this study.\n\nIn totals, five latent-vectors from the autoencoders were used. All these features were not used at once, however, models were built by using a single or combination of features. There were five feature parameters for the cry detection and pain classifier system: faces, dB-Scaled, amplitude, faces + dB-Scaled, and faces + amplitude. For a model that used more than one feature, the convolutional layer’s output was concatenated. Therefore, based on the multimodal models, there were four convolutional layers, three for face data and one for spectrogram, before concatenation process.\n\nFor the cry detection model, there were only two target classes. Therefore, one neuron output, and the sigmoid activation function was used. However, as there were three target classes for the pain classifier, three output neurons were needed. Additionally, the softmax activation function was used39 (Equation 9) to make the neuron’s output as the prediction probability for each class. For the cost function, binary cross-entropy for the detection system, and for the pain classifier, a categorical cross-entropy (Equation 10) were used. In these equations, N represents the number of output neurons.\n\nAs this study is a classification problem, accuracy as the performance measurement was used. On the other hand, the most widely used metric to measure model performances for classification problem is the F1 score (Equation 11). F1 score is the harmonic mean of precision (Equation 12) and recall (Equation 13). The final measurement is the Macro F1 Score. This measurement is the average of F1 scores for each class.\n\nThis study presents one model that was the best for the cry detection system. However, as a significant high F1 score for the pain classifier model could not be achieved, four models that provided a significant high F1 score were used instead. Each model had different parameters: face + dB-Scaled, face + amplitude, only dB-scaled, and only amplitude. From these results, it was decided to use all the models rather than choosing the best models. The prediction of the pain class was by using four models, and the majority votes method as the ensembling method was used. This method voted for all classifier results and used the majority class label as the final predicted class. In the case of tied votes, the class with higher pain labels were chosen. For example, if the severe pain and moderate pain classes had the same voting points, severe pain as the final prediction was selected.\n\n\nResults\n\nIn this paper, two major parts of the experiment were presented. In the first part, three autoencoder models were built, which were autoencoder for the infant’s face, amplitude spectrogram, and dB-scaled spectrogram of infant’s voices. In the second part, the latent-vector result from the autoencoders were used to build the cry detection and pain classification models.\n\nIn total, 20% of the 16,575 face dataset was used as the testing data, which resulted in 3,093 data. The results for the facial autoencoder can be seen in Table 3, and the image output sample can be seen in Figure 8. These results indicate that both CAE and VAE can recreate the data with a small SSIM loss value. From the reconstruction loss and the sample output, it can be seen that the best model was the use of CAE without dense latent-vector.\n\nA dense latent-vector had reduced the model performance for both CAE and VAE. Although, the performance was only slightly reduced, and there was sufficient reconstruction of the original face, the dense latent-vector used much more weight parameters because of its fully connected layers. Therefore, it can be concluded that autoencoders without dense latent-vector were the best option in this case.\n\nEven though CAE and VAE cannot be compared as they are different methods, it can be seen in Figure 8 that CAE gave a much better reconstruction result. It was assumed that VAE tried to build a more general model, as a result the model was forced to miss the small details.\n\nTwo spectrogram autoencoder models were built, one for dB-scaled spectrogram and one for amplitude spectrogram and the same structure and loss function for both spectrograms were used. Moreover, the same data training and testing distribution was used. The testing data was 506 data as it represents 20% of the total data (2530 short videos). The use of the dense latent-vector for the spectrogram autoencoder produced the same results as the face antoencoder (Results not shown). The results of the spectrograms CAEs and VAEs can be seen in Table 4, and the output samples were shown in Figure 9 for the dB-scaled spectrogram and Figure 10 for the amplitude spectrogram.\n\nFrom the output samples, it can be seen that VAEs’ reconstructions were not good for both spectrograms. Based on the results in Figure 10, it can be agreed that the amplitude spectrogram cannot be reconstructed by using VAE. For the dB-scaled spectrogram, the reconstruction may be similar to the original data. However, few spectrogram differences might give a huge difference in their audio signal. Therefore, the present study did not test with the classifier by using the VAE latent-vector for the spectrograms. It was also assumed that VAEs were unable to recreate the perfect original data due to their ability to generalize.\n\nTwo data training and testing distribution was tested. In the first distribution, seven original videos, which were three pre-surgery, and four post-surgery videos were excluded to prevent overfitting of the system. This resulted in the use of 1,836 training data and 432 testing data (Table 5). For the second distribution, the data order was mixed, and 25% of the data for the purpose of testing was excluded. Therefore, 1,701 training data and 567 data for testing was obtained. Further details about this distribution can be seen in Table 6. This distribution was provided to compare the result with the first distribution.\n\nIn this study several feature combinations by using both data distributions were tested (Table 7). The results show that the use of the second distribution gave a much higher results on all parameters. It is possible that using the second dataset distribution couldn’t detect an overfit model because of the high similarities between the training and testing data.\n\nBased on the result of the first data distribution, the facial expression was not a relevant feature for cry prediction. However, this feature can give a much better result on the pain problem. This result indicated that more data is required to avoid overfitting of the system. Face features using CAE gave a higher result; this statement was also supported by the multimodal feature result, which produced a better result when using CAE facial feature extraction. On the contrary, using voice features, especially dB-scaled spectrogram, resulted in a much higher F1 score and accuracy than the facial features. Therefore, it can be concluded that using the voice feature was more relevant and in need of less data than the facial feature. The use of a dB-scaled spectrogram had a better outcome than an amplitude spectrogram, even though the amplitude spectrogram also had better result than the facial features. However, the best result was obtained by the multimodal feature, which used the dB-scaled spectrogram as the audio representation, and CAE as the facial feature extraction. The multimodal feature slightly increased the accuracy even though it used more resources.\n\nAccording to these results, it can be said that with the existence of enough resources, it’s recommended to use multimodal features. However, in case of limited resources, it is best to use only the voice feature as it can still produce an acceptable result. The confusion matrix of using the multimodal and voice feature by using the dB-scaled spectrogram audio representation has been provided in Table 8.\n\nThe result for pain classification problem is shown in Table 9. It provided extremely high accuracy and F1 score for most cases, even when the first distribution gave a very low result. Therefore, the best method and feature from the first distribution was selected. The highest result came from the model that used the multimodal feature with CAE for face autoencoder, and the dB-scaled spectrogram as its audio representation. However, this parameter only produced a slightly better result than other parameters. This result was also not good enough to be titled as the best model for pain classification. Therefore, the top-four models were ranked based on their F1 scores. Ensemble of these four models were tested with the use of several methods, and the best result was produced using the majority votes technique and the tiebreaker of the sum of each model’s probability from the four models. This ensemble model had a better result based on the accuracy and F1 score. The confusion matrix for this ensemble model can be seen in Table 10. The input and output example in has also been provided in Figure 11.\n\n\nDiscussion\n\nIn this paper, several methods have been tested for building a deep learning model for pain and cry detection systems. It is evident that a voice feature was more relevant than a facial expression for pain detection. However, the combination of both features can achieve a higher score. Based on this finding, it can be suggested that multimodal representation such as combination with a physiological parameter of vital signs should be considered more in future work. Severe stimuli resulting vital sign parameters such as increase in heartbeat, changes in breathing patterns, oxygenation instead of a change of face and cry pattern should be explored.\n\nThe limited amount of data may introduce bias, however this paper was able to achieve a relatively good result from the use of the proposed method. To improve the performances even further, increasing the data amount would have a significant effect.\n\nA patient monitoring system is very important, as most of the pain scores are subjective. This findings support the hospital monitoring system and increase awareness of health care providers for the infant's pain. If the pain persists, modifying the pain medication may be needed.\n\n\nConclusion\n\nThis study has introduced a method for cry and pain detection by using the infant’s facial expression and voice. In addition, an alternative method in cases with limited resources have been provided. It has been shown that the infant’s voice is a more relevant feature than the facial expression, but the two features combined can obtain a better result.\n\nFor feature extraction, it has been demonstrated that CAE performs better than VAE for facial expression and voice spectrograms. This is because VAE is used more for generating new data rather than extracting features. Moreover, it has been shown that using dense latent-vector in the autoencoder increased the reconstruction loss.\n\n\nData availability\n\nFigshare: Ensemble of multimodal deep learning autoencoder for infant cry and pain detection. https://doi.org/10.6084/m9.figshare.16910299.v1.16\n\nThis project contains the following underlying data:\n\nThe data file contains the labels for video dataset for multi modal infant pain and cry classification.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 4.0 Public domain dedication).\n\n\nAuthor contributions\n\nConceptualization, Y.K. and M.T.A.S.; methodology, Y.K. and M.T.A.S.; software, Y.K. and N.S. validation, N.S., Y.K. and M.T.A.S.; formal analysis, N.S. and Y.K.; investigation, N.S., Y.K., M.T.A.S. and E.H.; resources, N.S. and E.H., and Y.K.; writing—original draft preparation, N.S., Y.K. and M.T.A.S.; writing—review and editing, N.S., Y.K. and M.T.A.S.; visualization, N.S. and Y.K.; supervision, Y.K., M.T.A.S., and E.H.; project administration, N.S., Y.K. and M.T.A.S.; funding acquisition, M.T.A.S. All authors have read and agreed to the published version of the manuscript.",
"appendix": "References\n\nVoepel-Lewis T, Shayevitz JR, Malviya S: for Scoring Postoperative Pain in Young Children. Pediatr. Nurs. 1997; 23(3).\n\nHudson-Barr D, Capper-Michel B, Lambert S, et al.: Validation of the pain assessment in neonates (PAIN) scale with the neonatal infant pain scale (NIPS). Neonatal Netw. 2002; 21(6): 15–21. PubMed Abstract | Publisher Full Text\n\nGarra G, et al.: Validation of the Wong-Baker FACES Pain Rating Scale in Pediatric Emergency Department Patients. Acad. Emerg. Med. 2010; 17(1): 50–54. PubMed Abstract | Publisher Full Text\n\nKarcioglu O, Topacoglu H, Dikme O, et al.: A systematic review of the pain scales in adults: Which to use?. Am. J. Emerg. Med. 2018; 36: 707–714. Publisher Full Text\n\nPetroni M, Malowany AS, Johnston CC, et al.: Classification of infant cry vocalizations using artificial neural networks (ANNs). 1995 International Conference on Acoustics, Speech, and Signal Processing. 1995; vol. 5: pp. 3475–3478.\n\nGarcia JO, Garcia CAR: Mel-frequency cepstrum coefficients extraction from infant cry for classification of normal and pathological cry with feed-forward neural networks. Proceedings of the International Joint Conference on Neural Networks, 2003. 2003; vol. 4: pp. 3140–3145.\n\nLogan B; Others: Mel frequency cepstral coefficients for music modeling. Ismir. 2000; vol. 270: pp. 1–11.\n\nMayorga P, Druzgalski C, Morelos RL, et al.: Acoustics based assessment of respiratory diseases using GMM classification. 2010 Annual International Conference of the IEEE Engineering in Medicine and Biology. 2010; pp. 6312–6316.\n\nCohen R, Lavner Y: Infant cry analysis and detection. 2012 IEEE 27th Convention of Electrical and Electronics Engineers in Israel. 2012; pp. 1–5.\n\nSikka K, et al.: Automated assessment of children’s postoperative pain using computer vision. Pediatrics. 2015; 136(1): e124–e131. PubMed Abstract | Publisher Full Text\n\nKristian Y, et al.: A Novel Approach on Infant Facial Pain Classification using Multi Stage Classifier and Geometrical-Textural Features Combination. IAENG Int. J. Comput. Sci. 2017; 44(1).\n\nKristian Y, Hariadi M, Purnomo MH: Ideal Modified Adachi Chaotic Neural Networks and active shape model for infant facial cry detection on still image. 2014 International Joint Conference on Neural Networks (IJCNN). 2014; pp. 2783–2787.\n\nEgede J, Valstar M, Martinez B: Fusing deep learned and hand-crafted features of appearance, shape, and dynamics for automatic pain estimation. 2017 12th IEEE international conference on automatic face & gesture recognition (FG 2017). 2017; pp. 689–696.\n\nWerner P, Al-Hamadi A, Niese R, et al.: Automatic pain recognition from video and biomedical signals. 2014 22nd International Conference on Pattern Recognition. 2014; pp. 4582–4587.\n\nHanindito E: Dynamic Acoustic Pattern as Pain Indicator on Baby Cries Post Surgery Procedure PhD thesis.2013.\n\nKristian Y, Sampurna MTA: Infant Pain and Cry Data Labels.csv. Figshare. Dataset. Publisher Full Text\n\nKristian Y, Sampurna MTA: Video files for Infant FLACC Pain Level Video Dataset IFPaLVD.csv. Figshare. Dataset. Publisher Full Text\n\nViola P, Jones MJ: Robust real-time face detection. Int. J. Comput. Vis. 2004; 57(2): 137–154. Publisher Full Text\n\nGong Y, Poellabauer C: Protecting Voice Controlled Systems Using Sound Source Identification Based on Acoustic Cues. 2018 27th International Conference on Computer Communication and Networks (ICCCN). 2018; pp. 1–9. Publisher Full Text\n\nDavis D, Patronis E: Sound system engineering. Routledge; 2012.\n\nRumelhart DE, Hinton GE, Williams RJ: Learning internal representations by error propagation.1985.\n\nVincent P, Larochelle H, Lajoie I, et al.: Stacked denoising autoencoders: Learning useful representations in a deep network with a local denoising criterion. J. Mach. Learn. Res. 2010; 11(Dec): 3371–3408.\n\nGao S, Zhang Y, Jia K, et al.: Single sample face recognition via learning deep supervised autoencoders. IEEE Trans Inf Forensics Secur. 2015; 10(10): 2108–2118. Publisher Full Text\n\nKingma DP, Welling M: Auto-encoding variational bayes. arXiv Prepr arXiv13126114. 2013.\n\nGrais EM, Plumbley MD: Single channel audio source separation using convolutional denoising autoencoders. 2017 IEEE Global Conference on Signal and Information Processing (GlobalSIP). 2017; pp. 1265–1269.\n\nYu W, et al.: Learning Deep Network Representations with Adversarially Regularized Autoencoders. Proceedings of the 24th ACM SIGKDD International Conference on Knowledge Discovery & Data Mining. 2018; pp. 2663–2671. Publisher Full Text\n\nBank D, Koenigstein N, Giryes R: Autoencoders. CoRR. 2020; vol. abs/2003.0 [Online]. Reference Source\n\nZhou Q, Zhou W, Yang B, et al.: Deep cycle autoencoder for unsupervised domain adaptation with generative adversarial networks. IET Comput. Vis. 2019; 13(7): 659–665. Publisher Full Text\n\nNair V, Hinton GE: Rectified linear units improve restricted boltzmann machines. Proceedings of the 27th International Conference on Machine Learning (ICML-10). 2010; pp. 807–814.\n\nNwankpa C, Ijomah W, Gachagan A, et al.: Activation functions: Comparison of trends in practice and research for deep learning. arXiv Prepr arXiv181103378. 2018.\n\nElkholy MM, Mostafa M, Ebied HM, et al.: Hyperspectral unmixing using deep convolutional autoencoder. Int. J. Remote Sens. 2020; 41(12): 4799–4819. Publisher Full Text\n\nWang Z, Bovik AC, Sheikh HR, et al.: Image quality assessment: from error visibility to structural similarity. IEEE Trans. Image Process. 2004; 13(4): 600–612. PubMed Abstract | Publisher Full Text\n\nBaltrušaitis T, Ahuja C, Morency L-P: Multimodal machine learning: A survey and taxonomy. IEEE Trans. Pattern Anal. Mach. Intell. 2018; 41(2): 423–443. PubMed Abstract | Publisher Full Text\n\nNgiam J, Khosla A, Kim M, et al.: Multimodal deep learning. Proceedings of the 28th International Conference on Machine Learning (ICML-11). 2011; pp. 689–696.\n\nNicolaou MA, Gunes H, Pantic M: Continuous prediction of spontaneous affect from multiple cues and modalities in valence-arousal space. IEEE Trans. Affect. Comput. 2011; 2(2): 92–105. Publisher Full Text\n\nYuan X, Huang B, Wang Y, et al.: Deep Learning-Based Feature Representation and Its Application for Soft Sensor Modeling With Variable-Wise Weighted SAE. IEEE Trans. Ind. Informatics. 2018; 14(7): 3235–3243. Publisher Full Text\n\nKristian Y, Purnama IKE, Sutanto EH, et al.: Klasifikasi Nyeri pada Video Ekspresi Wajah Bayi Menggunakan DCNN Autoencoder dan LSTM. J Nas Tek Elektro dan Teknol Inf. 2018; 7(3): 308–316. Publisher Full Text\n\nKazemi V, Sullivan J: One millisecond face alignment with an ensemble of regression trees. Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition. 2014; pp. 1867–1874.\n\nGibbs JW: Elementary Principles in Statistical Mechanics: Developed with Especial Reference to the Rational Foundation of Thermodynamics. C. Scribner’s Sons; 1902."
}
|
[
{
"id": "138998",
"date": "20 Jun 2022",
"name": "Ghazal Bargshady",
"expertise": [
"Reviewer Expertise Affective computing",
"deep learning",
"computer vision"
],
"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 good, the model and novelty is explained well, however there are some feedbacks which the authors need to address before indexing.\nDiscussion should discuss more details, explain well, and talk more about future works, please discuss the achievement and compare with other work. This section need more work.\n\nThe comparison with other work is not discussed well. It is better the authors use table for comparison with other works.\n\nIn method section, it is recommended to separate experimental setup such as database and experimental details in a separate section.\n\nIt is better to highlight more contributions in Introduction and discussion.\n\nIn the references list, I can see the author have not mentioned the other related works. There are so many important research related to deep learning and pain detection that have been done before by others and published in high quality journals which is required to bring in the reference list and compare the results with them.\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": [
{
"c_id": "9181",
"date": "30 Jan 2023",
"name": "Mahendra Tri Arif Sampurna",
"role": "Author Response",
"response": "We would like to thank the reviewer for reading and commenting on our submission. We will attempt to answer each question and suggestion as clearly as possible. Hopefully, revisions made on the manuscript would allow further considerations on indexing the article. Thank you for reviewing our manuscript. We hereby list the responses and revisions made on the original manuscript: Reviewer 1 The paper is good, the model and novelty is explained well, however there are some feedbacks which the authors need to address before indexing. Discussion should discuss more details, explain well, and talk more about future works, please discuss the achievement and compare with other work. This section need more work. Response: Thank you for your valuable suggestion. We acknowledge our paper lack on this part and now have added the table for comparison other works. The comparison with other work is not discussed well. It is better the authors use table for comparison with other works. Response: Thank you for your valuable suggestion. We acknowledge our paper lack on this part and now have added the table for comparison other works. In method section, it is recommended to separate experimental setup such as database and experimental details in a separate section. Response: Thank you for your suggestion. We now have separate the method. The first three subsection (study setting, ethics approval, and dataset) is related to study settings and data collection and continue with part of experimental settings. It is better to highlight more contributions in Introduction and discussion. Response: Thank you for your valuable suggestion. We agree with you comment and now have highlighted the contributions in several point on the last part of introduction and conclusion. In the references list, I can see the author have not mentioned the other related works. There are so many important research related to deep learning and pain detection that have been done before by others and published in high quality journals which is required to bring in the reference list and compare the results with them. Response: Thank you for your valuable suggestion. We have added other high quality journal to prove more understanding on our study."
}
]
},
{
"id": "144993",
"date": "02 Aug 2022",
"name": "Abdulaziz Saleh Ba Wazir",
"expertise": [
"Reviewer Expertise Deep Learning",
"Image processing",
"Computer Vision",
"Acoustics using deep learning",
"Audio and Signal Processing"
],
"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 presents a bright idea of deep learning usage for infants cry and pain detection. The paper used multimodal and utilized both visual and audio features of the dataset for training and testing purposes. The use of both features added more value in the field of infants cry researches using deep learning. Here is a few comments to boost the paper contribution and organization as well.\nMany of the literature on autoencoders was highlighted in details in the methods section. However, it is proper to be discussed as part of the literature in introduction section or as a separate literature section. And only refer to it in the methods section\n\nMany of the literature on infants cry and pain detection as references 11, 13, and 15 was highlighted in details in the methods section. However, it is proper to be further discussed as part of the literature in introduction section or as a separate literature section. And only refer to it in methods section.\n\nIt is highly recommended to separate methods and experimental settings into sections. evaluation and metrics can be part of the experimental settings.\n\nDiscussion either can be extended and detailed or added to results section and have one section (results and discussion) and detail the discussions within the results if combined.\n\nAlthough several literature was cited on the same dataset, the paper lacks comparison with those researches. As parts of the results and discussion a comparison should be tabulated and discussed, even if the size and type of the dataset are different. The table should highlight the dataset, approach, deep learning models, and achieved metrics. At least few literature can be compared such as 11, 12, 13, 14, and 15.\n\nFor the comparison table as in comment number 5, the table should highlight at least one or two common metrics. If common metrics is missing, adding one or two metrics is still acceptable than not having a comparison at all.\n\nThe comparison table shall be discussed to highlight the novelty and contributions of this paper over other methods, such as usage of audio and images, or out performance of current work over others in terms of metrics, or weights. One or two difference is enough, but the more the better.\n\nThe novelty and contributions based on the comparison table can be used to further detail the contributions in background and conclusion sections.\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": "9182",
"date": "30 Jan 2023",
"name": "Mahendra Tri Arif Sampurna",
"role": "Author Response",
"response": "We would like to thank the reviewer for reading and commenting on our submission. We will attempt to answer each question and suggestion as clearly as possible. Hopefully, revisions made on the manuscript would allow further considerations on indexing the article. Thank you for reviewing our manuscript. We hereby list the responses and revisions made on the original manuscript: Reviewer 2 The paper presents a bright idea of deep learning usage for infants cry and pain detection. The paper used multimodal and utilized both visual and audio features of the dataset for training and testing purposes. The use of both features added more value in the field of infants cry researches using deep learning. Here is a few comments to boost the paper contribution and organization as well. Many of the literature on autoencoders was highlighted in details in the methods section. However, it is proper to be discussed as part of the literature in introduction section or as a separate literature section. And only refer to it in the methods section Response: Thank you for your valuable comment. We agree that this can lead to more effective reading, therefore we have move part of method to introduction. Many of the literature on infants cry and pain detection as references 11, 13, and 15 was highlighted in details in the methods section. However, it is proper to be further discussed as part of the literature in introduction section or as a separate literature section. And only refer to it in methods section. Response: Thank you for your suggestion. We also think it will be better if there is “Related Work” section before method. However, to conform with other paper published in this journal we maintain several previous work on the method section which have the basis of our method and move several literature to the discussion section. It is highly recommended to separate methods and experimental settings into sections. evaluation and metrics can be part of the experimental settings. Response: Thank you for your suggestion. We now have separate the method. The first three subsection (study setting, ethics approval, and dataset) is related to study settings and data collection and continue with part of experimental settings. Discussion either can be extended and detailed or added to results section and have one section (results and discussion) and detail the discussions within the results if combined. Response: Thank you for you valuable suggestion. We have added several related in discussion and hope that there will provide more understanding for our study. Although several literature was cited on the same dataset, the paper lacks comparison with those researches. As parts of the results and discussion a comparison should be tabulated and discussed, even if the size and type of the dataset are different. The table should highlight the dataset, approach, deep learning models, and achieved metrics. At least few literature can be compared such as 11, 12, 13, 14, and 15. Response: Thank you for your valuable suggestion. We found that this is very brilliant and have added the table for comparison other works. For the comparison table as in comment number 5, the table should highlight at least one or two common metrics. If common metrics is missing, adding one or two metrics is still acceptable than not having a comparison at all. Response: Thank you for your valuable suggestion. We have added the different in one or two common metric as suggested The comparison table shall be discussed to highlight the novelty and contributions of this paper over other methods, such as usage of audio and images, or out performance of current work over others in terms of metrics, or weights. One or two difference is enough, but the more the better. Response: Thank you for your valuable suggestion. We have added the difference in one or two common metric as suggested The novelty and contributions based on the comparison table can be used to further detail the contributions in background and conclusion sections. Response: Thank you for your valuable suggestion. We have added the table comparison of other work to assist this findings."
}
]
}
] | 1
|
https://f1000research.com/articles/11-359
|
https://f1000research.com/articles/12-102/v1
|
27 Jan 23
|
{
"type": "Research Article",
"title": "Age-specific incidence of need for long-term care for men and women in Germany 2015: Cross-sectional study comprising 82 million people",
"authors": [
"Luisa Haß",
"Sabrina Tulka",
"Thaddäus Tönnies",
"Annika Hoyer",
"Rebecca Palm",
"Stephanie Knippschild",
"Ralph Brinks",
"Sabrina Tulka",
"Thaddäus Tönnies",
"Annika Hoyer",
"Rebecca Palm",
"Ralph Brinks"
],
"abstract": "Background: With the growing number of older people, the number of people in need of long-term care is increasing, too. Official statistics only report on the age-specific prevalence of long-term care. Therefore, there is no data on the age- and sex-specific incidence of the need for care at the population level for Germany available. Methods: Analytical relationships between age-specific prevalence, incidence rate, remission rate, all-cause mortality, and mortality rate ratio are used to estimate the age-specific incidence of long-term care among men and women in 2015. The data is based on the official prevalence data from the nursing care statistics for the years 2011 to 2019 and official mortality rates from the Federal Statistical Office. For Germany, there is no data on the mortality rate ratio of people with and without a need for care, which is why we use two extreme scenarios that were obtained in a systematic literature search to estimate the incidence. Results: The age-specific incidence is about 1 per 1000 person-years (PY) in men and women at the age of 50 and increases exponentially up to the age of 90. Up to about the age of 60, men have a higher incidence rate than women. Thereafter, women have a higher incidence. At the age of 90, women and men have an incidence rate of 145 to 200 and 94 to 153 per 1000 PY, respectively, depending on the scenario. Conclusion: We estimated the age-specific incidence of the need for long-term care for women and men in Germany for the first time. We observed a strong increase, leading to a huge number of people in need of long-term care in higher age groups. It is to be expected that this will result in an increased economic burden and a further increased need for nursing and medical staff.",
"keywords": [
"epidemiology",
"ageing",
"long-term care"
],
"content": "Introduction\n\nWith the growing number of older people and the age-related increasing impairment of independence and activities of daily living through illness or cognitive and communicative abilities, the number of people in need of care also increases.1–4 To quantify the extent of long-term care, commonly the prevalence, which represents the proportion of individuals in a population in need of care and the actual care situation, is used.5,6 In addition, the prevalence is frequently used to project future numbers of frail people in need of long-term care to form the basis for economic strategies and political decisions. Due to the fact that prevalence data is a composed estimate, which strongly depends on the rate of new cases of need for care and mortality, projections could be much more precise and comprehensive if exact information on incidence and mortality were used. In addition to being used as a suitable measure within projections, incidence can be used to assess the risk of needing care (e.g. age-spanning comparisons of the risk of requiring long-term care or comparisons between sexes). For questions of resource allocation, the age-specific incidence can be used to estimate at which age the risk of requiring care is particularly high and which sex in an age group is at higher risk. It can thus serve as a basis for calculations within different models for projections of future care needs.\n\nNevertheless, data on the incidence of the need for long-term care or the risk of developing need of long-term care are scarce for Germany. The Socio-Economic Panel (SOEP) found that for people aged 65 and over, the risk of needing long-term care increases by around 0.5 percentage points with each additional year of life.7 This finding indicates a linear increase in risk with age. In the SOEP, data from a representative annual repeated survey of private households between 1984 and 2018 were evaluated. However, only people who are cared for on an outpatient basis and not within nursing homes were considered. Estimates of risk or the incidence of the need for long-term care at the population level are not yet available for Germany and would have to be collected through complex, lengthy and cost-intensive longitudinal studies. Therefore, another method of estimating incidence is required, as its calculation appears to be considered as an opportunity that leads to a more precise and comprehensive estimation of future prevalence.\n\nOne way of estimating the incidence is to use the illness-death model. This method determines the age-specific prevalence, taking mortality into account. As such, the model quantifies the relationship between the incidence rate, mortality rate, remission rate, and prevalence. With this relationship, it is possible to estimate the age-specific incidence rate at the population level. The aim of this article is therefore to estimate the age-specific incidence of long-term care using the illness-death model as the basis of further projections of future numbers of people in need of care. As a result, incidence rates for men and women were presented, allowing them to be used as a first prudent trend.\n\n\nMethods\n\nThe data used for this study were retrieved from the official statistics about the need for long-term care in Germany published by the Federal Statistical Office. These are issued every two years and provide information on persons with long-term care insurance.5,8–11 The data was recorded as part of the national law in Germany (SGB XI) and includes information on people in inpatient, semi-stationary or outpatient care who received financial support5 in the German population. This “Pflegestatistik 2019 - Pflege im Rahmen der Pflegeversicherung Deutschlandergebnisse” uses the following definition of the need for long-term care as a basis: “People who experience impairment of their independence due to physical, cognitive or psychological impairments or health-related stresses or requirements, which they cannot compensate for independently and are therefore permanently – probably for at least six months – dependent on help” and are assigned to care grades one to five (§ 14 Abs. 1 SGB XI).5\n\nFor the period from 2011 to 2019, the age- and sex-specific number of people in the total population and the number of people in need of care were documented in two-year steps. The corresponding prevalence in different age groups (<15 years, 15-59 years, and in 5-year age steps from 60 years onwards up to 90+ years) were reported. To get prevalence data for every age, we logit-transformed the prevalence provided by the Federal Statistical Office and modeled it via multiple linear regression with calendar time (t) and age (a) as independent variables separately for men and women.\n\nWithin this analysis we used the illness-death model and the related partial differential equation (1), which specifies the change in prevalence in the course of calendar time and age. Thereby the analytical relationship between age-specific prevalence (p), incidence rate (i), remission rate (r), mortality rate ratio (R) (i.e., mortality rate of persons with need of long-term care divided by the mortality rate of persons without need for long-term care) and all-cause mortality rate (m)12 was described:\n\nBy rearranging the partial differential equation, the estimation of the incidence of long-term care can be calculated using the age- and sex-specific prevalence and all-cause mortality as well as the expected mortality rate ratio and remission as assumptions:\n\nThe calculations were carried out for men and women separately. The corresponding age-specific mortality rates (m) were determined as a function of the calendar year based on the mortality rates of the Federal Statistical Office.13–15 Due to incomplete data availability, assumptions have to be made for the mortality rate ratio (R), which is not yet known for Germany at the population level. Hence, the information for R was derived from existing literature on long-term care which documented mortality rates in certain subgroups.22 To account for the lacking information on mortality rates in long-term care, two different mortality rate ratios were used (as a constant factor) within the calculations to enable the assessment of a range of potential incidence rates. The lowest and highest values reported were selected and used in two scenarios for the incidence rate estimation. In scenarios 1 and 2, mortality rate ratios R = 3.216 and R = 1.1717 have been chosen, respectively. The two different scenarios of R offer the possibility to determine a lower and an upper limit of the age-specific incidence rate for women and men.\n\nIn addition, assumptions about the remission rate were necessary for the analysis. Since dependency on long-term care in old age is often seen in connection with multimorbidity, which results in particular from chronic somatic or mental illnesses,4 the need of long-term care was defined as a chronic and irreversible condition in this analysis. The remission rate r was therefore assumed to be zero. However, this assumption is supported by the recently published insurance report. In this report, a permanent termination of the need for long-term care (not due to death) of 0.3% in 2021 is stated.18\n\nPresentations of the results are given exclusively and by way of example for the year 2015 (which is the middle of the reporting period of the prevalence data) as age-specific incidence rate per 1000 person-years.\n\nAll calculations were performed in the freely accessible, open-source statistical software R Version 4.1.0 (The R Foundation for Statistical Computing). The underlying data and the source code for analysis of prevalences are available in the permanent, freely accessible online repository Zenodo.19\n\n\nResults\n\nThe underlying dataset showed a steady increase in the number of people in need of long-term care in Germany from 2.5 million in 2011 to 4.1 million people in 2019. Corresponding prevalences in the total population are 3.1% and 5% in 2011 and 2019, respectively.5,8 Figure 1 shows that the prevalence of long-term care was higher among women aged 70-74 than among men. In addition, the prevalence strongly depends on age. In particular, from the age group 75-79 years, there was a larger “jump” in the need for care (to over 10 percent) compared to the younger age groups.\n\nRepresentation of the age groups from <15, 15-59, from 60 in 5-year intervals up to 90+ (Data basis: care statistics from the Federal Statistical Office for the years 2011-2019).\n\nFor 2015, we found an exponential increase in the incidence rate in the age range of 50 to 90 years for both sexes (see Table 1 and Figure 2). Up to the age of about 65 years, men show a higher incidence rate for long-term care than women of the same age. From the age of about 65 years, the incidence of needing long-term care is higher for women than for men. With regard to the two scenarios of the mortality rate ratios, the incidence rate for a 50-year-old woman in scenario 1 (R = 3.2) was 1.03 per 1000 PY and 1.01 per 1000 PY in scenario 2 (R = 1.17). For men of the same age, there was a more than 20% higher incidence rate of 1.30 per 1000 PY in scenario 1 and 1.24 per 1000 PY for scenario 2. While in the lower age groups the differences between the two scenarios are small, the estimates between the scenarios differ with increasing age for both sexes. Men at age 90 had an incidence rate of 153 and 94.4 per 1000 PY in scenarios 1 and 2, respectively. For 90 year old women the corresponding values were 200 and 145 per 1000 PY in scenarios 1 and 2 (Table 1, Figure 2).\n\nScenario 1: R = 3.2, scenario 2: R = 1.17 for all ages.\n\nScenario 1: R = 3.2; Scenario 2: R = 1.17.\n\n\nDiscussion\n\nThe present analysis shows the first estimation of the age-specific incidence of the need for long-term care in Germany at the population level, stratified by sex. This incidence rate can be used to support economic and political planning in long-term care. Proper application of a partial differential equation related to the illness-death model provided an estimate of the incidence rate, taking into account a complete survey of the prevalence of the need for long-term care in Germany comprising the data of 82 million people. In contrast to the observation of a linear increase in risk,7 our estimated rates show an exponential increase with increasing age for the year 2015 in both scenarios 1 (R = 3.2) and 2 (R = 1.17) for both sexes. Women from the age of about 65 years had a higher incidence of needing care than men of the same age.\n\nDue to legislative amendments in definition of long-term care, changes in data collection and a deficient data situation, this analysis is subject to some limitations that must be taken into account when interpreting the results:\n\nThe care reform implemented in 2017 led to an adjustment of the definition of the need for care in replacing the existing care levels (I-III) by care grades (1 to 5). Although this change results in a more comprehensive and complete record of people in need of care, it also led to a larger number of people in need of care for this analysis. Some of the increases shown in Figure 1 might be due to this redefinition. In addition, changes in the context of data collection by the Federal Statistical Office must be taken into account. In particular, the number of people in need of care increased as a result of the first-time registration of people without a level of care and with significantly limited everyday skills in 2015. Moreover, the current care report 2019 integrated data from outpatient care services (according to § 71 paragraph 1a SGB XI) into the survey, which was previously not taken into account. Over time, these continuous adjustments may lead to a system-related increase in the prevalence of the need for long-term care, which means that the interpretation of the calculated risk might not be correctly represented. Due to these structural changes and the lack of information on the total number of persons with compulsory insurance in the reports, it was not possible to calculate the prevalence by different levels of care.\n\nIn addition to the data-based limitations listed above, further uncertainties must be taken into account due to the lack of information on the incidence calculation. In particular, the missing (real) mortality rate ratio, which is required for the calculation of the age- and sex-specific incidence of the need for long-term care, had to be replaced by considering extreme value scenarios from a literature search, which means that the incidence rates can only be narrowed down to a value range (lower and upper limit). Due to the lack of data on the subject of “mortality in need of long-term care” in Germany, a more precise estimation of the incidence remains impossible. This gap could be closed by transparent and comprehensive presentations of results in studies on aging and the need for long-term care, which should also include mortality. For a comprehensive result presentation of this analysis, incidences over time (general and stratified by sex) are available on Zenodo (Figure 320 and Figure 421). Due to lacking data on the mortality rate over time, these should be seen as possible trends only.\n\nFor further use of the results presented, consideration should be given to the fact that the remission rate in long-term care was set to zero. In general, and depending on existing comorbidities, a return of people in need of care to independence can possibly occur. However, a remission happens rather seldom than the termination of care due to death.18 This care report18 is the only published source of the remission rate in long-term care. It should be taken into account that this data is limited to one insurance, thus population-level data could not be used for this analysis. In accordance with the definition for determining the degree of need for care, according to § 15 SGB XI, the associated temporal classification of the need for care and based on the information from the available care report18 we suppose that remission may occur rarely, but it is not impossible. Especially, the extent of the underestimation of remission in the first level of care cannot be quantified at this point in time due to the insufficient data on the improvement of independence in this low level of care. Additionally this subgroup was excluded in the care report.18 An incorrect assessment of the need for help over a period of six months and the associated remission rate could not be taken into account as well. Therefore the remission rate r was assumed to be zero in our work. This leads to the fact that the calculated incidence rate can perform as the lower “limit” for the risk of needing care. As equation (2) shows a non-zero remission rate r > 0 would lead to an additional increase in the incidence rate. If remission is possible in grades with a low need for care, among patients in need of care who have diseases with an increased likelihood of remission, or in younger patients, the estimates of the incidence rates shown in this analysis represent a lower limit. However, given the lack of data, a quantitative statement about the influence of remission on the incidence estimation is not possible. In order to close the gaps in future estimates, data collection involving the relevant specialist sciences is still necessary.\n\n\nConclusion\n\nBy carrying out this analysis, we were able to use an indirect method to estimate the age-specific incidence for men and women in Germany. Our findings indicate an exponential increase in the incidence rate with age in both women and men, which should be accounted for in future estimations on resource planning in long-term care.\n\nWe have performed a calculation of incidence rates, offering the possibility to predict future prevalence based on more extensive and precise information than a simple extrapolation of prevalence by itself. With existing data gaps regarding the epidemiology of long-term care in Germany, only a calculation of trends in incidence rates was possible. This prediction, based on an increasing number of new cases of long-term care and increasing overall mortality (due to the expectation of an increasing number of people over 65 years of age around the year 2030), might result in an expected prevalence that exceeds previous predictions.\n\n\nEthics approval and consent to participate\n\nThe underlying data are aggregated and no individual subject can be identified. The data stem from a public data source (Federal Statistical Office). According to German National Laws, in this case no ethics approval and no consent to participate are necessary.\n\n\nConsent for publication\n\nThe underlying data are aggregated and no individual subject can be identified. The data stem from a public data source (Federal Statistical Office). According to German National Laws, no consent for publication is required.",
"appendix": "Data availability\n\nPublicly available datasets were analyzed in this study.\n\nThe underlying prevalence data can be accessed from the “Pflegestatistik - Pflege im Rahmen der Pflegeversicherung Deutschlandergebnisse“ from the years 2011 to 2019 (see literature link included in the text or https://www.statistischebibliothek.de/mir/receive/DESerie_mods_00000940 ). Age- and sex-specific prevalence data were extracted from Tab. 1.2 for women and calculated for men.\n\nMortality data were obtained from the official homepage of the Federal Statistical Office: https://service.destatis.de/bevoelkerungspyramide/ with the assumption of a moderate development of birth rate, life expectancy and migration (G2L2W2).\n\nDefinition of sexes within this analysis was used in accordance to the definition in the published data.\n\nFigures: The figures presented within this analysis based on the above mentioned data, were created by the authors of this article.\n\nZenodo: Estimation of incidence of need of long-term care from its prevalence in Germany, https://doi.org/10.5281/zenodo.6856273. 19\n\nZenodo: Age dependent incidence rates (1), https://doi.org/10.5281/zenodo.7440397. 20\n\nZenodo: Age dependent incidence rates (2), https://doi.org/10.5281/zenodo.7440523. 21\n\nZenodo: Age dependent incidence rates - literature search, https://doi.org/10.5281/zenodo.7440598. 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\nGijsen R, Hoeymans N, Schellevis FG, et al.: Causes and consequences of comorbidity: a review. J. Clin. Epidemiol. 2001; 54(7): 661–674. Publisher Full Text\n\nJacobs K, Kuhlmey A, Greß S, et al.: Pflege-Report 2020 - Neuausrichtung von Versorgung und Finanzierung. Berlin Heidelberg:Springer;2020.\n\nNowossadeck S: Demographic change, people needing long-term care, and the future need for carers. An overview. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2013; 56(8): 1040–1047. PubMed Abstract | Publisher Full Text\n\nvan den Bussche HSI , Koller D, Hansen H, et al.: Multimorbidität in der älteren Bevölkerung – Teil 1: Prävalenz in der vertragsärztlichen Versorgung. Deutscher Ärzte-Verlag|ZFA|Z Allg Med. 2012; 88(9).\n\nDESTATIS: Pflegestatistik 2019 - Pflege im Rahmen der Pflegeversicherung Deutschlandergebnisse. Edited by statistisches Bundesamt W.2020.Reference Source\n\nJacobs KKA, Greß S, Klauber J, et al.: Pflege-Report 2018 - Qualität in der Pflege. Berlin Heidelberg:Springer;2018.\n\nGeyer J, Haan P, Kröger H, et al.: Pflegebedürftigkeit hängt von der sozialen Stellung ab. DIW Wochenbericht. 2021; 44.\n\nDESTATIS: Pflegestatistik 2011 - Pflege im Rahmen der PflegeversicherungDeutschlandergebnisse. Edited by DESTATIS (Statistisches Bundesamt W.2013.Reference Source\n\nDESTATIS: Pflegestatistik 2013 - Pflege im Rahmen der PflegeversicherungDeutschlandergebnisse. Edited by DESTATIS (Statistisches Bundesamt W.2015.Reference Source\n\nDESTATIS: Pflegestatistik 2015 - Pflege im Rahmen der PflegeversicherungDeutschlandergebnisse. Edited by DSTATIS (Statistisches Bundesamt W.2017.Reference Source\n\nDESTATIS: Pflegestatistik 2017 - Pflege im Rahmen der PflegeversicherungDeutschlandergebnisse. Edited by statistisches Bundesamt W.2018.Reference Source\n\nBrinks R, Landwehr S: Change rates and prevalence of a dichotomous variable: simulations and applications. PLoS One. 2015; 10(3): e0118955. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDESTATIS: Bevölkerung Deutschlands bis 2060 - Ergebnisse der 14. koordinierten Bevölkerungsvorausberechnung - Hauptvarianten 1 bis 9. Edited by DESTATIS (Statistisches Bundesamt W.2019.\n\nDESTATIS: 14. koordinierte Bevölkerungsvorausberechnung. Welche Annahmen zu Geburtenhäufigkeit, Lebenserwartung und Wanderungssaldo wurden getroffen? Die Annahmen auf einen Blick. Statistisches Bundesamt.2019; vol. 2022.\n\nDESTATIS: Kohortensterbetafeln für Deutschland - Methoden- und Ergebnisbericht zu den Modellrechnungen für Sterbetafeln der Geburtsjahrgänge 1920 – 2020 DESTATIS. wissen.nutzen.2020.\n\nFried TR, Pollack DM, Tinetti ME: Factors associated with six-month mortality in recipients of community-based long-term care. J. Am. Geriatr. Soc. 1998; 46(2): 193–197. PubMed Abstract | Publisher Full Text\n\nPark C, Kim D, Briesacher BA: Association of Social Isolation of Long-term Care Facilities in the United States With 30-Day Mortality. JAMA Netw. Open. 2021; 4(6): e2113361. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRothgang H, Müller R: BARMER Pflegereport 2022. Stationäre Versorgung und COVID-19. Schriftenreihe zur Gesundheitsanalyse - Band. 38. .BARMER;2022.Reference Source\n\nBrinks R, Haß L:Estimation of incidence of need of long-term care from its prevalence in Germany. Dataset. Zenodo. 2022. Publisher Full Text\n\nHaß L, Tulka S, Tönnies T, et al.: Age dependent incidence rates (1). Zenodo. 2022. Publisher Full Text\n\nHaß L, Tulka S, Tönnies T, et al.: Age dependent incidence rates (2). Zenodo. 2022. Publisher Full Text\n\nHaß L, Tulka S, Tönnies T, et al.: Age dependent incidence rates - literature search. Zenodo. 2022. Publisher Full Text"
}
|
[
{
"id": "166417",
"date": "17 Mar 2023",
"name": "Andreas Wienke",
"expertise": [
"Reviewer Expertise Epidemiology and Biostatistics"
],
"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\nI would like to congratulate the authors for this excellent manuscript, which demonstrates how incidence of need for long-term care can be calculated based on prevalence, all-cause mortality and mortality rate ratio. A direct incidence estimation is impossible in Germany because of the lack of longitudinal data. Publicly available data are obtained from the Federal Statistics Office (all-cause mortality) and the nursing care statistics (prevalence). In the first part of the paper the relevant formula from previous work by the authors is given with respect to the relationship between incidence, prevalence, mortality, mortality rate ratio and remission. Based on this relationship the annual incidence is calculated.\nThe paper is written in a very clear and sound style, I have only very minor remarks:\nIn the description of the data, a short explanation is missing regarding private and statuary care insurances in Germany. Do the data about prevalence cover only the situation of the statuary care insurance or also private insurances?\n\nIn Figure 1 it is difficult to distinguish the lines based on the legends.\n\nI am not convinced by the decision to present the results of the calculations for the year 2015. Why not for the most recent year with data available?\n\nI would prefer to use the wording of 'calculation' instead of 'estimation' (e.g. first line of Discussion).\n\nAs an outlook I recommend a more detailed discussion about a possible extension of the model including care levels. This would require the extension of the illness-death model with information about transitions between the care levels (is such data available?) and mortality rate ratios dependent on care level.\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": "167164",
"date": "27 Mar 2023",
"name": "Emiel Hoogendijk",
"expertise": [
"Reviewer Expertise Geriatrics",
"Epidemiology"
],
"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\nThank you for the opportunity to review this interesting paper. In this work, the age-specific incidence of the need for long-term care in Germany at the population level was estimated, based on national statistical data and following the illness-death model. The paper is well-written and seems technically sound. I have the following comments:\n1. In this paper, a method is described that avoids costly longitudinal data collections. However, the current approach also has drawbacks, as it mainly leads to descriptive data. For example, it is not possible to explain the incidence: no micro (individual characteristics) or macro (policy or environmental characteristics) factors can be explored in relation to the incidence. This is a limitation of the current study that could be acknowledged, in addition to the already mentioned data-related limitations (Page 6).\n\n2. The approach chosen by the authors is one of several options to estimate the need for long-term care, such as simulation of scenarios. The method chosen is sound. However, I was wondering whether the authors have considered another option: linking representative cohort data to national statistical data? In many countries, this is possible, and it would enable even further exploration of factors driving the increase in need for long-term care. Could the authors reflect on whether this is an option in Germany? Or does GDPR prevents this?\n3. In the Introduction (Page 3), the authors write: “One way of estimating the incidence is to use the illness-death model”. This raises the question: what are the other methods? Perhaps the authors could briefly mention these in their Discussion?\n4. Do I understand it correctly that for the assumption on the mortality rate ratio (R) a literature search was done that was not necessarily restricted to studies in Germany? (reference 22) The authors have carefully approached this by looking at a broad range with two scenarios, but how representative are data from other countries for the German situation?\n5. The focus of the paper is Germany. I miss some international context. For example, in the Discussion the results could be compared with similar data from other Western countries, if available. This would be important for policy makers, to see whether patterns are similar to other countries.\n6. Adding a definition of long-term care would be helpful for the Introduction. This probably covers residential care, but without further specification it could also cover informal care. Please clarify.\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/12-102
|
https://f1000research.com/articles/11-1464/v1
|
09 Dec 22
|
{
"type": "Research Article",
"title": "Pre-exposure to azithromycin enhances gonococcal resilience to subsequent ciprofloxacin exposure: an in vitro study",
"authors": [
"Natalia González",
"Jolein Gyonne Elise Laumen",
"Saïd Abdellati",
"Tessa de Block",
"Irith De Baetselier",
"Christophe Van Dijck",
"Chris Kenyon",
"Sheeba S. Manoharan–Basil",
"Jolein Gyonne Elise Laumen",
"Saïd Abdellati",
"Tessa de Block",
"Irith De Baetselier",
"Christophe Van Dijck",
"Chris Kenyon",
"Sheeba S. Manoharan–Basil"
],
"abstract": "Background: The effect of sequential exposure to different antibiotics is an underexplored topic. Azithromycin can be detected in humans for up to 28 days post-ingestion and may prime bacterial responses to subsequently ingested antibiotics. Methods: In this in vitro study, we assessed if preexposure to azithromycin could accelerate the acquisition of resistance to ciprofloxacin in Neisseria gonorrhoeae reference strain, WHO–F. In a morbidostat, we set two conditions in 3 vials each: mono-exposure (preexposure to Gonococcal Broth followed by exposure to ciprofloxacin) and dual sequential exposure (preexposure to azithromycin followed by exposure to ciprofloxacin).The growth of the cultures was measured by a software (MATLAB). The program decided if gonococcal broth or antibiotics were added to the vials in order to keep the evolution of the cultures. Samples were taken twice a week until the end of the experiment i.e. until resistance was achieved or cellular death. Additionally, six replicates of WHO–F WT and WHO–F with rplV mutation, caused by azithromycin, were exposed to increasing concentrations of ciprofloxacin in plates to assess if there were differences in the rate of resistance emergence. Results: We found that after 12 hours of pre-exposure to azithromycin, N. gonorrhoeae's resilience to ciprofloxacin exposure increased. Pre-exposure to azithromycin did not, however, accelerate the speed to acquisition of ciprofloxacin resistance. Conclusions: We found that azithromycin does not accelerate the emergence of ciprofloxacin resistance, but there were differences in the molecular pathways to the acquisition of ciprofloxacin resistance: the strains preexpossed to azithromycin followed a different route (GyrA: S91F pathway) than the ones without antibiotic preexposure (GyrA:D95N pathway). However, the number of isolates is too small to draw such strong conclusions.",
"keywords": [
"N. gonorrhoeae",
"antimicrobial consumption",
"AMR",
"resistance",
"fluoroquinolone",
"macrolide"
],
"content": "Introduction\n\nThere is considerable controversy as to whether to treat Neisseria gonorrhoeae with ceftriaxone plus azithromycin or only ceftriaxone.1–3 Proponents of monotherapy have noted that dual therapy results in extremely high levels of macrolide consumption in core groups such as men who have sex with men taking pre-exposure prophylaxis.2,3 These high levels of macrolide exposure may directly induce macrolide resistance in not only N. gonorrhoeae but also in other bacteria. Recent studies have suggested that azithromycin may promote antimicrobial resistance to other classes of antimicrobials via inducing mutations that act as stepping–stones to antimicrobial resistance.4–6\n\nIn vitro, culture experiments with Mycobacterium smegmatis have found that antimicrobial–induced mutations in ribosomal proteins reduce susceptibility to various antimicrobials in a stepping–stone manner.4 Ciprofloxacin, for example, first selects for mutations in four ribosomal proteins. These mutations result in alterations in the transcriptome and proteome, facilitating the acquisition of mutations in other genes. These latter mutations were responsible for higher-level ciprofloxacin resistance. The ribosomal mutations were found to have an associated fitness cost and were lost once the bacteria acquired the definitive ciprofloxacin resistance-associated mutations. In a series of in vitro experiments with N. gonorrhoeae, we found that the pathway to high–level azithromycin resistance following azithromycin exposure likewise involved transitory mutations in genes rplD, rplV and rpmH (encoding the ribosomal proteins L4, L22 and L34, respectively). We found evidence that these mutations serve as stepping–stones to mutations in the MtrCDE–encoded efflux pump and the 23S rRNA genes, ultimately responsible for the high–level azithromycin resistance.6\n\nThe above findings may be one way to explain how macrolide consumption levels have been noted to be associated with resistance to a range of non–macrolide antibiotics in a number of bacteria, including N. gonorrhoeae.7–9 An important feature of the pharmacokinetics of azithromycin is its long intracellular half-life, meaning that it may remain detectable at various body sites for up to four weeks post-exposure.10,11 Suppose an individual were to be reinfected with N. gonorrhoeae soon after treatment with dual (ceftriaxone plus azithromycin) or mono (azithromycin) therapy or azithromycin for another indication; this long tail of exposure could select for the ribosomal stepping–stone mutations, which could then facilitate the acquisition of resistance to another antimicrobial which was given within or soon after four weeks. In the current study, we, for the first time, test this stepping–stones hypothesis by assessing if azithromycin exposure can accelerate the acquisition of ciprofloxacin resistance in N. gonorrhoeae. In addition, we tested if pre-exposure to azithromycin can enhance N. gonorrhoeae resilience when subsequently challenged by a different antimicrobial such as exposure to ciprofloxacin.\n\n\nMethods\n\nN. gonorrhoeae WHO–F reference strain was grown at 36°C, and 5% CO2 on a gonococcal (GC) medium (Gonococcal Medium Base, BD Difco™) supplemented with 1% IsoVitaleX (BD BBL™). Additionally, vancomycin, colistin, nystatin and trimethoprim selective supplement (VCNT) was added to the GC broth in the morbidostat to prevent contamination. GC agar, used for growth on plates, was not supplemented with VCNT. The WHO–F strain is susceptible to azithromycin and ciprofloxacin with minimum inhibitory concentrations (MIC) of 0.125 mg/L and 0.004 mg/L, respectively.12\n\n(i) Morbidostat set–up\n\nTo test the stepping stones hypothesis, N. gonorrhoeae WHO–F strain was subjected to sequential exposure – azithromycin followed by ciprofloxacin and mono exposure – ciprofloxacin, in a morbidostat containing GC broth (GCB) (Figure 1). The optimization and use of the morbidostat for mapping pathways to antimicrobial resistance in N. gonorrhoeae have been described elsewhere.6,13,14 In brief, the morbidostat exposes N. gonorrhoeae to antimicrobial selection pressure by pulses (addition of 1mL of media every 21 minutes) of antimicrobials triggered by the growth of N. gonorrhoeae above a certain turbidity threshold.6,13,14 More details can be found in the Extended data.31\n\n(a) Morbidostat set-up: N. gonorrhoeae WHO-F strain is grown in two different conditions: GCB+CIP (3×), population grown in GC broth without antibiotic for 5 days followed by exposition to ciprofloxacin for 28 days (n=3; vial 4, vial 5, vial 6). AZM+CIP (3×), population grown in GC broth with azithromycin antibiotic for 5 days followed by exposition to 0.5× MIC of ciprofloxacin for 50 days (n=3; vial 1, vial 2, vial 3). The concentration of ciprofloxacin doubles during the 50 days that the experiment is elapsing. Control (1×), population without antibiotic grown in GC broth for 27 days (b) Plates set-up: Isolates (n=2; WT and rplV mutant) from the morbidostat analysis were plated by increasing the concentrations of ciprofloxacin until the MIC reached >32 mg/L or until no visible growth was seen. (GCB: Gonococcal broth; CIP: Ciprofloxacin; GC: Gonococcal; AZM: Azithromycin; MIC: Minimum inhibitory concentration).\n\nIn this experiment, each condition was tested in 3 technical replicates. We refer to these as technical replicates as individual clones from single overnight culture plates were used to seed triplicate experiment culture and the overnight culture plates were used from one glycerol stock. During ciprofloxacin mono–exposure (GCB+CIP –vials 4, 5, 6; n=3), the WHO–F strain was grown in GC broth for five days, followed by pulsed dosing to ciprofloxacin (starting concentration of 0.5× MIC – 0.002 mg/L) that increased the concentration of ciprofloxacin in doubling dilution until the end of the experiment (day 34 – CIP concentration of 64×MIC – 0.256 mg/L). In the dual sequential exposure (AZM+CIP− vials 1, 2, 3; n=3), the WHO–F strain was first exposed to pulses of azithromycin for five days (constant concentration of 4× MIC – 0.125 mg/L), followed by pulses of ciprofloxacin (starting concentration of 0.5× MIC – 0.002 mg/L) which increased concentration in doubling dilution until the experiment ended (day 50 – CIP concentration of 1024×MIC – 4.096 mg/L). Each culture started with 10 μL 4.0 McFarland (McF) bacterial cell suspension in 15 mL GCB. Three replicate lineages were evolved in parallel for each condition. In total, seven morbidostat vials (vial 1 to vial 7) were used, including a control (vial 7) where the WHO–F strain was grown in GCB without antibiotics for the entirety of the experiment. Samples were collected twice a week with a maximum of five days between sampling time points (Figure 1).\n\nThe turbidity in each culture was recorded every 60 seconds on a computer in MATLAB software (The Math Works, Inc. MATLAB, version R2015b, GNU Octave could be used as an open source alternative). The bacterial growth value determined whether the culture would receive GCB (1.1–1.59 McFarland) or antibiotic (≥ 1.6 McFarland) (referred to as pulses) to regulate its growth.6 For GCB+CIP, 1 mL of GC broth was added at either turbidity for the first 5 days. For AZM+CIP, 1 mL of 4× MIC azithromycin–containing GC broth was added for the first 5 days; then, 1 mL of 0.5× MIC ciprofloxacin was added to both conditions. The concentrations of ciprofloxacin in the reservoir varied between 0.5× MIC and 1024× MIC, while the concentration of azithromycin remained unchanged at 4× MIC for the 5 day period of exposure. As the bacteria tolerated higher antimicrobial concentrations over time, ciprofloxacin concentrations of the GC broth were increased stepwise in doubling dilution to regulate growth.6 The experiments were carried out until a single colony reached a MIC value greater than 32 mg/L for ciprofloxacin or until there was no registered growth in the vials or visual growth in the plates (Table 1).\n\nGC (Growth Control) C1 (AZM+CIP); C2 (GCB+CIP). Shaded cells represent the isolates analyzed by WGS. (MIC: Minimum inhibitory concentration; GCB: Gonococcal broth; CIP: Ciprofloxacin; WGS: Whole genome sequencing).\n\n(ii) Assessment of the effect of azithromycin–induced rplV mutant on the genesis of ciprofloxacin resistance via cross–plating\n\nTo evaluate if the transitory insertion/deletion mutation in rplV could accelerate the development of resistance to ciprofloxacin, the isolate from the morbidostat experiment that was exposed to azithromycin and that had acquired only the transitory mutation in the ribosomal gene were used in a cross-plating experiment (Figure 1). WHO–F isolates with and without the ribosomal gene mutation, i.e. rplV–mutant from vial 2 at day 6 (n=1) and rplV–wild type (WT), reference strain (n=1) were exposed to increasing concentrations of ciprofloxacin. Both isolates had the same ciprofloxacin MIC (0.004 mg/L). The above isolates (n=2) were inoculated on GC agar plates (six replicates each) for 24 hours and incubated at 36°C at 6.5% CO2. Subculturing was carried out every day on a GC plate with a starting ciprofloxacin concentration of 0.004 mg/L. Ciprofloxacin concentrations in the plates were increased by doubling concentrations until the final concentration reached 0.032 mg/L (Figure 1, Table 2). MICs were determined using E-tests (BioMerieux).\n\n(mut= mutation; MIC: Minimum inhibitory concentration; CIP: Ciprofloxacin).\n\n* : contamination.\n\n(iii) Does pre-exposure with azithromycin enhance ciprofloxacin resilience in Neisseria gonorrhoeae?\n\nAn algorithm, as explained here13 determined the quantity of ciprofloxacin and GCB to be added to each vial in the morbidostat. If the vials pre-exposed to azithromycin (AZM+CIP) received a higher quantity of ciprofloxacin in the first 12 hours after being eligible to receive ciprofloxacin than the vials that received GCB (GCB+CIP), we concluded that azithromycin exposure had enhanced the resilience to ciprofloxacin.\n\nBacterial suspensions from the morbidostat were sampled from each vial two times a week, resulting in 69 samples (some vials were lost before the end of the experiment due to contamination). The suspensions were plated onto blood agar plates (BD Difco™) and incubated for 24 hours at 36°C and 5% CO2. The cultures were stored in 1 mL of skim milk supplemented with 20% glycerol and stored at –80°C. The azithromycin and ciprofloxacin MIC was determined by E-Test gradient strips (bioMerieux, France), as per manufacturer instructions, from the frozen stock cultures.\n\nGenomic DNA was extracted using the MasterPure Complete DNA and RNA Purification Kit (Epicenter, Madison, Wisconsin, USA), as per manufacters instructions, and eluted in nuclease-free water. DNA was outsourced for whole-genome sequencing (WGS) (GENEWIZ, Germany) and was sequenced on an Illumina instrument using the 150 bp paired-end sequencing chemistry (Illumina, San Diego, California, USA). Analysis was carried out as described in González et al., 2022.15 In brief, the quality of the raw reads was assessed using FASTQC, followed by trimming the reads for quality (Phred ≥20) and length (≥ 32 bases) using trimmomatic (v0.39).16,17 The quality-controlled reads were mapped to the WHO–F reference obtained from GenBank (NZ_LT591897) using BWA MEM, and single nucleotide polymorphisms (SNPs) were determined using freebayes implemented in snippy using default parameters (10× minimum read coverage and 90% read concordance at the variant locus)).18,19 WGS was carried out for three lineages (GCB+CIP – two lineages (vials 5 and 6) and AZM+CIP – one lineage (vial 3), and 18 colonies were isolated for genomic characterization from the population. Colonies that were subjected to WGS are as follows: (1) GCB+CIP – samples collected at 5–time points each from vial 5 (days 8, 11, 22, 29 and 34) and vial 6 (days 6, 11, 20, 29 and 34) (2) AZM+CIP– samples collected from 7–time points from vial 3 (days 2, 6, 8, 24, 27, 29 and 50) (3) Control – two–time points at day 2 and Day 27.\n\nThe effect of sequential azithromycin–ciprofloxacin versus ciprofloxacin monoexposure on the speed to the acquisition of ciprofloxacin resistance was assessed statistically by using linear regression. The outcome variable was ‘days’ from day 6 (the first day when the vials were eligible to receive ciprofloxacin) to the first time a ciprofloxacin MIC of 0.032 mg/L was measured. The exposure variable was a binary categorical variable where conditions 1 and 2 were coded as 1 and 2. A continuous control variable was included, which quantified the milligrams of ciprofloxacin the vial had received until that point. Sensitivity analyses were conducted using time till ciprofloxacin MICs were one dilution lower and higher than the outcome variable. The statistical analyses were performed in STATA MP v.16 (StataCorp).\n\nTo assess for enhanced resilience, we used the Wilcoxon rank-sum test to assess if the number of ciprofloxacin pulses received in the first 12 hours after eligibility for ciprofloxacin was higher in the azithromycin–ciprofloxacin condition (AZM+CIP) than the GCB ciprofloxacin condition (GCB+CIP; in vials with surviving N. gonorrhoeae at this time point). The Wilcoxon rank-sum test was used to assess if there was a difference in the number of days to ciprofloxacin resistance (0.032 mg/L) between the azithromycin–induced rplV mutant and the wild type.\n\n\nResults\n\nThe effect of azithromycin exposure on the acquisition of ciprofloxacin resistance in N. gonorrhoeae was assessed in two different conditions: (i) GCB+CIP– monoexposure ciprofloxacin (vials 4 to 6). (ii) AZM+CIP – sequential exposure; azithromycin for 5 days followed by ciprofloxacin (vials 1 to 3), Figures 1 and 2, Table 1.29\n\nPink boxes provides information about the AZM MIC after 5 days of AZM exposure in vials (Condition 2). The yellow boxes provide information about the CIP MIC in all vials from both conditions. The crossed red circle represents cell death or contamination. X-axis denotes the days and sampling time-points. Y-axis denotes the ciprofloxacin concentration in the reservoir expressed as the multiples of the initial MIC value of CIP. Contaminants isolated on blood agar were presumptively identified by a negative oxidase reaction. (AZM: Azithromycin; MIC: Minimum inhibitory concentration; CIP: Ciprofloxacin).\n\n(i) Ciprofloxacin monoexposure\n\nOut of the three vials from GCB+CIP that were exposed to ciprofloxacin from day 5, cultures from vials 4 and 5 survived for 34 days. In contrast, the cultures from vial 6 died 2.6 hours after receiving the first pulse of ciprofloxacin (Figure 2). Cultures from vial 4 reached 47.5× MIC (0.19 mg/L) and tolerated an average of 0.75× MIC (0.003 mg/L) of ciprofloxacin after 119 pulses ciprofloxacin. The cultures from vial 5 reached > 8000–fold MIC (>32 mg/L) and tolerated an average of 15.9× MIC (0.064 mg/L) of ciprofloxacin after 184 (1402) ciprofloxacin pulses.\n\n(ii) Sequential azithromycin–ciprofloxacin exposure\n\nBy day 5, the azithromycin MICs were as follows: vial 1 – ~31× MIC (0.125 mg/L, 17 azithromycin pulses), vial 2 – ~250× MIC (1 mg/L, 63 pulses) and vial 3 – ~ 24× MIC (0.094 mg/L, 82 pulses). Subsequently, cultures from vials 1 and 3 received 343 and 563 pulses of ciprofloxacin for a total of 29 and 27 days, increasing the MIC by 8–fold (0.032 mg/L) and 6–fold (0.023 mg/L), respectively, before cell death. Cultures from vial 1 and vial 3 tolerated 3.1× MIC (0.012 mg/L) and 5.25× MIC (0.021 mg/L) of ciprofloxacin, respectively. In contrast, the cultures from vial 2 reached a 500–fold higher MIC (2 mg/L), survived for 50 days and tolerated an average of 170.6× MIC (0.6825 mg/L) of ciprofloxacin after 2280 pulses of ciprofloxacin (Figure 2).\n\nSequential azithromycin–ciprofloxacin did not accelerate the acquisition of ciprofloxacin resistance (coef. –1.6 days, 95% CI –48.0 to 44.7; Table 3). The same was true in sensitivity analyses using the time to a MIC of 0.023 or 0.064 mg/L (data not shown). Moreover, the three vials from AZM+CIP were exposed to a higher number of pulses of ciprofloxacin in the first 12 hours of ciprofloxacin exposure (median 3; IQR 1–8; Figure 2) than the vials from GCB+CIP (median 12; IQR 9–33; P–0.049 [Wilcoxon rank–sum test]).\n\n(AZM: Azithromycin; GCB: Gonococcal broth; CIP: Ciprofloxacin; MIC: Minimum inhibitory concentration).\n\nThe three vials from AZM+CIP were exposed to a higher number of pulses of ciprofloxacin in the first 12 hours of ciprofloxacin exposure (median 3; IQR 1–8; Figure 2) than the vials from GCB+CIP (median 12; IQR 9–33; P–0.049 [Wilcoxon rank-sum test]).\n\nOut of the three lineages exposed to GCB+CIP, one of the lineages (vial 6) died after being exposed to 8 pulses (2.6 hours) of ciprofloxacin, and another lineage (vial 5) took more than 48 hours to exhibit detectable growth after receiving the first pulse of ciprofloxacin (Figure 2). The third lineage (vial 4) received 3 pulses of ciprofloxacin in the first hour. However, its growth was diminished and still detectable but not sufficient to trigger further pulses of ciprofloxacin for the following 19 days. In contrast, despite being exposed to a high level of ciprofloxacin in the first 12 hours, the lineages exposed to AZM+CIP recovered sufficiently to trigger a second round of ciprofloxacin pulses after 0, 3 and 6 days for vials 2, 3 and 1, respectively. One of these lineages (vial 2) was exposed to high ciprofloxacin than any other lineage and tolerated the highest concentration of ciprofloxacin (170.62× MIC), and survived for the longest time (50 days).\n\nIn total, ten clones from two lineages (vial 4 and vial 5) from GCB+CIP and seven clones from one lineage (vial 3) from AZM+CIP were subjected to WGS.28 The following mutations and distribution of the concentrations were observed.\n\n(i) GCB+CIP: Gene mutations were observed in gyrA, nqrB, parC and porB in one or both lineages. All the resistant (MIC >0.06 mg/L) clones carried the GyrA–S91F and/or GyrA–D95N substitutions that cause ciprofloxacin resistance. Substitutions in GyrA–D95N were acquired early on (at day 11, MIC 0.032 and 0.094 mg/L in Vial 4 and Vial 5, respectively) and remained present until the end of the experiment. While the GyrA–S91F substitution was present in one lineage (vial 5 –day 29, MIC–0.094 mg/L). The GyrA–D95N substitution was observed in 10 clones from two lineages (vial 4 – days 8, 11, 22 29, 34 with MIC 0.002, 0.032, 0.064, 0.047 and 0.19 mg/L, respectively and vial 5 – days 6, 11, 20, 29 and 34 with MIC 0.002, 0.094, 0.032, 0.094 and > 32 mg/L, respectively). This vial did not get any ciprofloxacin in the following days whilst the ciprofloxacin concentration in the reservoir doubled. Substitution in ParC–E91K, also known to cause ciprofloxacin resistance, was observed in a clone in one of the lineages (vial –6, day 29, MIC–0.094 mg/L), Figure 3C. Whereas frameshift (fs) mutation at nqrB that encodes the Na(+)–translocating NADH–quinone reductase subunit B was identified in two clones (vial 4 – days 11 and 29 with a MIC of 0.032 and 0.047 mg/L) in another lineage, Figure 3B. Frameshift duplication (dup) in NqrB-A29fs (82_83dupGA) was always accompanied by substitution in GyrA–D95N. Lastly, two clones acquired porB mutations in both the lineages. This involved a frameshift caused by a deletion (del), PorB–G120_F122del (358_366delGGCGGCTTC) (vial 4, day 34, MIC–0.19 mg/L), PorB–T119_F122del (356_367delCCGGCGGCTTCA) (vial 5, day 34, MIC >32 mg/L). In both lineages, the mutation in porB was accompanied by a mutation in gyrA (GyrA–D95N). A pulse of 0.5× MIC lowered cell growth in vial 5 to a no–visible growth state for the following two days. After this time, it recovered its optimum growth rate, and it got exposed to 23.3 hours (70 pulses) of 0.5× MIC, leading to a MIC of 0.094 mg/L and the emergence of GyrA–D95N mutation.\n\nVial 6 (GCB+CIP) is not depicted because the colonies did not survive past day 6 - after first exposure to CIP. The red markers show at which days samples were taken and the colored lines represent the MIC threshold for azithromycin (orange: 1mg/L) and ciprofloxacin (blue: 0.064 mg/L). In Figure 2 (B), (C) and (E), the mutations found in the samples subjected to WGS (red squares) were presented above the graph with the specifics of the mutation. The blue diamond in Figure 2 (C) represents the inability to sample due to the extremely low growth rates. (MIC: Minimum inhibitory concentration; GCB: Gonococcal broth; CIP: Ciprofloxacin; GC: Gonococcal; WGS: Whole genome sequencing).\n\n(ii) AZM+CIP: Gene mutations were observed in gyrA, mshA, nqrB, parC and porB (Figure 3E). A duplication emerged in L22 protein encoded by rplV gene, L22–A87K90dup (260_271dupCTCGCGCCAAAG) on day 6 close to the mutations previously noted to act as stepping stones to resistance: rplV – I96del, G91A, +RAKG92– 95, F85S and NRIE94– 97del6 and lasted until day 32 (MIC– 0.002 to 0.125 mg/L). This isolate was used in the cross-plating experiment. Substitution in L22 was present along with substitutions in GyrA–S91F (day 8, MIC –0.064 mg/L), GyrA–D95N (day 14, MIC– 0.023 mg/L), MshA–A214 fs (639dupC) (day 32, MIC–0.125 mg/L), ParC–L306dup (916_918dupCTG) (day 50, MIC 2 mg/L), PorB–Y130insCY (386_391dupGCTACT (day 32, MIC 0.125 mg/L) and PiiC–N212Y fs (634_636delAACinsTAT) (day 50, MIC–2 mg/L).\n\nThe list of all the mutations detected is provided in Figure 4, and further details on the hypothetical proteins are provided in the Extended data.30\n\n(*) refers to a stop codon.\n\nSix replicates of both the WHO–F WT and WHO–F rplV mutant were exposed to increasing concentrations of ciprofloxacin. Of these, one WT colony on day 4 and one rplV mutant on day 3 were lost due to contamination. There was no difference in the final number of days (10 days each) needed to reach 8x MIC (0.032 mg/L) between WHO–F rplV–WT and WHO–F rplV mutant (P–1.0; Table 2).\n\nThe genome from the control population (n=1, vial 7, day 2) grown in GC broth was compared to the published reference genome (NZ_LT591897). Two mutations were identified and are as follows: frameshift deletion in two hypothetical proteins, WHOF_00530 – Ala31fs (90delC) and WHOF_00643 – Ser166fs (497_500delGCCA) (Figure 3A). These mutations were not detected in any other vial.\n\n\nDiscussion\n\nWe found that pre-exposure to azithromycin did not have any appreciable effect on the speed of emergence of resistance to ciprofloxacin in N. gonorrhoeae.\n\nThese results do not support the concern that the slow decline in concentration of azithromycin in vivo (over up to 4 weeks after treatment administration) may accelerate the acquisition of resistance to other antimicrobials.4,20 There are however a number of important caveats to this conclusion. We only investigated the effect of a single antimicrobial (azithromycin) on the speed of acquisition of resistance to a single other antimicrobial (ciprofloxacin). Furthermore, this was done in only one strain of N. gonorrhoeae. We and others have previously found strain specific differences between gonococcal strains in the molecular pathways to ciprofloxacin resistance as well speed at which the resistance emerges.15 Our experiment was further limited by the relatively small number of replicates for each condition. There were also differences in the ciprofloxacin exposures between vials. These differences stem from stochastic differences in gonococcal growth between vials. Whilst we controlled for these differences in our analyses, we cannot exclude the possibility that a degree of residual confounding remained.\n\nAn additional limitation of the morbidostat is that some vials were lost during the experiment due to contamination likely during sample collection. This problem has been noted in previous gonococcal experiments using the morbidostat.6 Furthermore, there may be pheno- and genotypic differences between the population of N. gonorrhoeae within a vial and a single clone taken from this population. Our results based on the single clones may thus not be reflective of the population as a whole.\n\nOur findings suggest that azithromycin exposure enhances the resilience of N. gonorrhoeae to subsequent ciprofloxacin exposure. Lineages first exposed to azithromycin were exposed to a higher number of pulses of ciprofloxacin in the first 12 hours of ciprofloxacin exposure than lineages first exposed to GC broth. Despite this higher exposure, none of the azithromycin pre-exposure lineages versus one of the GC broth pre-exposure lineages died after the first 12 hours of ciprofloxacin exposure (vial 6 after 8 pulses; Figure 2). In a similar vein, none of the azithromycin pre-exposure lineages versus one of the GC broth exposure lineages exhibited absence of growth after the first round of ciprofloxacin exposure. Whilst we cannot draw any firm conclusions from such small sample sizes, this pre-exposure effect may explain the findings of an ecological level study from Europe that found that national consumption levels of macrolides were positively associated with the time-lagged prevalence of gonococcal ciprofloxacin resistance.21 These findings are also commensurate with evidence from a case control study of methicillin resistant Staphylococcus aureus (MRSA) infections, where exposure to macrolides in the past year tripled the risk of MRSA infection.8 The possible mechanisms for this priming effect are unknown but may include the induction of bacterial tolerance.22–24\n\nIn a previous study, we found gonococcal strain–specific variations in the molecular pathway to ciprofloxacin resistance. WHO–P followed the canonical pathway to resistance proceeding via substitutions in GyrA–S91F, then GyrA–D95N and ParC. By contrast, WHO–F was more likely first to acquire the GyrA–D95N substitution. The GyrA–S91F pathway was associated with more rapid acquisition of ciprofloxacin resistance.15 In the current study, both surviving lineages exposed to GC broth then ciprofloxacin, first acquired the GyrA–D95N substitution. In contrast, the lineage exposed to azithromycin followed by ciprofloxacin proceeded to ciprofloxacin resistance via the canonical GyrA–S91F pathway. Once again, the small number of isolates included in these experiments precludes making firm conclusions.\n\n\nConclusions\n\nBystander selection has been shown to play an important role in the genesis of AMR, including gonococcal AMR.21,25 This is likely true for antimicrobials such as azithromycin with a long intracellular half–life. We found that gonococcal pre–exposure to azithromycin enhances resilience to subsequent ciprofloxacin exposure. Further research is required to confirm this effect and more systematically evaluate the effects of different combinations of antimicrobials in a greater range of bacterial species.26,27",
"appendix": "Data availability\n\nBioProject: WGS sequences. Accession number PRJNA837546, https://identifiers.org/NCBI/bioproject:PRJNA837546. 28\n\nFigshare: Morbidostat Raw data. https://doi.org/10.6084/m9.figshare.21357639. 29\n\nFigshare: Supplementary document 1. https://doi.org/10.6084/m9.figshare.21357630. 30\n\nFigshare: Morbidostat and plates set-up protocol. https://doi.org/10.6084/m9.figshare.21357645. 31\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\nUnemo M, Workowski K: Dual antimicrobial therapy for gonorrhoea: what is the role of azithromycin? Lancet Infect. Dis. 2018; 18: 486–488. PubMed Abstract | Publisher Full Text\n\nKenyon C: Dual Azithromycin/Ceftriaxone Therapy for Gonorrhea in PrEP Cohorts Results in Levels of Macrolide Consumption That Exceed Resistance Thresholds by up to 7-Fold. J. Infect. Dis. 2021; 224: 1623–1624. 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PubMed Abstract | Publisher Full Text\n\nKong FYS, Horner P, Unemo M, et al.: Pharmacokinetic considerations regarding the treatment of bacterial sexually transmitted infections with azithromycin: a review. J. Antimicrob. Chemother. 2019; 74: 1157–1166. PubMed Abstract | Publisher Full Text\n\nUnemo M, Golparian D, Sánchez-Busó L, et al.: The novel 2016 WHO Neisseria gonorrhoeae reference strains for global quality assurance of laboratory investigations: Phenotypic, genetic and reference genome characterization. J. Antimicrob. Chemother. 2016; 71: 3096–3108. PubMed Abstract | Publisher Full Text\n\nVerhoeven E, Abdellati S, Nys P, et al.: Construction and optimization of a ‘NG Morbidostat’ - An automated continuous-culture device for studying the pathways towards antibiotic resistance in Neisseria gonorrhoeae [version 1; peer review: 2 approved with reservations]. F1000Research. 2019; 8: 1–16. Publisher Full Text\n\nToprak E, Veres A, Yildiz S, et al.: Building a morbidostat: An automated continuous-culture device for studying bacterial drug resistance under dynamically sustained drug inhibition. Nat. Protoc. 2013; 8: 555–567. Publisher Full Text\n\nGonzález N, Abdellati S, De Baetselier I, et al.: Alternative Pathways to Ciprofloxacin Resistance in Neisseria gonorrhoeae: An in vitro Study of the WHO-P and WHO-F Reference Strains. Antibiotics. 2022; 11: 499. PubMed Abstract | Publisher Full Text\n\nAndrews S: FastQC. Babraham Bioinforma.2010.Reference Source\n\nBolger AM, Lohse M, Usadel B: Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30: 2114–2120. PubMed Abstract | Publisher Full Text\n\nSeemann T: Snippy-Rapid haploid variant calling and core genome alignment.2020.\n\nLi H, Durbin R: Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25: 1754–1760. PubMed Abstract | Publisher Full Text\n\nKenyon C, Laumen J, Manoharan-Basil S: Choosing new therapies for gonorrhoea: We need to consider the impact on the pan-neisseria genome. a viewpoint. Antibiotics. 2021; 10. PubMed Abstract | Publisher Full Text\n\nKenyon C, Buyze J, Spiteri G, et al.: Population-Level Antimicrobial Consumption Is Associated With Decreased Antimicrobial Susceptibility in Neisseria gonorrhoeae in 24 European Countries: An Ecological Analysis. J. Infect. Dis. 2020; 221: 1107–1116. Publisher Full Text\n\nLevin-Reisman I, Ronin I, Gefen O, et al.: Antibiotic tolerance facilitates the evolution of resistance. Science (80-). 2017; 355: 826–830. PubMed Abstract | Publisher Full Text\n\nWindels EM, Michiels JE, van den Bergh B , et al.: Antibiotics: Combatting tolerance to stop resistance. MBio. 2019; 10. PubMed Abstract | Publisher Full Text\n\nKim J, Jo A, Chukeatirote E, et al.: Assessment of antibiotic resistance in Klebsiella pneumoniae exposed to sequential in vitro antibiotic treatments. Ann. Clin. Microbiol. Antimicrob. 2016; 15: 60–67. PubMed Abstract | Publisher Full Text\n\nTedijanto C, Olesen SW, Grad YH, et al.: Estimating the proportion of bystander selection for antibiotic resistance among potentially pathogenic bacterial flora. Proc. Natl. Acad. Sci. U. S. A. 2018; 115: E11988–E11995. PubMed Abstract | Publisher Full Text\n\nMutations DAS, Szili P, Draskovits G, et al.: crossm Rapid Evolution of Reduced Susceptibility against a Balanced.2019; 63: 1–15\n\nKenyon C: Population level consumption of cephalosporins and macrolides may select for reduced antimicrobial susceptibility to unrelated antimicrobials in Neisseria gonorrhoeae: an ecological analysis.medRxiv 2020.07.08.20148957.2020. Publisher Full Text\n\nInstitute of Tropical Medicine:Ribosomal mutations and evolution of CIP resistance in Neisseria gonorrhoeae in a Morbidostat set-up. [Dataset]. BioProject. 2022.Reference Source\n\nGonzález N:Morbidostat Raw Data. figshare. [Dataset].2022. Publisher Full Text\n\nGonzález N: Supplementary document 1.docx. figshare. Journal Contribution. 2022. Publisher Full Text\n\nGonzález N: Morbidostat and plates set-up protocol. figshare. Journal Contribution. 2022. Publisher Full Text"
}
|
[
{
"id": "157947",
"date": "15 Dec 2022",
"name": "Fabian Yuh Shiong Kong",
"expertise": [
"Reviewer Expertise Infectious disease epidemiology with a focus on Neisseria gonorrhoea antimicrobial resistance"
],
"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 novel and interesting study to understand if prior exposure of NG to azithromycin can affect the treatment outcomes of another treatment given shortly after it e.g. within 30 days of giving azithromycin. These concerns have been raised in the literature as azithromycin has a very long half-life, and it can be detected in the body for up to 28 days after dosing. Re-exposure to NG while there might be low (sub-MIC) levels of azithromycin still in the body has the potential to put selective pressure on NG and results in NG resistance. Previous studies have shown recent azithromycin use (past month) was associated with latter NG AMR.1\nThis small study (with its reported, important caveats) found, while there was no acquisition of AMR among one susceptible NG strain treated with ciprofloxacin after exposing it to azithromycin, it did find NG was able to tolerate higher concentrations of ciprofloxacin. This could have important implications if ciprofloxacin was given as treatment within a recent exposure to azithromycin – but this is unlikely to be seen in practice for NG infections since the first line treatment for NG is ceftriaxone 0.5-1g, with ciprofloxacin only given if NG is known to be susceptible, given its high background resistance.\nMy only comment is in relation to the exposure MICs used for azithromycin. The highest MIC exposure was 2mg/mL. Azithromycin concentrations at various tissue/infection sites are an important factor for cure at non-genital sites, especially in the oropharynx where we see greatest treatment failure to NG compared to other infection sites (genital and rectal). Concentrations of azithromycin can reach up to 8mcg/g at the tonsils following a 500mg dose – the site which is more likely to generate NG AMR from horizontal gene transfer but lower azithromycin levels are seen in uterine/cervical tissue and mucus (1.4-2.8 mcg/g). Rectal concentrations are higher even still after a 1g dose (133mcg/g).2\nTherefore, your results may be more applicable to infections at female reproductive tissue but perhaps not for the oral or rectal site where higher azithromycin concentrations are reported? While there is no need to comment formally in the paper, I wonder if you can comment on if higher concentrations had been used in your experiments, whether this would have made any difference to the results as it may apply to oropharyngeal treatments? Otherwise, no further comments and the findings are interesting given the caveats.\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": [
{
"c_id": "9197",
"date": "27 Jan 2023",
"name": "Natalia González",
"role": "Author Response",
"response": "We thank the reviewer for their interest, time and valuable advice. We have attempted to reply to the best of our ability to their comment. These are detailed in bold font as follows: This is a novel and interesting study to understand if prior exposure of NG to azithromycin can affect the treatment outcomes of another treatment given shortly after it e.g. within 30 days of giving azithromycin. These concerns have been raised in the literature as azithromycin has a very long half-life, and it can be detected in the body for up to 28 days after dosing. Re-exposure to NG while there might be low (sub-MIC) levels of azithromycin still in the body has the potential to put selective pressure on NG and results in NG resistance. Previous studies have shown recent azithromycin use (past month) was associated with latter NG AMR.1 This small study (with its reported, important caveats) found, while there was no acquisition of AMR among one susceptible NG strain treated with ciprofloxacin after exposing it to azithromycin, it did find NG was able to tolerate higher concentrations of ciprofloxacin. This could have important implications if ciprofloxacin was given as treatment within a recent exposure to azithromycin – but this is unlikely to be seen in practice for NG infections since the first line treatment for NG is ceftriaxone 0.5-1g, with ciprofloxacin only given if NG is known to be susceptible, given its high background resistance. My only comment is in relation to the exposure MICs used for azithromycin. The highest MIC exposure was 2mg/mL. Azithromycin concentrations at various tissue/infection sites are an important factor for cure at non-genital sites, especially in the oropharynx where we see greatest treatment failure to NG compared to other infection sites (genital and rectal). Concentrations of azithromycin can reach up to 8mcg/g at the tonsils following a 500mg dose – the site which is more likely to generate NG AMR from horizontal gene transfer but lower azithromycin levels are seen in uterine/cervical tissue and mucus (1.4-2.8 mcg/g). Rectal concentrations are higher even still after a 1g dose (133mcg/g).2 Therefore, your results may be more applicable to infections at female reproductive tissue but perhaps not for the oral or rectal site where higher azithromycin concentrations are reported? While there is no need to comment formally in the paper, I wonder if you can comment on if higher concentrations had been used in your experiments, whether this would have made any difference to the results as it may apply to oropharyngeal treatments? Otherwise, no further comments and the findings are interesting given the caveats. Many thanks for these interesting reflections and suggestions. We have added the following text to the discussion to acknowledge the importance of including these suggestions in future research: L388-406 Future research Due to the low number of replicates of a single strain of N. gonorrhoeae used in this experiment, we plan to repeat this experiment with other gonococcal strains and a higher number of duplicates. Moreover, we would like to test if macrolide pre-exposure enhances resilience to other antibiotics, such as ceftriaxone. We would also like to test the effect of various doses of azithromycin pre-exposure. The highest azithromycin dose we used was 2mg/L, but concentrations of azithromycin range between 1.4 and 133 μg/g in the body sites colonized by N. gonorrhoeae following standard doses of azithromycin [1]. It would be useful to test these physiological concentrations of azithromycin in future studies. In other experiments, including some in the morbidostat, we and others have found that it is both harder to induce gonococcal AMR to ceftriaxone, and the resistance associated mutations do not mimic those found in vivo. Gonococcal resistance to extended spectrum cephalosporins (ESCs) in circulating isolates typically occurs (amongst other mechanisms) via the acquisition of mutations in penA, typically in a stepwise fashion and frequently via horizontal gene transfer (HGT) from commensal Neisseria [2–5]. This type of HGT is very difficult to reproduce in our study’s in vitro experimental set-up. A previous study that attempted to induce CRO resistance in N. gonorrhoeae via a similar passaging strategy found that they could only induce resistance in one of six different strains used[5]. - - - - - - New references Kong FYS, Rupasinghe TW, Simpson JA, et al. (2017) Pharmacokinetics of a single 1g dose of azithromycin in rectal tissue in men. PLOS One 12(3): e0174372. Publisher Full Text Kueakulpattana N, Wannigama DL, Luk-In S, et al. (2021) Multidrug-resistant Neisseria gonorrhoeae infection in heterosexual men with reduced susceptibility to ceftriaxone, first report in Thailand. Sci Rep 11, 21659. Publisher Full Text Vincent LR, Kerr SR, Tan Y, et al. (2018) In Vivo-Selected Compensatory Mutations Restore the Fitness Cost of Mosaic penA Alleles That Confer Ceftriaxone Resistance in Neisseria gonorrhoeae. MBio 9. Publisher Full Text Laumen JGE, Manoharan-Basil SS, Verhoeven E, et al. (2021) Molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae. J Antimicrob Chemother 32, 7. Publisher Full Text Gong Z, Lai W, Liu M, et al. (2016) Novel Genes Related to Ceftriaxone Resistance Found among Ceftriaxone-Resistant Neisseria gonorrhoeae Strains Selected In Vitro. Antimicrob Agents Chemother 60:2043–2051. Publisher Full Text"
}
]
},
{
"id": "157951",
"date": "20 Dec 2022",
"name": "Crista B. Wadsworth",
"expertise": [
"Reviewer Expertise Evolution",
"genomics",
"antibiotic resistance",
"Neisseria"
],
"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 by González et al. seeks to test the impact of azithromycin pre-exposure on the rate and pathways by which ciprofloxacin resistance is acquired in Neisseria gonorrhoeae. This work is an interesting contribution to the field of Neisseria AMR as the long half-life of azithromycin, and decreased bioavailability at some sites of infection (pharynx), could lead to the potential for sub-lethal concentrations of azithromycin to drive the accumulation of resistance mutations in vivo. Here, the authors use a morbidostat to evolve both mono-exposed (ciprofloxacin only) vs. dual sequential exposed (azithromycin + ciprofloxacin) cell lines; and subsequently use WGS to characterize derived mutations. Below are a few comments for the authors to consider:\nWhat was the rationale for the authors choosing only one strain of N. gonorrhoeae (the WHO-F strain) to evolve? The authors acknowledge in text that the results of their experiment may have been different if they had started with other strains (i.e., genomic composition will impact evolutionary outcome due to additivity and epistasis); however, if there is a reason for choosing this strain in particular, it would be beneficial to describe in text.\n\nIt would be beneficial for the reader if the authors described their rationale for investigating azithromycin pre-exposure on ciprofloxacin resistance, rather than resistance to any of the other anti-gonococcal antibiotics. For example, why not ceftriaxone as this is the current recommended treatment for uncomplicated cases of gonorrhea? Do the authors expect mutations involved in azithromycin resistance to give cross-resistance to ciprofloxacin? If so, please describe which mutations they expect to confer cross-resistance in the introduction.\n\nThe number of experimental replicates is low. This is acknowledged in text, but makes it hard to make generalizations about the paths/speed of resistance acquisition in gonococci at large. Are there any plans to increase the number of replicates? If so, this may be worth acknowledging in the discussion in a sentence or two as a future direction.\n\nWhy were variable time periods selected for experimental evolution for the different treatment conditions? For example, the ciprofloxacin monotherapy group (5 days pre-exposure, 28 days exposure), the azithromycin + ciprofloxacin group (5 days azi, 50 days cip), and the control population (no antibiotic 27 days). I wonder if the extended selection experienced by the azithromycin + ciprofloxacin group may have impacted the derived mutations uncovered and, if the authors disagree, it would be helpful to indicate why in text.\n\nFor whole genome sequencing, why were particular strains and days chosen, and why are they variable in the day sampled across conditions (see Table 1)?\n\nIn Table 1, what do the “X”s indicate? Please provide a footnote.\n\nThe authors cite their previously published morbidostat methods paper on multiple occasions to describe the mechanics behind the machine, however I think that additional details should be provided here for clarity. The decision framework for addition of drug or GCB during evolution must be further described in this paper as it is a major component of the selective pressures exerted on Ngo populations throughout the experiment, and different concentrations of drug or time periods between pulses may impact evolutionary outcome. For example, adding the OD value which triggers a pulse of drug may be useful.\nRelated minor comment: Abstract: How did the MATLAB program decide to add GCB or antibiotics to the cultures? Please add the parameters here or save this point for the Methods section.\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": "9198",
"date": "27 Jan 2023",
"name": "Natalia González",
"role": "Author Response",
"response": "We thank the reviewer for their interest, time and valuable advice. We have attempted to address all their valid concerns to the best of our ability. These are detailed in bold font as follows: The report by González et al. seeks to test the impact of azithromycin pre-exposure on the rate and pathways by which ciprofloxacin resistance is acquired in Neisseria gonorrhoeae. This work is an interesting contribution to the field of Neisseria AMR as the long half-life of azithromycin, and decreased bioavailability at some sites of infection (pharynx), could lead to the potential for sub-lethal concentrations of azithromycin to drive the accumulation of resistance mutations in vivo. Here, the authors use a morbidostat to evolve both mono-exposed (ciprofloxacin only) vs. dual sequential exposed (azithromycin + ciprofloxacin) cell lines; and subsequently use WGS to characterize derived mutations. Below are a few comments for the authors to consider: What was the rationale for the authors choosing only one strain of N. gonorrhoeae (the WHO-F strain) to evolve? The authors acknowledge in text that the results of their experiment may have been different if they had started with other strains (i.e., genomic composition will impact evolutionary outcome due to additivity and epistasis); however, if there is a reason for choosing this strain in particular, it would be beneficial to describe in text. We thank the reviewer for this comment. The reasons for choosing the WHO-F strain have been added to main text as follows: L: 39-42. The strain chosen for this experiment was N. gonorrhoeae WHO–F, which has been widely used in comparable experiments. In particular, the effects of fluoroquinolone and macrolide exposure in-vitro (including in the NGmorbidostat) have been evaluated in detail. Being a WHO-reference strain also makes this experiment easy to replicate and get comparable data between laboratories. Finally compared to other reference strains, this strain is susceptible to both of the antibiotics tested. [1] It would be beneficial for the reader if the authors described their rationale for investigating azithromycin pre-exposure on ciprofloxacin resistance, rather than resistance to any of the other anti-gonococcal antibiotics. For example, why not ceftriaxone as this is the current recommended treatment for uncomplicated cases of gonorrhea? Do the authors expect mutations involved in azithromycin resistance to give cross-resistance to ciprofloxacin? If so, please describe which mutations they expect to confer cross-resistance in the introduction. We thank the reviewer for this opportunity to explain this concept better: See answer below. The number of experimental replicates is low. This is acknowledged in text, but makes it hard to make generalizations about the paths/speed of resistance acquisition in gonococci at large. Are there any plans to increase the number of replicates? If so, this may be worth acknowledging in the discussion in a sentence or two as a future direction. As suggested by the reviewer, a proper explanation of these two questions has been added to the discussion: L388-406 Future research Due to the low number of replicates of a single strain of N. gonorrhoeae used in this experiment, we plan to repeat this experiment with other gonococcal strains and a higher number of duplicates. Moreover, we would like to test if macrolide pre-exposure enhances resilience to other antibiotics, such as ceftriaxone. We would also like to test the effect of various doses of azithromycin pre-exposure. The highest azithromycin dose we used was 2mg/L, but concentrations of azithromycin range between 1.4 and 133 μg/g in the body sites colonized by N. gonorrhoeae following standard doses of azithromycin [1]. It would be useful to test these physiological concentrations of azithromycin in future studies. In other experiments, including some in the morbidostat, we and others have found that it is both harder to induce gonococcal AMR to ceftriaxone, and the resistance associated mutations do not mimic those found in vivo. Gonococcal resistance to extended spectrum cephalosporins (ESCs) in circulating isolates typically occurs (amongst other mechanisms) via the acquisition of mutations in penA, typically in a stepwise fashion and frequently via horizontal gene transfer (HGT) from commensal Neisseria [2–5]. This type of HGT is very difficult to reproduce in our study’s in vitro experimental set-up. A previous study that attempted to induce CRO resistance in N. gonorrhoeae via a similar passaging strategy found that they could only induce resistance in one of six different strains used[5]. Why were variable time periods selected for experimental evolution for the different treatment conditions? For example, the ciprofloxacin monotherapy group (5 days pre-exposure, 28 days exposure), the azithromycin + ciprofloxacin group (5 days azi, 50 days cip), and the control population (no antibiotic 27 days). I wonder if the extended selection experienced by the azithromycin + ciprofloxacin group may have impacted the derived mutations uncovered and, if the authors disagree, it would be helpful to indicate why in text. We thank the reviewer for the opportunity to clarify this misunderstanding. The time difference between each group is due to differences in the timing of the emergence of contamination or the time taken for ciprofloxacin resistance to emerge. All experiments were conducted until a ciprofloxacin MIC of 32 mg/L was attained or there was bacterial death. This is reflected in the main text: L68-70: The experiment continued until a ciprofloxacin MIC of 32 mg/L was attained or there was a loss of gonococcal culture viability. For whole genome sequencing, why were particular strains and days chosen, and why are they variable in the day sampled across conditions (see Table 1)? We thank the reviewer for this comment. Strains were chosen for WGS if they showed an increase in ciprofloxacin MIC. The timing of the sampling was directed to sampling each time point when the MIC increased or decreased as well as intervening time points if the time period between WGS samples was long. In Table 1, what do the “X”s indicate? Please provide a footnote. This information (loss of gonococcal culture viability) has been added to Table 1. The authors cite their previously published morbidostat methods paper on multiple occasions to describe the mechanics behind the machine, however I think that additional details should be provided here for clarity. The decision framework for addition of drug or GCB during evolution must be further described in this paper as it is a major component of the selective pressures exerted on Ngo populations throughout the experiment, and different concentrations of drug or time periods between pulses may impact evolutionary outcome. For example, adding the OD value which triggers a pulse of drug may be useful. Thanks to the reviewer’s comment, we replaced the texts in lines 71-74 with the following texts (Lines 62-71) for more detailed explanations: In brief, from 4.0 McF suspension of N. gonorrhoeae WHO-F suspended in 12 mL GC Broth supplemented with 1% IsoVitaleX (BD BBL™), 10 µl of the inoculum was added to each of the morbidostat culture vial. All culture vials were autoclaved at 121°C for 20 minutes before use. N. gonorrhoeae grew in the morbidostat in cycles of 21 minutes and after each cycle, depending on turbidity measurements and growth rate, an algorithm in the software diluted the suspension with 1 mL fresh medium or with 1 mL fresh medium containing antibiotics. The threshold was set at 1.3 McF for the addition of fresh medium, to allow N. gonorrhoeae to adapt to the environment without being diluted. Fresh medium with antibiotic was injected when a threshold of 2.0 McF was exceeded and the net growth was positive, otherwise, fresh medium was injected. Related minor comment: Abstract: How did the MATLAB program decide to add GCB or antibiotics to the cultures? Please add the parameters here or save this point for the Methods section. This has been modified as follows, “The growth of the cultures was monitored, and gonococcal broth or antibiotics were added to the vials based on the turbidity threshold in order to keep the evolution of the cultures”."
}
]
}
] | 1
|
https://f1000research.com/articles/11-1464
|
https://f1000research.com/articles/12-101/v1
|
27 Jan 23
|
{
"type": "Review",
"title": "Do macrophages follow the beat of circadian rhythm in TIME (Tumor Immune Microenvironment)?",
"authors": [
"Amelia M. Knudsen-Clark",
"Juliana Cazarin",
"Brian J. Altman",
"Amelia M. Knudsen-Clark",
"Juliana Cazarin"
],
"abstract": "Advances in cancer research have made clear the critical role of the immune response in clearing tumors. This breakthrough in scientific understanding was heralded by the success of immune checkpoint blockade (ICB) therapies such as anti-programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), as well as the success of chimeric antigen receptor (CAR) T cells in treating liquid tumors. Thus, much effort has been made to further understand the role of the immune response in tumor progression, and how we may target it to treat cancer. Macrophages are a component of the tumor immune microenvironment (TIME) that can promote tumor growth both indirectly, by suppressing T cell responses necessary for tumor killing, as well as directly, through deposition of extracellular matrix and promotion of angiogenesis. Thus, understanding regulation of macrophages within the tumor microenvironment (TME) is key to targeting them for immunotherapy. However, circadian rhythms (24-hour cycles) are a fundamental aspect of macrophage biology that have yet to be investigated for their role in macrophage-mediated suppression of the anti-tumor immune response Circadian rhythms regulate macrophage-mediated immune responses through time-of-day-dependent regulation of macrophage function. A better understanding of the circadian biology of macrophages in the context of the TME may allow us to exploit synergy between existing and upcoming treatments and circadian regulation of immunity.",
"keywords": [
"Circadian",
"immunity",
"tumor immunology",
"cancer"
],
"content": "Introduction\n\nIn this review, we discuss circadian regulation of macrophages, how this may contribute to their function in the tumor, and how we can leverage this in the clinic. We will investigate the current literature linking circadian rhythms to the anti-tumor immune response, focusing on macrophages, whose circadian regulation and role in tumor progression have been well-characterized. We will detail how circadian regulation of macrophages may contribute to the anti-tumor immune response, and how the tumor microenvironment (TME) may impact circadian regulation of tumor-associated macrophages. Finally, we will address how circadian immunity may be leveraged to increase efficacy of currently available treatments in the clinic, highlighting recent studies implementing this approach.1,2 As we are examining the intersection and application of these two fields, we do not provide a comprehensive review of either; both fields have been thoroughly and elegantly reviewed elsewhere.3–5\n\n\nDysregulation of the immune response occurs in cancer, allowing tumor growth\n\nTumorigenesis originates with cancer cell-intrinsic factors, yet inflammation and a dysregulated immune response lie at the heart of almost all cancers.6,7 Tumor growth is associated with the release of immunogenic damage-associated molecular patterns (DAMPs), due to cell stress as a result of mutations and DNA damage, which cause rapid growth and division of cancer cells. In addition, many of the oncogenic mutations acquired by cancer cells promote inflammation through cytokine secretion, which leads to an immune response being directed at the site.7 Through immunosurveillance (the process by which agents recognized as non-self, such as pathogens and pre-cancerous cells, are detected and eliminated), the immune response is critical for the prevention of cancer and tumor clearance,8–12 and proper coordination can result in elimination of cancer cells.13 However, dysregulation of one or more of the steps in orchestrating the anti-tumor immune response can lead to chronically inflamed areas with “damaged” cancer cells, setting the stage for immune escape.3 Both tumor growth and immune suppression are supported by this low-grade chronic inflammation in the TME, a characteristic that has led to tumors being described as “wounds that do not heal”.14 The chronically inflamed TME is further perpetuated by several different cells within the tumor including macrophages and other myeloid cells, fibroblasts, and the cancer cells themselves, whose secretion of pro-inflammatory cytokines promotes recruitment of different varieties of immune cells, termed leukocytes, to the tumor site.15–17 Upon recruitment to the tumor, leukocytes are exposed to factors in the TME that inhibit cytotoxic anti-tumor activity, even in the presence of immune stimulatory agents such as DAMPs.18–20 These factors drive leukocytes to adopt an immunosuppressive phenotype (in the case of macrophages, a pro-resolution state, sometimes referred to as ‘M2’, as opposed to a pro-inflammatory state, sometimes referred to as ‘M1’), which function to promote immune suppression by inhibiting the pro-inflammatory activity of cytotoxic CD8+ T cells, CD4+ T helper 1 cells, and natural killer (NK) cells necessary for tumor cell killing.18,21 As such, chronic inflammation leads to the persistent activation of inflammatory activity, while paradoxically suppressing the cytotoxic functions necessary for immune-mediated tumor cell killing.3,22\n\nImmune suppression promotes tolerance, thus becoming unresponsive to an antigen that would otherwise provoke an immune response. This allows cancer cells to escape immunosurveillance. At the same time, macrophages polarized toward a pro-resolution phenotype within the TME can directly promote tumor growth through the secretion of growth factors and proteins that remodel the extracellular matrix. In this way, dysregulation of the anti-tumor immune response by the chronically inflamed TME facilitates immune escape and tumor growth. There has been much success in cancer therapies targeting immune cell function in the tumor by using immune checkpoint blockade (ICB) therapy. One such example are treatments targeted against the inhibitory receptors programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). Chimeric antigen receptor (CAR) T cells also use this approach, with the goal of stimulating the immune response to eliminate the cancer cells.23 However, the degree to which immunosuppressive immune cells infiltrate a tumor and suppress or exclude cytotoxic CD8+ T cells exists in a wide spectrum across cancer.23–25 This serves to explain why ICB and CAR T cell therapy are ineffective against many solid tumors, and also why targeting immunosuppressive myeloid cells such as macrophages in combination with ICB has become of interest.\n\n\nCircadian control of macrophage function contributes to regulation of immune responses\n\nCircadian rhythms are 24-hour rhythms that drive oscillations in the levels of circadian-regulated gene transcripts and proteins in a tissue- and cell-specific manner.26,27 This results in time-of-day-dependent variations in circadian-regulated cell processes and functions28 that are maintained by the molecular clock, which is formed by a series of transcription/translation feedback loops.28 Molecular clocks are present in almost every cell of the human body and are synchronized by signals sent out from the central clock, which entrains molecular clocks to the time of day.28 This results in the temporal coordination of cells in spatially distinct tissues, and thus tissue functions.28 While peripheral clocks receive entraining signals from the central clock, they do not rely on these external signals to maintain rhythmicity and will continue to oscillate in the absence of external cues. In mouse experiments, the time of the day with respect to circadian rhythm is usually marked by ‘Zeitgeber time’ (ZT), which corresponds to when the lights are turned on and off. ZT0 corresponds to when the lights are turned on (usually 7 AM) and ZT 12 corresponds to when the lights are turned off (usually 7 PM). It is important to note that since mice are nocturnal, daytime / lights on corresponds to their inactive phase when they sleep, and nighttime/lights off corresponds to their active phase when they are most active and eat the most. This is opposite in humans, as we are diurnal. For the purposes of this review, we will use the terms “active phase” and “inactive phase” to refer to circadian experiments.\n\nIt has been suggested that circadian regulation of immune responses has evolved in part to leverage the benefit of inflammatory responses (i.e., elimination of pathogens) while reducing the costs incurred from the drawbacks of inflammation (i.e., tissue damage).4 Current data indicate that macrophage-mediated immune responses are elevated at the end of the inactive phase, potentially to prime responses during the time when an organism is active (in humans, corresponding to daytime), allowing heightened protection against environmental insults and pathogens when encounter is most likely.5,29,30 Conversely, macrophage-mediated immune responses are dampened during the time when an organism is at rest (in humans, corresponding to nighttime), and encounter with environmental insults and pathogens is least likely.31,32 In this way, immune responses are tuned, but not restricted, to different times of day. However, this is a general framework for some infection models that does not apply to all cases. Notably, regulation of inflammation (i.e., interferon responses) and immune cell recruitment is also regulated by non-immune structural cells in distinct organs, with evidence that this may manifest in tissue-specific differences in timing of peak inflammatory response.33,34 Conceivably, this could reflect a mechanism through which circadian regulation optimizes tissue-specific responses, as different parts of the body are susceptible to different pathogens/insults at different times of day.\n\nSuch modulation of the magnitude of inflammatory response is key, as tissue damage from inflammation can be pathogenic. Tissue damage in the absence of pathogen is considered sterile inflammation and is important for tissue repair.35,36 However, if sterile inflammation is not well-managed and resolved in a timely manner, it results in chronic inflammation, increasing risk of immune dysregulation that can ultimately lead to autoimmunity or cancer.6,35,37 Thus, inflammatory activity must be self-limiting, so as to reach a natural resolution of inflammation and return to homeostasis. At the same time, the immune response must be strong enough to clear the pathogen so that it can be cleared quickly. Otherwise, elongation of the duration of inflammatory response can also promote immune regulatory mechanisms to minimize tissue damage. This is particularly relevant for cancer, as the lack of a strong enough response can contribute to failed immunosurveillance. Failed immunosurveillance can lead to cancer formation and progression. Given the emerging yet evident role of circadian regulation in coordination of immune responses, better understanding this additional layer of regulation on immune cell function in health and disease will better inform on how best to target for treatment.\n\nCircadian rhythms regulate key aspects of macrophage function (Figure 1), but the extent to which this is relevant in cancer is unknown. As we will discuss below, there is some evidence that circadian regulation of macrophages is disrupted in tumor-bearing mice. However, more studies are required to determine whether circadian regulation of immunity is intact systemically or within the tumor, and if it remains entrained to the day/light cycle across different types of cancer and in humans. Understanding how circadian rhythms influence macrophage-mediated immune suppression may inform on new approaches to cancer treatment.\n\nWhile the potential circadian regulation of various aspects of macrophage biology remain unknown, proteins downstream of pathogen sensing confer a circadian signature on the magnitude of cytokine secretion. KLF4, which promotes silent clearance of cells via a pro-resolution profile on macrophage following efferocytosis has also been found to be circadian. RhoA, which is key to phagocytosis, appears to be circadian-regulated, but whether phagocytosis is circadian-regulated remains unclear. Figure created with BioRender.com. KLF4, Krüppel-like factor 4; RhoA, Ras homolog family member A; PD-L1, programmed death-ligand 1; ARG1, Arginase 1; PAMP, pathogen-associated molecular patterns; DAMP, damage-associated molecular patterns; TLR, toll-like receptors; PD-1, programmed cell death protein 1; MHC II, major histocompatibility complex class II.\n\nIn this review, we highlight the role of macrophages in tumor biology and the anti-tumor immune response. In order to understand how the immune response is dysregulated in the TME, we must first understand the role of macrophages during homeostasis and in response to inflammation, and how circadian regulation contributes to this. We then discuss the role of macrophages in tumor development and the anti-tumor immune response, shedding light onto how they are dysregulated in the TME. Finally, we review the current literature on circadian regulation of macrophages and discuss how this may contribute to their function in the tumor.\n\n\nMacrophages are circadian-regulated innate immune cells with diverse functions that are major contributors to immune suppression within the TME\n\nOne of the most abundant leukocytes found in many solid tumors are tumor-associated macrophages (TAMs).38 Macrophages are tissue-resident immune cells (leukocytes) of the myeloid lineage that are present in all organs. As professional phagocytes, macrophages are specialized in their ability to phagocytose dead and dying cells in the body through a process called efferocytosis (discussed in “Efferocytosis”, below). Macrophages respond to diverse environmental signals to adopt tissue-specific phenotypes; as such, macrophages are shaped by their environment, enabling them to perform a wide variety of tissue-specific homeostatic functions.39,40 Due to their ability to sense and respond to the environment, macrophages play a key role in coordinating the immune response, responding rapidly to infection or tissue damage.\n\nTime-of-day-dependent macrophage response to stimuli, conferred by the molecular clock, can modulate the magnitude of the resulting adaptive immune response and determine disease progression.31,41,42 Upon sensing pathogen-associated molecular patterns (PAMPs) and DAMPs, macrophages can become activated, adopting a pro-inflammatory phenotype. Pro-inflammatory macrophages are broadly characterized by upregulation of phenotypic markers major histocompatibility complex class II (MHC II) and CD86 on the cell surface, and secretion of pro-inflammatory cytokines such as IL-6, IL-1β, TNFα, and IL-12. However, this response is tuned by a variety of factors including environment, pathogen type, and even pathogen strain; thus, in vitro-characterized markers of macrophage phenotype and the M1/M2 paradigm are only to be viewed as a loose guideline.43,44 Upon activation, macrophages secrete pro-inflammatory mediators to initiate an immune response, recruiting circulating leukocytes (neutrophils, monocytes, NK cells) to the site of infection. In the context of acute inflammation, this can help eliminate pathogen. However, in a chronically inflamed environment such as in cancer, recruited immune cells such as macrophages can be driven to instead perform immunosuppressive functions. Thus, continued recruitment of these cells to the chronically inflamed TME is one way in which macrophages can contribute to immune suppression.\n\nChemokine and cytokine secretion by macrophages in response to stimuli is subject to circadian regulation.31,42,45–47 Peak macrophage response to stimuli varies, likely due to tissue-specific and pathogen-specific context.34,45,47–49 Collectively, current data indicate that stimulation of macrophages between the mid-inactive phase and the early active phase (ZT6-15) induces increased secretion of pro-inflammatory cytokines and chemokines compared to when stimulation occurs between the late active and early inactive phase (ZT18-3).31,42,45–47,49 By contrast, secretion of the anti-inflammatory cytokine IL-10 has been observed to be higher when stimulated during the early inactive phase (ZT0) than the early active phase (ZT12).46 Data indicate this is driven by a molecular predisposition toward pro-inflammatory activity at a certain time of day,42,46,50,51 with some evidence that macrophages may indeed be poised for activation at a certain time of day.42 Additionally, well-known neuroendocrine timing signals controlled by the central clock, including the adrenergic system and oscillating levels of serum glucocorticoids and melatonin have been shown to modulate macrophage function or differentiation, suggesting that multiple signals are potentially contributing to macrophage circadian control.52–55 Whether this is simply a mechanism to limit macrophage-mediated inflammatory activity during late active/early inactive phase, or whether this translates more broadly to circadian patterns in macrophage phenotype and function at homeostasis requires further study. Importantly, future work characterizing which pathways in macrophages are under circadian control must focus on changes at the protein and phospho-protein level, as circadian patterns in mRNA transcripts do not always equate to circadian patterns in levels of the encoded protein.56\n\nOf note, the majority of studies interrogating circadian control of macrophage function thus far have been performed using lipopolysaccharide (LPS) exposure or bacterial infection as a model of acute inflammation. More studies are required to determine whether these findings apply across the full spectrum of pathogens, although the limited studies using non-bacterial models of acute inflammation are in line with these findings.49,57 There is some evidence that this time-of-day macrophage response extends to stimulation by DAMPs.34,41 The response of macrophage to stimuli is highly context-dependent based on receptor signaling; while in part determined by expression levels of the receptor, it is also dependent on downstream signaling.58 Indeed, few pattern recognition receptors (PRRs) have been observed to be circadian in macrophages; instead, data indicate that circadian patterns in macrophage response to stimuli are broadly conferred by circadian regulation of proteins involved in signaling downstream of PRRs. Thus, circadian regulation of proteins involved in signaling downstream of PRRs as well as of the PRRs themselves could represent a way to regulate by time of day not only ability to sense pathogen, but the activation threshold for PRR signaling.\n\nAside from recruiting cells to the site of infection, macrophages can promote clearance of extracellular pathogens through phagocytosis. There is ample evidence for circadian regulation of phagocytosis, but a wide range of findings in the literature make this a subject of continued debate.42,47,59–62 The clearest evidence of the mechanism driving circadian regulation of phagocytosis in macrophages is through regulation of Ras homolog family member A (RhoA) activity, which promotes phagocytosis, downstream of the molecular clock.42 However, an extensive study performed by a separate group showed evidence that there were no in vivo rhythms in phagocytosis and that, furthermore, rhythms in phagocytosis observed ex vivo were independent of the macrophage molecular clock.47 As a result, the role of circadian rhythms in phagocytic activity of macrophages in response to stimuli remains unclear.\n\nDirect clearance of pathogens by macrophages is not limited to extracellular pathogens; macrophages can promote clearance of intracellular pathogens by efferocytosis of infected cells.63 In doing so, the pathogen within the infected cell is contained and degraded, and can stimulate PRRs including toll-like receptors (TLRs) in macrophages to trigger a pathogen-specific response.\n\nA key homeostatic function of macrophages, efferocytosis is a highly coordinated process involving the detection of dead and dying cells by “find me” signals, engulfment through “eat me” signals, processing, and context-dependent response.64 This is distinct from phagocytosis of pathogens. If not cleared from tissue in a timely manner, apoptotic cells can undergo secondary necrosis and become highly inflammatory.65 Under homeostatic conditions, efferocytosis can trigger macrophages to release factors that suppress inflammation and promote tissue repair, maintaining homeostasis during normal tissue turnover.66 As a result, macrophages are uniquely well-equipped to protect tissue integrity under normal homeostatic conditions.66,67 However, as we will discuss (below in “Macrophages in tumorigenesis”), this process can be taken advantage of by cancer cells to evade immunity.\n\nImportantly, the pathways involved in efferocytosis are distinct from those utilized when phagocytosing extracellular pathogens.62 RhoA activity can preferentially facilitate phagocytosis by suppressing efferocytosis.62,68 Thus, regulation of RhoA by the molecular clock could conceivably present a mechanism through which a predisposition toward phagocytosis (of extracellular pathogens) or efferocytosis (of cells) could be imposed on macrophages at distinct times of day. Nonetheless, efferocytosis is a highly coordinated process that involves several steps prior to engulfment, such as recognition of “find me” and “eat me” signals69; phagocytosis as well occurs downstream of “tasting” and “feeling” the target.70 Better understanding whether receptors and signaling mediators involved in efferocytosis and phagocytosis are circadian-regulated will help elucidate how circadian regulation may contribute to this key aspect of macrophage function during health and disease.\n\nEfferocytosis is of particular importance to clear neutrophils, which must be cleared daily due to their short lifespan. Circadian variations in efferocytosis under homeostatic conditions have been observed, with neutrophil-engulfing macrophages more frequent in peripheral tissues at the end of the inactive phase in mice (ZT11) than at the beginning of the inactive phase (ZT3).60 Whether these circadian rhythms in efferocytosis at homeostasis are regulated directly through the macrophage molecular clock, or indirectly as a result of circadian patterns in neutrophil trafficking is unclear and requires further study. Of note, expression of genes encoding proteins involved in efferocytosis71 followed a similar circadian pattern in peritoneal macrophages, as did the frequency of CD206+ splenic macrophages under homeostatic conditions – higher at the end than the beginning of the inactive phase.50,72 Further studies are required to determine the significance of circadian regulation of efferocytotic machinery with respect to coordination of macrophage function at different times of day.73\n\nTissue environment imprints macrophage function and phenotype, and even within a given tissue, different populations of macrophages can be specialized toward certain functions.58,73,74 As a particularly relevant example, a subset of macrophages within certain tissues were found to be pre-programmed by the tissue microenvironment to silently clear apoptotic cells, which is important for suppressing inflammation during homeostasis.58 This non-inflammatory clearance of apoptotic cells was promoted by decreased expression of the Toll-like receptor TLR9, which has been shown to be circadian-regulated,31 coupled with increased expression of negative regulators of TLR signaling. Expression of receptors recognizing apoptotic cells was also increased in these macrophages; as a result, apoptotic cells were predominately engulfed by macrophages that were pre-programmed to be less sensitive to TLR agonists associated with apoptotic cells such as DNA and RNA, decreasing the likelihood of an inflammatory response. This was driven in part by expression of Krüppel-like factor 4 (KLF4) and KLF2, which control expression of genes important for silent clearance of apoptotic cells. KLF4 was found to be diurnally expressed in peritoneal macrophages at homeostasis, peaking at the end of the inactive phase (ZT12).61 The potential contribution of circadian expression of KLF4 to maintenance of homeostasis by non-inflammatory clearance of apoptotic cells is unknown. Whether KLF4 expression is circadian-regulated in the whole population of peritoneal macrophages or if the observed circadian variation in expression was driven by a subset of macrophages within the peritoneal cavity remains to be seen, as does whether KLF4 expression is circadian in macrophages of other tissues. It is not illogical that certain functions or responses to certain pathogens may be circadian regulated in macrophages of certain tissue but not in others, as certain tissues, such as barrier tissues, may be more at risk of being exposed to certain pathogens. This is supported by the observation that expression of certain PRRs have been found to be circadian in some macrophage populations but not in others. Certainly, in order to gain a broader understanding of how circadian regulation of macrophages contributes to homeostasis and host defense, it will be important to characterize macrophages from diverse tissues, with attention to subpopulations within the tissue itself.\n\nThe risk of cancer and other chronic inflammatory diseases is higher in older individuals. Aging was recently found to diminish circadian rhythms in macrophages, in a manner that might negatively affect rhythmic efferocytosis. In macrophages of aged mice, diurnal patterns in KLF4 expression were muted, leading to decreased KLF4 expression at times of day it would otherwise be heightened.61 This was coupled with a general loss of circadian transcriptional control and rhythmic phagocytosis in macrophages from aged mice. Of note, it has been shown that macrophages from older individuals tend to be more inflammatory at baseline, promoting chronic inflammatory conditions, yet less capable of elevating inflammatory activity to mediate bacterial clearance, leading to susceptibility to infection in older populations. Further studies are required to determine if loss of circadian rhythmicity and an increased propensity towards inflammation in aged macrophages could contribute to tumorigenesis.\n\nIn the context of cancer, efferocytosis of cancer cells is one way in which macrophages can obtain tumor antigen to present to intra-tumoral T cells. However, in the immunosuppressive TME, an immunosuppressive or pro-resolution phenotype is often promoted such that presentation of antigen can suppress cytotoxic responses and confer tolerance. Whether the potential circadian regulation of macrophage efferocytosis would apply in the context of inflammation is unknown and may be something to consider when assessing the contribution of macrophages to rhythms in clearance of intracellular pathogens.\n\nAside from effector functions to clear pathogens, macrophages can also present antigen to T cells at the site of inflammation. This promotes optimal T cell effector functions. Data indicates that expression of CD86, a co-stimulatory protein involved in T cell activation, is circadian-regulated in macrophages.50,72 Of note, macrophages upregulate CD86 when upon activation, and CD86 has also been used as a phenotypic marker for pro-inflammatory macrophages. This may be yet another layer of circadian regulation on macrophages that prime them for activation at certain times of day.\n\nMacrophage phenotype and function is highly dependent on metabolic programming, in that macrophage function is limited in its effectiveness without the required metabolic switch to support these functions.75,76 To accommodate effector functions that are highly energetic and must be quickly produced (like sprinting instead of running a marathon), upon activation macrophages undergo a metabolic switch to glycolysis.77 By contrast, oxidative phosphorylation is prioritized when macrophages are polarized toward a pro-resolution phenotype.78 Macrophage metabolism is less glycolytic under homeostatic conditions than upon activation, but the main pathways utilized appear to vary by tissue, likely due to tissue-specific functions.75 Circadian gating of macrophage response to stimuli is in part facilitated by circadian modulation of macrophage metabolism.56 Data indicates that circadian modulation of macrophage metabolism confers an increased capacity for glycolytic shift following stimulation at the end of the inactive phase.41,79,80 This corresponds with the current data on macrophage response to stimuli, collectively indicating a multi-pathway role for circadian regulation of macrophage response to stimuli through time-of-day-dependent macrophage metabolism and signaling pathways downstream of PRRs. Additionally, nutrient availability is circadian: several studies have shown that metabolites oscillate in circulation in a manner that can be disrupted by shift-work or sleep disturbance,81–83 but the role of this in gating macrophage polarization or activation has not yet been determined. Whether circadian regulation of metabolism influences macrophage function during homeostasis (for example, balance of efferocytosis vs. tissue-specific functions) remains unknown.\n\nIn line with metabolic control of macrophage function, metabolism contributes to the various feedback mechanisms that are in place to promote self-limiting inflammation. When there are many active (and thus highly glycolytic) immune cells in a location, such as pro-inflammatory macrophages and activated CD4 and CD8 T cells, the local microenvironment will become more acidic/high in lactate, which feeds back to suppress glycolysis.84 This limits pro-inflammatory effector function and promotes a metabolic switch to oxidative phosphorylation. Coupled with metabolism-mediated negative feedback mechanisms on inflammatory function are immunologic feedback mechanisms. Macrophages can upregulate PD-1 upon activation, and engagement of PD-1 with the ligand PD-L1 (through interaction with other cells) can promote a switch back to oxidative phosphorylation, supporting a pro-resolution phenotype.85,86 Macrophages can also upregulate PD-L1 upon activation, which can suppress inflammatory activity of other PD-1 expressing-cells.41,87 Lactate, which increases following activation due to glycolysis, further upregulates PD-L1 expression, acting as a feedback loop to limit inflammatory activity.88 As inflammation continues, tissue damage increases, and with it the presence of apoptotic cells.71 Engulfment of uninfected apoptotic cells induces a pro-resolution phenotype in macrophages. Among other things, this promotes secretion of IL-10, which further feeds back to suppress the glycolytic metabolism needed to support inflammatory functions – thereby creating a feed-forward loop that reinforces the shift to the resolution of inflammation.89 Normally, these feedback mechanisms function to limit the pathogenic effects of the inflammatory immune response and promote the natural resolution of inflammation. However, as we will discuss below, these feedback mechanisms to limit inflammation are co-opted by cancer to create an immunosuppressive TME.\n\nAs pathogen or target mammalian cell is cleared by phagocytosis or efferocytosis, cues in the microenvironment such as the absence of PAMPs in combination with increased lactate, acidity of the environment, and apoptotic cells drive macrophages to downregulate inflammatory functions and adopt pro-resolution functions.84,90,91 Pro-resolution macrophages have been characterized by expression of CD206 and Arginase 1 (ARG1), but in vivo they exist across a spectrum of phenotypes that are dependent on many factors, including tissue environment and stage of resolution.90 During the resolution phase, macrophages promote tissue repair by secreting growth factors and proteases to remodel the extracellular matrix, such as VEGF and MMPs. Clearance of dead cells by efferocytosis removes potentially inflammatory cell debris from the environment, suppressing further inflammation. Efferocytosis reinforces an immunoregulatory (pro-resolution) phenotype in macrophages by suppressing TLR signaling and inducing ARG1 expression and secretion of anti-inflammatory factors such as IL-10, TGFβ, and PGE2.71,92,93 These anti-inflammatory proteins can suppress inflammatory activity of other cells. There is a dearth of studies on the role of circadian regulation in macrophage-mediated resolution of inflammation and homeostatic functions. Given the key role macrophages play in maintaining homeostasis and resolution of inflammation, this merits further investigation. As we will discuss, the TME fosters adoption of these pro-resolution and anti-inflammatory functions of macrophages, which are key drivers of tumor growth and immune suppression in the TME.\n\nDisruption of the molecular clock in myeloid cells predisposes mice to developing exacerbated inflammatory responses in both acute and chronic inflammatory disease models and can lead to impaired resolution of inflammation.42,46,94 This suggests that circadian regulation of macrophages by the molecular clock functions to restrict inflammatory activity, thereby promoting resolution of inflammation. This is of particular interest considering that tumor growth and immunosuppression within the TME are both promoted by chronic inflammation. However, how circadian control of macrophages influences immune suppression in the TME remains unknown.\n\n\nMacrophages in tumorigenesis\n\nWithin the tumor, macrophages can phagocytose tumor cells, present tumor-associated antigen to intratumoral T cells, and secrete pro-inflammatory cytokines such as TNFα and IL-12 to promote T cell activity and effector function (Figure 2).95 However, macrophage activation and inflammatory activity is limited in the TME. This is largely due to the subversion of immune regulatory mechanisms in the chronically inflamed TME. While immunogenic DAMPs can elicit an inflammatory response from macrophages, chronic stimulation of TAMs by DAMPs can promote an immunoregulatory phenotype.18 Efferocytosis of apoptotic cells in the TME can also induce immunoregulatory functions and suppresses activation of TAMs. Along with chronic stimulation and abundance of apoptotic cells, various metabolic factors in the TME disrupt immune homeostasis to suppress inflammatory activity and promote tissue repair/wound-healing functions to facilitate restoration of homeostasis.96 These factors include hypoxia, acidity, high lactate, and release of adenosine from dying tumor cells.20,97–99 These are related to: a) poor vascularization, leading to poor oxygen flow and nutrient delivery, b) chronic inflammatory activity of cells in the TME and rapid growth of cancer cells, all of which is supported by glycolytic activity – leading to excretion of lactic acid, acidifying environment, and potentially depletion of glucose, and c) poor drainage of the TME due to poor vasculature and lymphatics, leading to the accumulation of waste products instead of being washed away/drained. Metabolic heterogeneity of different TAM subsets may also contribute to how they behave in the TME. As an example, a recent study showed that pro-resolution TAMs can utilize lactate as a fuel source. while, in contrast, elevated lactate concentration can decrease the glycolytic activity of pro-inflammatory TAMs.100\n\nWhile tumor-associated macrophages are heterogeneous, they are overall immunosuppressive due to the tumor microenvironment. Hypoxia, lactate, and acidic pH in the tumor microenvironment promote pro-growth, tissue repair, and immunosuppressive functions of tumor-associated macrophages while suppressing their pro-inflammatory functions. What aspects of macrophage function in the tumor microenvironment remain under circadian regulation is an open question. Figure created with BioRender.com. ARG1, Arginase 1; MHC II, major histocompatibility complex class II; PD-L1, programmed death-ligand 1; ECM, extracellular matrix.\n\nMacrophage inflammatory activity is also modulated by factors secreted by cells within the tumor, including infiltrating immune cells, fibroblasts, and the cancer cells themselves. Anti-inflammatory factors such as IL-10 and PGE2 secreted by other immune-infiltrating cells and the tumor cells themselves suppress inflammatory activity.101 Type 2 CD4+ T helper cells can secrete IL4/IL13, which promotes a pro-resolution macrophage phenotype, suppressing a pro-inflammatory phenotype.102 Cancer-associated fibroblasts can deposit collagen, increasing extracellular matrix (ECM) density, which can promote a pro-resolution phenotype in macrophages. The degree to which macrophages are exposed to each of these factors in the TME varies within tumors depending on several factors including the distance from blood vessels and neighboring cells.103,104 Thus, phenotype is dependent on the location of the macrophage within the TME, due in part to the ability of macrophages to sense and adapt to the local microenvironment. As a result, there is significant phenotypic heterogeneity of TAMs within tumors105,106; while regions of the TME confer immunosuppressive or pro-tumorigenic functions to TAMs, there are regions in the tumor where anti-tumorigenic TAMs are found as well.107,108 Traditionally, anti-tumor/pro-inflammatory macrophages have a phenotype associated with expression of MHCII and CD86 and secretion of TNFα. By contrast, pro-tumor/anti-inflammatory TAMs have a phenotype associated with expression of CD206, ARG1, PD-L1 and secretion of IL10. However, in practice the TAMs exist in the tumor across a spectrum of these phenotypes, which, along with their role/function in the tumor, can vary across different types of cancer.109 Despite the heterogeneity of TAMs both across and within tumors, overall high intra-tumoral TAM density generally correlates with poor prognosis/poor patient outcome across cancer types,96,110,111 suggesting that the bulk of macrophages within the tumor are immune suppressive/pro-tumorigenic.\n\nTAMs can promote tumorigenesis directly, through supporting tumor growth and metastasis, and indirectly, through suppression of the anti-tumor immune response. In the context of the chronically inflamed TME, failure to resolve the inflammation can lead to uncontrolled secretion of pro-resolution tissue repair factors by TAMs, which promote tumor growth and metastatic capacity.37,112,113 Secretion of VEGFa can promote angiogenesis, accommodating tumor growth/increased tumor mass by supplying it with more nutrients. ECM remodeling proteases such as MMP8-10 can promote metastasis by motility and invasiveness of cancer cells. TAM-derived TGFβ can promote activation of cancer-associated fibroblasts and together, through ECM remodeling and increased ECM deposition, they can promote exclusion of CD8+ cytotoxic T cells from the tumor, facilitating immune evasion.\n\nWithin the tumor, there can be an abundance of apoptotic cells due to the metabolically stressful TME and pathogenic effects of chronic inflammation. Efferocytosis of apoptotic cells by macrophages induces expression of immunoregulatory proteins IL-10, TGFβ, and ARG1 to dampen inflammation, promoting suppression of CD8+ T cell cytotoxic activity.18,92,93,101,114 TAMs can also inhibit cytotoxic lymphocyte activity through expression of the checkpoint inhibitor PD-L1, upregulation of which is promoted by hypoxia and lactic acid.88,109,115 Expression of PD-L1 by TAMs has been shown to be pro-tumorigenic and a poor prognostic indicator. There is recent evidence that PD-L1 is indirectly regulated by the molecular clock in macrophages downstream of PKM2, which has been shown to promote PD-L1 expression.41,87 Whether PKM2 expression by TAMs is circadian in tumors, and whether this translates to circadian variations in PD-L1 expression, remains to be seen.\n\nRecent studies have begun to decipher the potential role of the macrophage circadian clock in specifying TAM roles in the TME. In B16-F10 (melanoma) tumor-bearing mice, the time of day variation in CD86+ splenic macrophage frequency was lost, which suggests that systemic cues in tumor-bearing mice can alter circadian rhythms of macrophages in distal peripheral tissues. Of note, in the tumor itself, circadian variations in frequency of CD86+ macrophages was observed, but the peak of CD86+ cells was reversed from in peripheral tissues.72 It was not clear if this circadian variation in CD86 was due to circadian oscillation of phenotype in the TAMs (from a pro-inflammatory to a pro-resolution phenotype) or due to rhythmic recruitment of macrophages that adopted different polarization states. This discordance with the time-of-day peak and trough of macrophages in tissues of healthy mice (spleen, peritoneal cavity)50,72 may suggest a disruption in circadian regulation of macrophages within the tumor microenvironment, perhaps through altered entrainment. One factor that may modulate and alter the circadian clock in TAMs is tumor fibrosis, which is known to occur particularly in pancreatic cancer.116 Factors associated with fibrosis, including matrix stiffness and TGFβ, were shown to modulate the molecular clock in a cell-type specific fashion. Additional investigation into how this may alter clocks of cells in tumors and in pre-tumor chronically inflamed tissue, particularly how it affects immune cells, could be fruitful.\n\nGenetic ablation of the macrophage circadian clock dysregulates macrophage metabolism and promotes tumor growth,117 underscoring the potential importance of TAM circadian rhythms in regulating their role in the tumor microenvironment. However, the role of the circadian clock in regulating TAM phenotype and function remained unclear. Nonetheless, if additional aspects of macrophage phenotype are shown to vary by time of day in TAMs, this could inform on using chronotherapy (treatment timed in a circadian fashion to maximize efficacy) that is aimed at reprogramming TAMs. Further studies on circadian regulation of macrophage functions within the tumor microenvironment relative to peripheral tissues will arm us with the information we need to employ chronotherapeutic-based approaches of immunotherapy treatments for cancer.\n\n\nApplication of macrophage circadian biology to the clinic\n\nDue to the major role of TAMs in promoting immune suppression, some approaches to cancer therapy have focused on re-polarizing macrophages from a pro-tumorigenic, pro-resolution state to an anti-tumorigenic, pro-inflammatory state to alleviate macrophage-mediated immune suppression in the TME and further promote anti-tumor immunity.118 There are numerous TLR agonists currently in clinical trials for combination with immune checkpoint therapy, as well as inhibitors of CD47/SIRPa to block efferocytosis of cancer cells by macrophages.119 Given observations of time-of-day dependency in macrophage response to stimuli, leveraging time-of-day variations in targets could be promising avenue to increase efficacy, as showcased by recent studies using PD-1/PD-L1 ICB.1,2\n\nIn humans and mice, frequency of PD-1+TAMs increases with disease stage and tumor progression, respectively.120 Expression of PD-1 by TAMs has been shown to promote tumor progression by facilitating induction of oxidative metabolism that supports pro-tumorigenic and anti-inflammatory functions.86 As such, PD-1+ TAMs expressed high levels of CD206, ARG1 and IL-10, relative to their PD-1 counterparts. By contrast, blocking engagement of macrophage PD-1 by PD-1/PD-L1 blockade or deletion of macrophage PD-1 resulted in a shift toward glycolytic metabolism and elevated expression of cytokines associated with a pro-inflammatory macrophage phenotype. This suggested that the skewing of TAM population phenotype from pro-tumorigenic to anti-tumorigenic following anti-PD-1/PD-L1 treatment in various tumor models is due to direct effects on macrophages in addition to indirect effects from T cell-dependent alterations.86,121 These findings are particularly intriguing, as circadian patterns in frequency of PD-1+ TAMs has been observed in B16/BL6 (melanoma) tumor-bearing mice (Figure 3).1 Taking a chronotherapeutic approach, increased efficacy of PD-1/PD-L1 ICB therapy was observed when administered at the time of day when PD-1+ TAMs were most frequent (in the middle of the active phase) compared to when treatment was administered at time of day when PD-1+ TAMs were lowest (in the middle of the inactive phase).1 These data suggest that the phenotype of TAMs can vary by time-of-day, and that synchronizing treatment to take advantage of these rhythms could be beneficial.\n\nIn B16/BL6 (melanoma) tumor-bearing mice, the administration of PD-1/PD-L1 inhibitor during the dark phase (ZT16) results in higher anti-tumor effects when compared with the same treatment administered during the light phase (ZT8). Figure created with BioRender.com. PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1.\n\nOf note, these data were confirmed in a recent retrospective study of human melanoma patients who received ICB therapy. Those patients who received less than 20% of their ICB infusions before 4:30 PM (near the end of the human active phase) had a statistically significant increase in overall survival as compared to those who received more than 20% of their infusions after 4:30 PM,2 mirroring findings from mice, though circadian trafficking of T cell populations likely also played a major role in this observation. Further investigation of whether frequency of PD-1+ TAMs is circadian across different types of cancer, and whether this is true in humans as well as mice, will help further our understanding of the potential application of this therapeutic approach.\n\nSeparately, other groups have experimented with delivering IL-12 intratumorally to repolarize macrophages and other immunosuppressive myeloid cells towards a pro-inflammatory phenotype. This improved the efficacy of radiotherapy, eliciting a more potent anti-tumor immune response.122 Knowledge of how circadian rhythms control macrophage phenotype and function, especially in the TME, may inform clinicians on the most effective use of these approaches.\n\n\nConclusions, open questions, and future perspectives\n\nOverall, current evidence, however limited, suggests that exploiting circadian regulation of key macrophage-derived immunoregulatory factors may allow us to seek further benefits from clinical treatments targeted to these factors. However, we know very little about how circadian regulation of macrophages is affected by cancer.\n\nOne challenge that remains is determining if macrophages within tumors have normal or disrupted circadian rhythms. Computational analysis has suggested that molecular clocks are disrupted in human tumor samples across 12 different types of cancer.123,124 As this analysis was performed using transcriptomic data from whole tumors, factors that cause disruption of the molecular clock in the TME, and cells in which the clock is disrupted, remains unclear. Several metabolically stressful factors associated with the TME such as nutrient limitation, hypoxia, and acidic pH can disrupt the molecular clock.125–128 This is likely to change across tumor progression, since when the tumor is still small it will be relatively well-vascularized and thus have less hypoxia, less acidic pH and maybe less nutrient limitation. However, as the tumor progresses and grows larger, it would conceivably become less well-vascularized and will thus begin to have areas of hypoxia and acidic pH and possibly also nutrient limitation. How this affects circadian regulation of immune cells within the TME is unknown. There is ample evidence that these same stressors can influence immune cell phenotype and function, but the role of the clock in these phenotypical and functional changes is unknown.97,129–132 As this may influence how clinicians plan to deliver TAM-modulating therapies in a chronotherapeutic fashion, this is a possible subject of future study.\n\nIn conclusion, an emerging body of literature suggest that macrophage phenotype and function are heavily influenced by circadian rhythm control. The molecular clock influences and tunes functions such as cytokine secretion, efferocytosis, phagocytosis, surface marker expression, and interaction with other immune cell types such as T cells. This molecular clock control may be influenced in part by internal metabolic shifts and changes in external metabolic cues. TAMs are heavily skewed towards a pro-resolution phenotype that leads to suppression of the anti-tumor immune response and direct pro-tumorigenic activity, and this is shaped by changes in the TME. A better understanding of how macrophage circadian rhythms are modulated by the TME will aid in determining how this pathway contributes to the pro-tumorigenic nature of macrophages. More importantly, knowledge of TAM circadian rhythms may aid in therapy decisions that directly and indirectly target macrophages, by using time of day information to maximize efficacy.",
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{
"id": "161785",
"date": "20 Feb 2023",
"name": "Carla Finkielstein",
"expertise": [
"Reviewer Expertise circadian rhythms",
"cancer",
"cell cycle",
"DNA damage",
"chronotherapy"
],
"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\nIn this review article, the authors effectively summarize a large volume of information regarding the many roles that macrophages play as components of the tumor immune microenvironment (TME) and during tumor growth. Furthermore, the authors incorporate findings that relate to the circadian biology of macrophages and discuss their relevance in the context of metabolism, immune remodelling, and tumor growth. More importantly, they stress the importance of more research in macrophages’ clock to better exploit their different functionalities therapeutically. This reviewer believes the article is well-written, contains updated and critical information, and will be highly cited based on its quality.\nA number of minor recommendations are listed below:\nIntroduction: Remove the sentence “We will investigate……well-characterizes.” The sentence is redundant with the info provided in the same paragraph.\n\nThe section in “Dysregulation of the immune response…” would benefit from a comprehensive figure that summarizes the information in that section.\n\nIn the same section, the authors introduce the “immune checkpoint blockade therapy”; however, there is not any explanation what this is all about. This reviewer believes the reader would benefit from a few sentences that explains what ICB therapy is all about.\n\nTo me, it seems that there is a figure missing between Fig. 1 and Fig. 2 that summarizes the many functions of macrophages and how they are regulated. The information is overwhelming, and the reader would benefit from a summary figure.\n\nThere are instances in which the data discussed in the article merits the addition of specific information such as whether the data were collected from mice or humans specimens. For example, when discussing the chemokine and cytokine secretion by macrophages in response to stimuli and at specific phases of the day.\n\nFigure 2 is referenced within the first sentence of the “Macrophages in tumorigenesis” section. However, the section is incredibly richer in information that is not depicted in Figure 2. The way that figures are embedded in the manuscript look like the authors needed to add figures to the review but they do not take good advantage of those figures to convey complex information to the reader. I suggest to revisit the info in figures and integrate the text and figures better.\n\nA \".\" is missing in the abstract between the words \"response Circadian rhythms\".\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? Partly\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
},
{
"id": "181754",
"date": "17 Jul 2023",
"name": "Kristin Eckel-Mahan",
"expertise": [
"Reviewer Expertise circadian rhythms"
],
"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\nIn “Do macrophages follow the beat of circadian rhythms in TIME (Tumor Immune Microenvironment)?” Knudsen-Clark et al. provide a nice review of the role of circadian rhythms in the tumor microenvironment in tumor progression. Specifically, the authors do a nice job of highlighting circadian regulation of immune response at the level of macrophage activity. The article highlights the heterogeneity of tumor- and tumor microenvironment-associated macrophages at the level of activity and circadian function. I think the authors could discuss the molecular clock of macrophages in more detail, and highlight some of the initial findings underscoring a role of the circadian clock within this cell type.\nComments:\nIn the first section, where authors describe the dysregulation of immune response in cancer, the author may wish to further explain what the “pro-resolution” state means in the context of macrophage function. Some of the material from the “contextual cues dictate macrophage function” might be introduced earlier as it relates to the resolution phase. Furthermore, some additional details related to M2 vs. M1 states would be helpful for those outside of the field.\n\nRelated to point #1, some of the background in the next section related to macrophages might be placed earlier in the review.\n\nIn discussing some studies, the authors should provide more experimental and molecular details. In places, the discussion is rather vague.\n\nI get the impression that the authors wish to avoid describing the molecular clock. However, I think in doing so, they could add more details related to disruption of immune response in macrophages by the presence or absence of specific clock proteins (CRYs vs. BMAL1, for example).\n\nThe authors could expand the last section discussing the potential for clinical relevance, and discuss the half life and properties of currently used PD-L1 inhibitors (for example) since they focus on the potential for time-of-day response.\nMinor Concerns:\nA period appears to be missing in the abstract before the sentence starting with, “circadian rhythms”.\n\nThe authors can probably eliminate the reference to ZT0 as “usually 7 AM”, as this will vary from facility to facility. Describing ZT0 as “lights on” or “beginning of the resting/light phase” should be sufficient.\n\nMissing word in the sentence after reference 70.\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/12-101
|
https://f1000research.com/articles/11-1036/v1
|
12 Sep 22
|
{
"type": "Study Protocol",
"title": "(Semi)automated approaches to data extraction for systematic reviews and meta-analyses in social sciences: A living review protocol",
"authors": [
"Amanda Legate",
"Kim Nimon",
"Kim Nimon"
],
"abstract": "Background: An abundance of rapidly accumulating scientific evidence presents novel opportunities for researchers and practitioners alike, yet such advantages are often overshadowed by resource demands associated with finding and aggregating a continually expanding body of scientific information. Across social science disciplines, the use of automation technologies for timely and accurate knowledge synthesis can enhance research translation value, better inform key policy development, and expand the current understanding of human interactions, organizations, and systems. Ongoing developments surrounding automation are highly concentrated in research for evidence-based medicine with limited evidence surrounding tools and techniques applied outside of the clinical research community. Our objective is to conduct a living systematic review of automated data extraction techniques supporting systematic reviews and meta-analyses in the social sciences. The aim of this study is to extend the automation knowledge base by synthesizing current trends in the application of extraction technologies of key data elements of interest for social scientists. Methods: The proposed study is a living systematic review employing a partial replication framework based on extant literature surrounding automation of data extraction for systematic reviews and meta-analyses. Protocol development, base review, and updates follow PRISMA standards for reporting systematic reviews. This protocol is preregistered in OSF: (Semi)Automated Approaches to Data Extraction for Systematic Reviews and Meta-Analyses in Social Sciences: A Living Review Protocol on August 14, 2022. Conclusions: Anticipated outcomes of this study include: (a) generate insights supporting advancement in transferring existing reliable methods to social science research; (b) provide a foundation for protocol development leading to enhancement of comparability and benchmarking standards across disciplines; and (c) uncover exigencies that spur continued value-adding innovation and interdisciplinary collaboration for the benefit of the collective systematic review community.",
"keywords": [
"Automated data extraction",
"systematic review",
"meta-analysis",
"evidence synthesis",
"social science research",
"APA Journal Article Reporting Standards (JARS)"
],
"content": "Introduction\n\nAcross disciplines, systematic reviews and meta-analyses are integral to exploring and explaining phenomena, discovering causal inferences, and supporting evidence-based decision making. The concept of metascience represents an array of evidence synthesis approaches which support combining existing research results to summarize what is known about a specific topic (Davis et al., 2014; Gough et al., 2020). Researchers use a variety of systematic review methodologies to synthesize evidence within their domains or to integrate extant knowledge bases spanning multiple disciplines and contexts. When engaging in quantitative evidence synthesis, researchers often supplement the systematic review with meta-analysis (a principled statistical process for grouping and summarizing quantitative information reported across studies within a research domain; Shamseer et al., 2015). As technology advances, in addition to greater access to data, researchers are presented with new forms and sources of data to support evidence synthesis (Bosco et al., 2017; Ip et al., 2012; Wagner et al., 2022). An abundance of accumulated scientific evidence presents novel opportunities for translational value, yet advantages are often overshadowed by resource demands associated with locating and aggregating a continually expanding body of information. In the social sciences, the number of published systematic reviews and meta-analyses have experienced continual growth over the past 20 years, with an annual increase approximating 21% based on citation reports from Web of Science (see Figure 1).\n\nNote. Figure was generated using the Web of Science Core Collection database. A title search was conducted in the Social Sciences Citation Index (SSCI) for articles and reviews published between 2000-2022 including variations of the terms “Systematic Review” and “Meta-analysis”. Search Syntax: ((TI=(\"meta-analy*\" or \"meta analy*\" or metaanaly* or \"system* review\" or \"literature review\")) AND PY=(2000-2022)) AND DT=(Article OR Review).\n\n\nBackground\n\nComprehensive data extraction activities associated with evidence synthesis have been described as time-consuming to the point of critically limiting the usefulness of existing approaches (Holub et al., 2021). Moreover, research indicates that it can take several years for original studies to be included in a new review due to the rapid pace of new evidence generation (Jonnalagadda et al., 2015). As such, research communities are increasingly interested in the application of automation technologies to reduce the workload associated with systematic reviews. Tsafnat et al. (2014, p. 2) delineated fifteen tasks associated with systematic reviews and meta-analyses, illuminating the automation potential for each — including the steps involved in repetitive data extraction. Recent studies and conference proceedings have outlined critical factors influencing the development and adoption of automation efforts across social and behavioral sciences. Including, but not limited to, (a) an absence of tools developed for use outside of medical science research (Marshall & Wallace, 2019); (b) a lack of universal terminology (Gough et al., 2020); and (c) nonuniformity in presenting and reporting data (Yarkoni et al., 2021). Notwithstanding these contributions, important questions related to how social scientists are addressing known challenges remain unanswered.\n\nSocial sciences encompass a broad range of research disciplines, however, what social scientists share is an interest in expanding a collective understanding of human behaviors, interactions, systems, and organizations (National Institute of Social Sciences, n.d.). Systematic reviews and meta-analyses are fundamental to supporting reproducibility and generalizability of research surrounding social and cultural aspects of human behavior, however, the process of extracting data from primary research is a labor-intensive effort, fraught with the potential for human error (see Pigott & Polanin, 2020; Yu et al., 2018). In contrast with the more defined standards that have evolved throughout the clinical research domain, within and across social sciences, substantial variation exists in research designs, reporting protocols, and even publication outlet standards (Davis et al., 2014; Short et al., 2018; Wagner et al., 2022). Notwithstanding that application of automation technologies in the social sciences could benefit from greater standardization of reporting protocols and terminology, understanding of the current state of (semi) automated extraction across these disciplines is largely speculative.\n\nIn the clinical research community, automation technologies are rapidly evolving for data extraction. Tools applying intelligent technologies for the purpose of data extraction are increasingly common for research involving Randomized Control Trials (RCT; see Schmidt et al., 2021). As data elements targeted for extraction from clinical studies and healthcare interventions often differ from those targeted by social scientists, transferability of technological solutions remains constrained. Figure 2 presents a general overview of methodologies covered by quantitative reporting guidelines applicable to social sciences per the American Psychological Association (APA, 2020). As of 2018, the APA Journal Article Reporting Standards (JARS) were updated to include clinical trial reports (represented in Figure 2 by the block labeled “Clinical Trials Module C”), incorporating elements also identified by the Cochrane Handbook for Systematic Reviews of Interventions; Higgins et al., 2022).\n\nNote. Figure adapted from Appelbaum et al. (2018, Tables 1-9).\n\nTo elaborate, in health intervention research, targeted data elements generally include Population (or Problem), Intervention, Control, and Outcome (i.e., PICO; see Eriksen et al., 2018; Tsafnat et al., 2014). In social research, elements targeted for extraction are similarly a function of study design, but targets can take numerous forms based on research questions considered. Researchers in social sciences often rely on APA JARS guidelines, which delineate key elements and respective reporting locations for authors to follow when presenting results of qualitative (JARS-Qual) and quantitative (JARS-Quant) research (APA, 2020; Appelbaum et al., 2018; see also Purdue Online Writing Lab, n.d.). For example, in addition to descriptive statistics (e.g., sample size, mean, standard deviation), meta-analytic efforts typically aim to extract and aggregate inferential elements such as effect sizes and p-values. Where structural equation models are involved, a researcher may be interested in extracting model fit indices; or when conducting a reliability generalization, extraction of instrument psychometric properties would be imperative (Appelbaum et al., 2018; see “Extended Data” for supplementary files containing target data elements).\n\nTo further illustrate the scope of eligible extraction targets for which automation technologies could benefit social science research, we used wordcloud2 package (v0.2.2; Lang, 2022; R Statistical Software v4.1.2; R Core Team 2021) to present simple comparative visualizations of reporting items for systematic reviews and meta-analyses (see Figures 3 and 4). In Figure 3, the gray text represents data collection elements identified by both the Cochrane Handbook for Systematic Reviews of Interventions (Li et al., 2022) and data reporting standards for clinical trials recommended by APA JARS (Applebaum et al., 2018; Table 2, Module C). The orange text represents reporting elements unique to APA JARS. Notwithstanding substantial overlap, the minimal unique terms are likely attributable to variation in disciplinary phrasing. Figure 4 similarly shows target data elements (with orange text likewise representing items unique to APA) but also includes recommended reporting items for all study designs (e.g., replications, structural equational modeling, Bayesian techniques, etc.). If automation techniques experiencing rapid growth in clinical research hold potential for transferability to the range of study designs prevalent throughout social and behavioral sciences, benefits could be far reaching for the development and validation of theoretical models, measurement scales, and much more.\n\nNote. Gray represents element identified in American Psychological Association (APA) reporting standards involving clinical trials (Appelbaum et al., 2018, Table 2, Module C) and The Cochrane Handbook checklist of items to consider in data collection (Table 5.3.a). Orange represents element unique to Appelbaum et al. (2018, Table 2, Module C). Terms appearing in word cloud are not exhaustive and are limited to frequencies greater than one.\n\nNote. Gray represents element identified in American Psychological Association (APA) reporting standards (Appelbaum et al., 2018, Tables 1— 9) and The Cochrane Handbook checklist of items to consider in data collection (Table 5.3.a). Orange represents element unique to Appelbaum et al. (2018, Tables 1 — 9). Terms appearing in word cloud are not exhaustive and are limited to frequencies greater than two.\n\nGiven that evidence-based medicine is often associated with superior protocol standards and systematic guidelines (i.e., gold standards; Grimmer et al., 2021), the task of transferring even the most reliable automation technologies to social science research presents a substantial challenge. Even within more technical disciplines, such as Information Systems, researchers grapple with automation challenges associated with a lack of uniformity in description and presentation of constructs and measurement items (Wagner et al., 2022, p. 12). While discourse surrounding the delayed uptake of automation tools in the social sciences is occurring, the question of application transferability to domains outside of clinical research remains underexplored. Despite known barriers, delays in interdisciplinary methodological progress inhibit opportunities for collaborative knowledge synthesis both within and across fields (Gough et al., 2020).\n\nThe purpose of this study is to conduct a living systematic review (LSR) to extend the automation knowledge base by identifying existing and emergent systems for (semi) automated extraction of data used by social science researchers conducting systematic reviews and meta-analyses. Following Schmidt et al. (2020b, 2021), who are conducting a review of data extraction techniques for healthcare interventions (i.e., RCTs, case studies, and cohort studies; see Schmidt et al., 2020a), we apply an adapted version of their methodological strategy for social science disciplines where observational research is widespread practice. This effort entails targeting extraction of JARS data elements identified by the APA (Appelbaum et al., 2018; see “Extended Data”).\n\nEmploying a differentiated replication framework, we apply the LSR methodology to iteratively aggregate and report: (a) the extant state of technology-assisted data extraction in social science research; (b) application trends in automation tools/techniques for extraction of data from abstracts and full text documents outside of biomedical and clinical research corpora; (c) evidence synthesis stages and tasks for which automation technologies are predominantly applied across social science disciplines; (d) specific data elements and structures targeted for automated extraction efforts by social science researchers; and (e) applied benchmarking standards for performance evaluation.\n\nTo inform this protocol and assess the extent to which our questions have been addressed in prior literature, we explored existing (semi) automated data extraction reviews. We identified six literature reviews (three static, one living, one scoping, and one cross-sectional pilot survey), two software user surveys, and one conference proceeding report. Table 1 provides a summary of scoped studies. Where some efforts focused on software applications, or “tools” that perform or assist with systematic review tasks (Harrison et al., 2020; Scott et al., 2021), others directed attention to underlying methods or techniques (e.g., machine learning algorithms) or reviewed multiple categorizations (see Blaizot et al., 2022; Schmidt et al., 2021; O’Connor et al., 2019).\n\nThe extant knowledge base and ongoing developments surrounding systematic review automation are highly concentrated in research for evidence-based medicine (e.g., medical research, clinical trials, healthcare interventions) with limited evidence supporting how automation techniques are applied outside of the medical community (see O’Connor et al., 2019). This is not surprising given the unique relevance of systematic reviews for informing healthcare practice and policy development (Moher et al., 2015). However, while technologies to support data extraction from primary literature have advanced rapidly, many existing tools were not developed for application outside of research on the effectiveness of health-related interventions. O’Mara-Eves et al. (2015), for example, reported that text-mining techniques for classifying and prioritizing (i.e., ranking) relevant studies had undergone substantial methodological advancement, yet also highlighted that where assessment methods could be implemented with relatively high confidence in clinical research, much work was needed to determine how systems might perform in other disciplines. Other researchers similarly noted issues such as heterogeneity in testing and performance metrics (Blaizot et al., 2022; Jonnalagadda et al., 2015; Tsafnat et al., 2014) as well as risk of systemic biases resulting from inconsistent annotations in training corpora (Schmidt et al., 2021). Across projects reviewed, calls resounded for additional assessment of automation methods, including testing methods across different datasets and domains and testing the same datasets across different automation methods (Schmidt et al., 2021, O’Mara-Eves et al., 2015; O’Connor et al., 2019; Jonnalagadda et al., 2015). Despite research presenting evidence of trends toward more complete reporting (i.e., past five years; Schmidt et al., 2021), dialogue emerging from the systematic review community indicates that the time is ripe for dedicating more attention toward enhancing interdisciplinary comparability and benchmarking standards (O’Connor et al., 2019).\n\nExisting platforms are available to support research teams in a range of time-consuming manual tasks (Blaizot et al., 2022). Even with these expediencies, not all key activities within the overall review process have received equal attention in application and technique development (O’Connor et al., 2019; Scott et al., 2021). Only a few years ago (semi) automated screening approaches such as text-mining for processing full-texts were not commonly available (O’Mara-Eves et al., 2015). As relevant study details were not always included in abstracts and often appeared throughout and across various sections of a given study (including tables and figures) discussion turned toward development of data extraction methods supporting full-text corpora (Tsafnat et al., 2014). Today, researchers supporting evidence-based medicine benefit from more robust data extraction techniques; especially efforts targeting PICO-related elements (Schmidt et al., 2021). Software tools are available for data extraction (e.g., Abstracktr, Robot Reviewer, SWIFT-Review; see Blaizot et al., 2022, p. 359), however, they have received mixed reviews related to their respective effectiveness. Notwithstanding substantial methodological strides in recent years, limited multidisciplinary reviews evaluating application effectiveness in non-clinical contexts may offer some explanation for the reported delays in uptake outside of evidence-based medicine. Further, the nominal extant research comparing techniques applied in both clinical and social contexts suggests that existing tools may not “perform as well on ‘messy’ social science datasets” (Miwa et al., 2014; as cited in O’Mara-Eves et al., 2015, p. 16). Even within structured tabular reporting contexts (i.e., tables), our understanding of technology applicability and transferability across disciplines is limited (Holub et al., 2021).\n\nServing as a model for the present study, Schmidt et al. (2021) reviews tools and techniques available for (semi) automated extraction of data elements pertinent to synthesizing the effects of healthcare interventions (see Higgins et al., 2022). Their noteworthy living review is exploring a range of data-mining and text classification methods for systematic reviews. The authors uncovered that early often employed approaches (e.g., rule-based extraction) gave way to classical machine-learning (e.g., naïve Bayes and support vector machine classifiers), and more recently, trends indicate increased application of deep learning architectures such as neural networks and word embeddings (for yearly trends in reported systems architectures, see Schmidt et al., 2021, p. 8). Overall, the future of automated data extraction for systematic reviews and meta-analytic research is very bright. As the earlier (i.e., preliminary) stages of the systematic review process have experienced rapid advancement in functionality and capability, development of techniques for all stages is foreseeable in the near future. Just as software tools and data extraction techniques vary in scope, purpose, and financial commitment, so too will research questions, goals, and study designs. Interdisciplinary groups and applied researchers alike call for increased collaboration to spur innovation and further advance the state of computer-assisted evidence synthesis (O’Mara-Eves et al., 2015; O’Connor et al., 2019). Though it can be inferred that not all developments spawned by the medical sciences community are easily transferrable to social sciences, necessity in fields inundated with new evidence production has carved a path for other disciplines; a path in which challenges and opportunities are openly displayed to serve as a foundation for the entire systematic review community to build upon. Additional inquiries surrounding approaches applied in social sciences may introduce previously unencountered demands that spur innovation and create valuable contributions for the entire systematic review community.\n\n\nProtocol\n\nA LSR involves similar resource demands as would a static review, but is ongoing (i.e., continually reprised). The methodological rationale for selecting LSR for the proposed study is based predominantly on the pace of emerging evidence (Khamis et al., 2019). Given the uncertainty surrounding existing evidence, and the rapid pace of technological advancement, continual surveillance will allow for faster presentation of new and emergent information that may impact findings and offer value for readers (Elliott et al., 2014, 2017). The following sections present the planned methodological approach of our living review.\n\nThis protocol is pre-registered in the Open Science Framework (OSF), an openly accessible repository facilitating the management, storage, and sharing of research processes and pertinent data files (Soderberg, 2018). This protocol adheres to the PRISMA-P guidelines (Moher et al., 2015; Shamseer et al., 2015). A completed PRISMA-P checklist is available at (Semi) Automated Approaches to Data Extraction for Systematic Reviews and Meta-Analyses in Social Sciences: A Living Review Protocol (https://osf.io/j894w). No human subjects are involved in this study.\n\nSearch strategy for this review follows existing research with protocol strategy adapted to fit goals and key elements of interest in social science domains. The model study initiated a LSR of processes supporting the (semi) automation of data extraction from research studies (e.g., clinical trials, epidemiological research; Schmidt et al., 2021, p. 26). Drawing upon the successful search strategy implemented by Schmidt et al., (2020b, 2021), we will conduct searches via the Web of Science Core Collection, IEEE Xplore Digital Library, and the DBLP Computer Science Bibliography. Databases and collections specific to clinical, medical, and biomedical literature are excluded from the search strategy (i.e., MEDLINE and PubMed). A preliminary search of Web of Science per protocol was conducted; 4,835 records were identified from Social Sciences Citation Index (SSCI), Arts & Humanities Citation Index (A&HCI), Conference Proceedings Citation Index – Social Science & Humanities (CPCI-SSH), and Emerging Sources Citation Index (ESCI). Based on the goals of the proposed study, several adjustments were made to the replicated search syntax. See “Extended Data” for relevant search strategy details, including syntax adjustments and preliminary search results. For the base review, this strategy will be replicated (to the extent possible) for remaining databases and any deviations openly reported in the project repository and subsequent publications.\n\nThe workflow structure follows existing research and guidance developed by Elliott et al. (2017) for transitioning to living status, frequency of monitoring, and incorporation of new evidence (see Figure 5). Transparent reporting of the base review and updates will follow PRISMA guidelines (Page et al., 2021). We intend to report results from the base review and later searches separately (Kahale et al., 2022). As quantity of new citations is unknown, necessary adjustments to the workflow described in this protocol will be detailed in future versions of the manuscript, noted in corresponding PRISMA reporting framework, and made available via the project repository.\n\nNote. Arrows represent stages involved in a static systematic review; the dotted line (from “Publish Report” to “Search”) represents the stage at which the review process is repeated from the beginning while the review remains in living status.\n\nThe base review will begin upon publication and peer approval of this protocol. All citations (i.e., titles and abstracts) identified by the search(es) will be independently screened by two researchers. Citation and abstract screening will be coordinated using Rayyan (Ouzzani et al., 2016). Full-text documents retrieved will be reviewed in duplicate and reliability assessment will be based on all documents screened. In the event of questionable inter-rater reliability, additional qualified reviewer(s) will be consulted. All relevant details pertaining to review decisions, including resolutions, will be available in the project repository (see “Data Availability Statement”). The review will be continually updated via living methodological surveys of newly published literature (Khamis et al., 2019). Updates will include search and screening of new evidence quarterly (every three months) with a cross-sectional analysis of relevant full texts at intervals of no less than twice per year (Khamis et al., 2019). Synthesis and publication of new evidence arising from continual surveillance will occur no less than once per year or until the review is no longer in living status.\n\nPapers considered for inclusion are refereed publications and conference proceedings in social sciences and tangent disciplines which describe the application of automation techniques or tools to support tasks associated with the extraction of data elements from primary research studies. As in prior reviews, English language reports, published 2005 or later will be considered for inclusion (Jonnalagadda et al., 2015; O’Mara-Eves et al., 2015; Schmidt et al., 2020b, 2021). The model article includes secondary goals related to reproducibility, transparency, and assessment of evaluation methods (Schmidt et al., 2021). The present study will also consider and synthesize reported evaluation metrics; however, we will not exclude studies omitting robust performance tests. To refine and test eligibility criteria, the complete list of Web of Science subject categories was reviewed, and inclusion decisions determined jointly by both researchers. Each category was evaluated based on the scientific branches and academic activity boundaries described by Cohen (2021). See the project supplementary data files for category selection procedures and criteria. Subjects deemed appropriate for inclusion in the initial search, title, and abstract screening stages (see Tsafnat et al., 2014) include foundational and applied formal sciences, social sciences, and social science tangent disciplines. Excluded subjects include natural sciences and applied clinical or medicinal science categories. In all cases, over-inclusion is prioritized to maximize search recall. See “Extended Data” for comprehensive search strategy details.\n\nEligible records include those which:\n\n• employ an evidence-synthesis method (e.g., systematic reviews, psychometric assessments, meta-analysis of effect sizes, etc.) and/or present a proof of concept, tool tests, or otherwise review automation technologies.\n\n• apply an existing or proposed tool or technique for the purpose of technology-assisted data extraction from the abstracts or full-text of a literature corpus.\n\n• report on any automated approach to data extraction (e.g., NLP, ML, TM), provided that at least one entity is extracted semi-automatically and sufficient detail is reported for:\n\n○ entities (i.e., data elements) targeted for automated extraction (per APA JARS)\n\n○ location of the extracted entities or data elements (e.g., abstract, methods, results)\n\n○ the automation tool and/or technique used to support data extraction\n\nStudies considered ineligible for inclusion in this review are those which:\n\n• apply tools or techniques to synthesize evidence from medical, biomedical, clinical (e.g., RCTs), or natural science research.\n\n• present guidelines, protocols, or user surveys without applying and/or testing at least one automation technique or tool.\n\n• are labeled as editorials, briefs, or opinion pieces.\n\n• do not apply an existing, proposed, or prototype tool or technique for the purpose of technology-assisted data extraction from the abstracts or full-text of a literature corpus (e.g., extraction of citation data only, narrative discussion that is not accompanied by application or testing).\n\n• do not apply automation for the extraction of data from scientific literature (e.g., web scraping, electronic communications, transcripts, or alternative data sources).\n\nO’Connor et al., (2019) described data extraction activities as the process of “extracting the relevant content data from a paper’s methods and results and the meta-data about the paper” (p. 4), therefore, we primarily target key reporting items for methods and results sections recommended by the APA. However, to support an exhaustive review and accommodate anticipated variation across automation approaches and reporting formats, a secondary area of interest includes identifying all paper sections for which data extraction technologies have been applied (see “Extended Data”).\n\nPrimary anticipated outcomes include identification of (a) tools/techniques applied to (semi) automate the extraction of data elements from research articles; (b) data elements targeted for extraction based on APA JARS standards; (c) systematic review and meta-analysis stages for which automation technologies are utilized; (d) evaluation metrics reported for applied automation technologies; and (e) where tools or technologies are presented, the potential for transferability to social sciences. Secondary anticipated outcomes include identification of (a) specific sections of research papers from which data is successfully extracted from primary corpora; (b) structure of content extracted using automation technologies; and (c) challenges reported by social science researchers related to the application of (semi) automated data extraction tools or technologies. Primary and secondary outcome items of interest are further described below, and supplementary data files referenced for readers to access additional information.\n\n\n\n1. Techniques, tools, systems architectures, and/or automation approaches applied for data extraction from research documents (abstracts and full text).\n\n○ A comprehensive list is provided in extended data files; see “Extraction Techniques.doc.”\n\n2. Data elements targeted for extraction using automation technologies as outlined by JARS (APA, 2020) and further explicated by Appelbaum et al. (2018, p. 6).\n\n○ A table containing a comprehensive list of targeted data elements is provided in the extended data files, see “Target Data Elements.doc”.\n\n3. Review tasks and stages for which extraction technologies are applied.\n\n○ A list of fifteen tasks along with stage classifications is adapted from Tsafnat et al. (2014). See extended data files; “Review Classifications.doc”.\n\n4. Evaluation metrics used to assess performance of the techniques or tools applied to support data extraction.\n\n○ Extended data file “Extraction Techniques.doc” provides a comprehensive list of metrics along with a description for each metric.\n\n5. Transferability, availability, and accessibility of technique or tool. Target questions include:\n\n○ Does the tool or technology easily transfer to research targeting the extraction of non-PICO prescribed elements?\n\n○ Is the technology publicly available for use by social science researchers?\n\n○ Where an established tool or platform was used, is it cataloged in the Systematic Review Toolbox (Marshall et al., 2022)?\n\n○ If a technique or tool is proprietary, is it open source code?\n\n\n\n1. Location (e.g., paper section) from which elements were extracted from research documents. To account for expected variation in reporting, paper sections of interest include, but are not limited to:\n\n○ (a) Title, abstract, and author notes; (b) Introduction and background; (c) Methods; (d) Results; and (e) Discussion\n\n○ A table containing a comprehensive list of targeted data elements is provided in the extended data files, see “Comprehensive List of Eligible Data Elements.xlsx”.\n\n2. Structure of content from which data entities were extracted (where named).\n\n○ Content formats may include unstructured (e.g., text); structured (e.g., tables), or images (e.g., figures).\n\n3. Challenges identified by social science researchers when applying automation technology to support data extraction efforts.\n\nAuthors plan to submit the base review results and subsequent update(s) to F1000Research for publication. Following the FAIR principles (i.e., findable, accessible, interoperable, and reusable; Wilkinson et al., 2016), all corresponding data will be available via the OSF project repository.\n\nTo support preparation of this protocol, a preliminary search was conducted in Web of Science. No formal search, screening, or review activities have been initiated. This protocol was preregistered via OSF Registries on August 14, 2022.\n\n\nData availability\n\nNo data are associated with this article.\n\nRepository: (Semi) Automated Approaches to Data Extraction for Systematic Reviews and Meta-Analyses in Social Sciences: A Living Review Protocol. https://doi.org/10.17605/OSF.IO/YWTF9 (Legate & Nimon, 2022).\n\nThis project contains the following extended data:\n\n• Extraction Techniques.docx – categories and descriptions of data extraction techniques, architecture components, and evaluation metrics of interest\n\n• Review Classifications.docx – review tasks and stages of interest\n\n• Target Data Elements.docx – key elements of interest for targeted data elements\n\n• Comprehensive List of Eligible Data Elements.xlsx – comprehensive list of elements with extraction potential per APA JARS\n\n• Search Syntax.docx – search syntax for preliminary search in Web of Science\n\nData are available under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0).\n\n\nReporting guidelines\n\nThis protocol follows PRISMA-P reporting guidelines (Moher et al., 2015). Open Science Framework (OSF) Repository: (Semi) Automated Approaches to Data Extraction for Systematic Reviews and Meta-Analyses in Social Sciences: A Living Review Protocol. https://doi.org/10.17605/OSF.IO/YWTF9 (Legate, & Nimon, 2022).",
"appendix": "References\n\nAmerican Psychological Association: Publication manual of the American Psychological Association. 7th ed.2020.\n\nAppelbaum M, Cooper H, Kline RB, et al.: Journal Article Reporting Standards for Quantitative Research in Psychology: The APA Publications and Communications Board Task Force report. Am. Psychol. 2018; 73(1): 3–25. PubMed Abstract | Publisher Full Text\n\nBlaizot A, Veettil S, Saidoung P, et al.: Using artificial intelligence methods for systematic review in health sciences: A systematic review. Res. Synth. Methods. 2022; 13(3): 353–362. PubMed Abstract | Publisher Full Text\n\nCohen E:The boundary lens: theorising academic activity. The university and its boundaries: Thriving or surviving in the 21st Century. Routledge;1st ed.2021; pp. 14–41. Publisher Full Text\n\nBosco F, Uggerslev K, Steel P: MetaBUS as a vehicle for facilitating meta-analysis. Hum. Resour. Manag. Rev. 2017; 27(1): 237–254. Publisher Full Text\n\nDavis J, Mengersen K, Bennett S, et al.: Viewing systematic reviews and meta-analysis in social research through different lenses. Springerplus. 2014; 3(1): 1–9. PubMed Abstract | Publisher Full Text\n\nElliott J, Turner T, Clavisi O, et al.: Living systematic reviews: An emerging opportunity to narrow the evidence-practice gap. PLoS Med. 2014; 11(2): E1001603. Publisher Full Text\n\nElliott J, Synnot A, Turner T, et al.: Living systematic review: 1. Introduction—the why, what, when, and how. J. Clin. Epidemiol. 2017; 91: 23–30. PubMed Abstract | Publisher Full Text\n\nEriksen MB, Frandsen TF: The impact of patient, intervention, comparison, outcome (PICO) as a search strategy tool on literature search quality: a systematic review. J. Med. Libr. Assoc. 2018; 106(4): 420–431. PubMed Abstract | Publisher Full Text\n\nGough D, Davies P, Jamtvedt G, et al.: Evidence Synthesis International (ESI): Position Statement. Syst. Rev. 2020; 9(1): 155. PubMed Abstract | Publisher Full Text\n\nGrimmer J, Roberts ME, Stewart BM: Machine learning for social science: An agnostic approach. Annu. Rev. Polit. Sci. 2021; 24: 395–419. Publisher Full Text\n\nHarrison H, Griffin S, Kuhn I, et al.: Software tools to support title and abstract screening for systematic reviews in healthcare: An evaluation. BMC Med. Res. Methodol. 2020; 20(1): 7. PubMed Abstract | Publisher Full Text\n\nHiggins JPT, Thomas J, Chandler J, et al.: Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane;2022.Reference Source\n\nHolub K, Hardy N, Kallmes K: Toward automated data extraction according to tabular data structure: Cross-sectional pilot survey of the comparative clinical literature. JMIR Form. Res. 2021; 5(11): E33124. PubMed Abstract | Publisher Full Text\n\nIp S, Hadar N, Keefe S, et al.: A Web-based archive of systematic review data. Syst. Rev. 2012; 1(1): 15. PubMed Abstract | Publisher Full Text\n\nJonnalagadda S, Goyal P, Huffman M: Automating data extraction in systematic reviews: A systematic review. Syst. Rev. 2015; 4(1): 78. PubMed Abstract | Publisher Full Text\n\nKahale L, Elkhoury R, El Mikati I, et al.: Tailored PRISMA 2020 flow diagrams for living systematic reviews: a methodological survey and a proposal [version 3; peer review: 2 approved]. F1000Res. 2022; 10: 192. PubMed Abstract | Publisher Full Text\n\nKhamis A, Kahale L, Pardo-Hernandez H, et al.: Methods of conduct and reporting of living systematic reviews: A protocol for a living methodological survey [version 1; peer review: 2 approved]. F1000 Res. 2019; 8: 221. Publisher Full Text\n\nLang D: Wordcloud2: Create Word Cloud by htmlWidget. R package version 0.2.2.2022.Reference Source\n\nLegate A, Nimon K: (Semi) automated approaches to data extraction for systematic reviews and meta-analyses in social sciences: A living review protocol. OSF. [Dataset]. 2022, August 14. Publisher Full Text\n\nLi T, Higgins JP, Deeks JJ, editors.Chapter 5: Collecting data.Higgins JPT, Thomas J, Chandler J, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane;2022.Reference Source\n\nMarshall C, Sutton A, O’Keefe H, et al., editors. The Systematic Review Toolbox. 2022.Reference Source\n\nMarshall I, Wallace B: Toward systematic review automation: A practical guide to using machine learning tools in research synthesis. Syst. Rev. 2019; 8(1): 110–163. PubMed Abstract | Publisher Full Text\n\nMiwa M, Thomas J, O’Mara-Eves A, et al.: Reducing systematic review workload through certainty-based screening. J. Biomed. Inform. 2014; 51: 242–253. Publisher 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\n\nNational Institute of Social Sciences:n.d. What Is “Social Science?”. Reference Source\n\nO’Connor A, Tsafnat G, Thomas J, et al.: A question of trust: Can we build an evidence base to gain trust in systematic review automation technologies? Syst. Rev. 2019; 8(1): 143. PubMed Abstract | Publisher Full Text\n\nO’Mara-Eves A, Thomas J, McNaught J, et al.: Using text mining for study identification in systematic reviews: A systematic review of current approaches. Syst. Rev. 2015; 4(1): 5. PubMed Abstract | Publisher Full Text\n\nOuzzani M, Hammady H, Fedorowicz Z, et al.: Rayyan-a web and mobile app for systematic reviews. Syst. Rev. 2016; 5(1): 210. PubMed Abstract | Publisher Full Text\n\nPage M, McKenzie J, Bossuyt P, et al.: The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. J. Clin. Epidemiol. 2021; 88: 105189–105906. Publisher Full Text\n\nPigott T, Polanin J: Methodological guidance paper: High-quality meta-analysis in a systematic review. Rev. Educ. Res. 2020; 90(1): 24–46. Publisher Full Text\n\nPurdue Online Writing Lab: APA Style Introduction. Purdue Online Writing Lab;n.d.Reference Source\n\nR Core Team: R: A language and environment for statistical computing. R Foundation for Statistical Computing;2021.Reference Source\n\nShamseer L, Moher D, Clarke M, et al.: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation. BMJ: British Medical Journal. 2015; 350: 1–25. PubMed Abstract | Publisher Full Text\n\nSchmidt L, Olorisade BK, McGuinness LA, et al.: Data extraction methods for systematic review (semi)automation: A living systematic review [version 1; peer review: 3 approved]. F1000Res. 2021; 10: 401. PubMed Abstract | Publisher Full Text\n\nSchmidt L, McGuinness LA, Olorisade BK, et al.: Protocol.2020a, March 11. Publisher Full Text\n\nSchmidt L, Olorisade BK, McGuinness LA, et al.: Data extraction methods for systematic review (semi)automation: A living review protocol [version 2; peer review: 2 approved]. F1000Res. 2020b; 9: 210. PubMed Abstract | Publisher Full Text\n\nScott A, Forbes C, Clark J, et al.: Systematic review automation tools improve efficiency but lack of knowledge impedes their adoption: A survey. J. Clin. Epidemiol. 2021; 138: 80–94. PubMed Abstract | Publisher Full Text\n\nShort JC, McKenny AF, Reid SW: More than words? Computer-aided text analysis in organizational behavior and psychology research. Annu. Rev. Organ. Psych. Organ. Behav. 2018; 5(1): 415–435. Publisher Full Text\n\nSoderberg C: Using OSF to share data: A step-by-step guide. Adv. Methods Pract. Psychol. Sci. 2018; 1(1): 115–120. Publisher Full Text\n\nTsafnat G, Glasziou P, Choong M, et al.: Systematic review automation technologies. Syst. Rev. 2014; 3(1): 74. PubMed Abstract | Publisher Full Text\n\nWagner G, Lukyanenko R, Paré G: Artificial intelligence and the conduct of literature reviews. J. Inf. Technol. 2022; 37(2): 209–226. Publisher Full Text\n\nWilkinson M, Dumontier M, Aalbersberg I, et al.: The FAIR Guiding Principles for scientific data management and stewardship. Nature. 2016; 3(1): 160018. PubMed Abstract | Publisher Full Text\n\nYarkoni T, Eckles D, Heathers JAJ, et al.: Enhancing and accelerating social science via automation: Challenges and opportunities. Harv. Bus. Rev. 2021. Publisher Full Text\n\nYu Z, Kraft N, Menzies T: Finding better active learners for faster literature reviews. Empir. Softw. Eng. 2018; 23(6): 3161–3186. Publisher Full Text"
}
|
[
{
"id": "152219",
"date": "24 Oct 2022",
"name": "Frederick L. Oswald",
"expertise": [
"Reviewer Expertise Meta-analysis",
"psychometrics",
"individual differences",
"employment testing",
"open 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\nAuthors propose to review the available-and-growing literature, technologies, and practices pertaining to conducting systematic reviews and meta-analysis by automated or semi-automated means. This review will be continuously updated via the living systematic review (LSR).\n\nThe importance of this work is evident - because meta-analyses are extremely popular, useful, and necessary in many research domains, any technologies that stand to improve the conduct and quality of meta-analyses are welcome.\n\nAutomated methods could apply not only to the extraction of data, but also to literature searching itself (e.g., see the Elicit AI assistant at https://elicit.org/).\n\nAuthors might dive deeper on what benchmark standards might be used (overall and within domains); maybe the comparison across the technologies reviewed are relative benchmarks across a variety of dimensions (e.g., errors of omission vs. commission across JARS elements, extent of human involvement, domain-specific effectiveness).\n\nFrom this birds-eye view, the LSR might make summary recommendations of things such as (a) the conditions under which some tools are more useful than others; (b) how specific tools might be improved or technologies advanced more generally; (c) best reporting practices for authors (and reporting errors to avoid); (d) how humans tend to be most helpful (e.g., automation might err on the side of inclusion, for the human to winnow down).\n\nSide notes:\np. 4 refers to 'social research' but I think this is 'social sciences research' top of Fig 2 looks like a header, but it only refers to the content of Table 1 (in other words, the reader wouldn't want to think that 'Bayesian techniques' are 'recommended for inclusion in manuscripts regardless of design') Instead of the word clouds in Figs 3 and 4, I'd suggest tabling the similarities and differences, or perhaps not including them at all (e.g., the comparison wouldn't be as helpful in domains that do not conduct clinical trials)\n\nGood luck to the authors in pursuing this LSR; I think many scholars (including myself) will find it very useful.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "8968",
"date": "01 Nov 2022",
"name": "Amanda Legate",
"role": "Author Response",
"response": "Dear Dr. Oswald, Thank you for serving as a reviewer for our protocol manuscript. We greatly appreciate your thoughtful feedback. When all reviewer reports have been received and considered, we will incorporate suggestions where appropriate and respond directly to each point outlined in your report. Kind regards, Amanda Legate Dr. Kim Nimon"
},
{
"c_id": "9162",
"date": "27 Jan 2023",
"name": "Amanda Legate",
"role": "Author Response",
"response": "Comment 3 Automated methods could apply not only to the extraction of data, but also to literature searching itself (e.g., see the Elicit AI assistant at https://elicit.org/). Thank you for this feedback. We could have better described our goals as they relate to SR stages that are considered relevant within the scope of this review. We have incorporated a statement to enhance clarity related to potential for application across various stages of the review process. See section: “Key items of interest” (Paragraph 1) Comment 4 Authors might dive deeper on what benchmark standards might be used (overall and within domains); maybe the comparison across the technologies reviewed are relative benchmarks across a variety of dimensions (e.g., errors of omission vs. commission across JARS elements, extent of human involvement, domain-specific effectiveness). We agree and believe that incorporating your suggestions will offer readers more context for understanding our research goals and anticipated outcomes related to benchmarking and performance assessment. In the revised protocol, we have included a summary of anticipated LSR outcomes related to benchmarking standards and performance assessment measures. See section: “Key items of interest” (Paragraph 2) Comment 5 From this birds-eye view, the LSR might make summary recommendations of things such as (a) the conditions under which some tools are more useful than others; (b) how specific tools might be improved or technologies advanced more generally; (c) best reporting practices for authors (and reporting errors to avoid); (d) how humans tend to be most helpful (e.g., automation might err on the side of inclusion, for the human to winnow down). This is wonderful feedback, thank you. We have incorporated your suggestions under the item of interest pertaining to challenges identified by researchers that may offer meaningful summary recommendations for the social science research community. See section: “Secondary items of interest” (Number 3) Comment 6, Bullet 1 p. 4 refers to 'social research' but I think this is 'social sciences research' Thank you for bringing this to our attention, we have corrected the sentence. See section: “The need for this review in social sciences” (Paragraph 3) Comment 6, Bullet 2 top of Fig 2 looks like a header, but it only refers to the content of Table 1 (in other words, the reader wouldn't want to think that 'Bayesian techniques' are 'recommended for inclusion in manuscripts regardless of design') We appreciate this feedback; upon thoughtful consideration, we agree that the figure is potentially misleading, especially for audiences less familiar with APA reporting guidelines. In the revised protocol, we have updated the figure and added additional figure notes to enhance clarity surrounding APA JARS guidance for applying tables/modules based on research design. See section: “The need for this review in social sciences” (Figure 2) Comment 6, Bullet 3 Instead of the word clouds in Figs 3 and 4, I'd suggest tabling the similarities and differences, or perhaps not including them at all (e.g., the comparison wouldn't be as helpful in domains that do not conduct clinical trials) Figures 3 and 4 have been removed in the revised version of the protocol. Due to size, a comparative table is inappropriate for inclusion within the body of the manuscript. However, we have added a file containing the tabled data elements for Cochrane reviews, APA Module C (clinical trials), and APA (all study designs) to the OSF project. See section: “Extended data” – Filename “APA & Cochrane Data Elements.xlsx”. Closing Comments Good luck to the authors in pursuing this LSR; I think many scholars (including myself) will find it very useful. Thank you for lending your time and expertise for the improvement of our protocol manuscript. We hope that we have been able to effectively address your concerns in the revised version of this protocol."
}
]
},
{
"id": "155953",
"date": "24 Nov 2022",
"name": "Michèle B. Nuijten",
"expertise": [
"Reviewer Expertise Research methods in psychology",
"meta-science",
"automated extraction of statistical results"
],
"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 it is useful to have a thorough overview of the available data extraction tools applicable to the social sciences. Meta-analysis and other synthesis methods are increasingly necessary to deal with the increasing scientific output, and automated data extraction can play an important role in this.\nThe authors present a thorough protocol for their LRS. I am happy to see that they preregistered their protocol and published their detailed supplemental materials online.\nI do have some questions/concerns I would like the authors to address.\nFirst, the authors plan to exclude data extraction tools published/applied in the medical sciences. They correctly argue that data extraction tools for the medical sciences often rely on the systematic reporting in medical papers, which means they can often not be applied in the social sciences. However, by excluding ALL tools from the medical sciences, it seems possible to overlook tools that WOULD be applicable to the social sciences as well. This would make the overview of tools in the LRS incomplete. Did the authors consider this?\nSecond, related to the point above, the authors intend to exclude tools from clinical research, but what does this mean for tools applied in fields that are on the overlap of the social sciences and clinical sciences, such as clinical psychology?\nThird, the authors plan to extract a lot of information from the included articles. I think it is important to mention in the protocol how this information will be presented. Will the authors use tables to present everything? Visualizations? A database? Summary statistics? Something else?\nSome small additional comments/questions:\nP.8 (of the pdf) Search and Updates: what exactly will the reliability be calculated about? Reliability of what? Also: please define what qualifies as “questionable” inter-rater reliability.\n\nP.9: why is psychometric assessment considered an evidence-synthesis method?\nBest wishes and good luck with this project,\n\nIs the rationale for, and objectives of, the study clearly described? Yes\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": "9163",
"date": "27 Jan 2023",
"name": "Amanda Legate",
"role": "Author Response",
"response": "Concern 1 First, the authors plan to exclude data extraction tools published/applied in the medical sciences. They correctly argue that data extraction tools for the medical sciences often rely on the systematic reporting in medical papers, which means they can often not be applied in the social sciences. However, by excluding ALL tools from the medical sciences, it seems possible to overlook tools that WOULD be applicable to the social sciences as well. This would make the overview of tools in the LRS incomplete. Did the authors consider this? You highlight a relevant concern. First, we have given this thoughtful consideration. The ongoing LSR conducted by Schmidt et al., (2021) focuses exclusively on semi-automated extraction techniques in medical domains. Additionally, several recent studies (including user surveys of SR automation tools) address application of (semi)automation tools for clinical, medical, and healthcare research. We aim to complement the growing body of automated data extraction research by uncovering evidence related to how, where, and for what purpose(s) technologies are being applied across social science domains. This strategy is intended to reduce redundancy while allowing for comparison against a similar LSR that is currently in progress. That said, we understand that additional clarity surrounding the purpose and scope of our proposed LSR is needed. To address this concern, we have updated the protocol to add clarity surrounding the purpose and scope of the review. See section: “Objectives of this living review” (paragraph 1) - added clarity surrounding aims of the present study considering similar ongoing efforts targeting medical/clinical research domains. Second, we will not exclude tools that have been published and/or applied in the medical sciences. Our goal is to identify tools that have been or are being applied in social science research (regardless of domain of origin). Given the discourse surrounding the lack of tools developed for use outside of the medical research community, we anticipate that existing tools, even those developed for the medical community (or for specific methodologies - e.g., RCTs), have been and/or are being applied/tested outside of those areas. It is possible that a substantial amount these activities are already occurring, however, existing systematic efforts to synthesize and present evidence focus on evidence-based medicine. We hope that by systematically and transparently aggregating what is known about how these tools/technologies are applied in social science research, our study will offer sufficient evidence for side-by-side comparison with existing research and support future research and/or opportunities for application of existing technologies supporting evidence synthesis in social sciences. While our search strategy does not contain exclusion criteria related to the tools/technologies themselves, we have updated the protocol to enhance clarity surrounding our search strategy goals and eligibility criteria. (A) See section: “Eligibility criteria” (Paragraph 2) – added paragraph to better describe search strategy goals and exclusion criteria. (B) See section: “Excluded papers” (Bullet 1) - added “exclusively” to enhance specificity in exclusion criteria. Concern 2 Second, related to the point above, the authors intend to exclude tools from clinical research, but what does this mean for tools applied in fields that are on the overlap of the social sciences and clinical sciences, such as clinical psychology? Our search strategy applies subject category filters with the goal of identifying studies that are not already included in extant projects addressing clinical research (e.g., clinical trials). However, a variety of potentially overlapping subject categories are targeted for inclusion in our search strategy (e.g., applied psychology, developmental psychology, experimental psychology, social psychology, among many other subjects). We limited the scope of our study not to exclude potentially transferable tools and technologies, but rather, to mitigate potential for research redundancy and focus on an underrepresented area in research automation reviews. In reflecting on your comments, we noticed that our search strategy document was mislabeled in the protocol manuscript such that readers could reasonably assume the document only contains search syntax. We have corrected the filename in our revised protocol. See section: “Extended data” (Bullet 5) - Corrected filename: “Search Strategy.docx” Concern 3 Third, the authors plan to extract a lot of information from the included articles. I think it is important to mention in the protocol how this information will be presented. Will the authors use tables to present everything? Visualizations? A database? Summary statistics? Something else? This is an excellent suggestion, thank you. We have added a section (immediately following key items of interest section) in the revised protocol to describe our plan for presenting results of the LSR. See section: “Presentation of results” Some small additional comments/questions Bullet 1 P.8 (of the pdf) Search and Updates: what exactly will the reliability be calculated about? Reliability of what? Also: please define what qualifies as “questionable” inter-rater reliability. Thank you for bringing this omission to our attention. Our revised protocol includes additional detail related to a structured plan for assessing and reporting the reliability of screening and coding activities. See section: “Search and updates” (Paragraphs 2 & 3) Bullet 2 P.9: why is psychometric assessment considered an evidence-synthesis method? Our intent was to reference assessment of psychometric properties (e.g., reliability/validity of instrumentation) which often involves extracting/synthesizing a substantial amount of evidence from published research. This content has been adjusted to reflect more accurate terminology. See section: “Included papers” (Bullet 1) Closing Comments Best wishes and good luck with this project. Thank you, Dr. Nuijten. We appreciate your thoughtful review and value-enhancing feedback. We hope that we have been able to effectively address your concerns in the revised version of this protocol."
}
]
},
{
"id": "155957",
"date": "19 Dec 2022",
"name": "Sean Rife",
"expertise": [
"Reviewer Expertise Metascience",
"social psychology",
"moral and political psychology",
"quantitative methods"
],
"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 proposes a living review of papers that describe automated methods of data extraction in the social sciences that support meta analyses and other types of systematic reviews. This work is needed, as the number of tools of this type is increasing rapidly, and it is increasingly clear that they will play a prominent role in metascientific endeavors going forward. It is well written and clearly explicates the task at hand.\nI have two concerns: first, the paper has a unique task at hand, as it is describing an ongoing review of tools that themselves are used to conduct reviews. For reasons I'm not entirely aware of, when first reading the paper, I assumed that the proposed living review would itself be using automated tools (it wasn't until I reached the \"Search and updates\" section that I realized my error - at which point I had to go back and review the Introduction and Background. I'm not sure if this warrants any changes in the manuscript, but I thought it was worth pointing out. (I am reminded of this cartoon: https://xkcd.com/1447/.)\nSecond, I worry that by focusing on published papers, this project will miss many programs of great interest. Tools for the automated analysis of scientific papers are often developed without any accompanying publication, at least initially (I am thinking here of projects such as Barzooka [https://github.com/quest-bih/barzooka] and Jetfighter [https://github.com/smsaladi/jetfighter]). Would it not be useful to also monitor code repositories such as GitHub and GitLab?\nI also have a few minor notes:\nThe last two items in the \"Excluded papers\" section seem redundant with the criteria laid out in the preceding \"Included papers\" section (that is, the inclusion criteria should be enough to cover those instances.)\n\nThere are a number of references to \"tangent disciplines\" to social science. I've not heard this term previously (although perhaps I am just out of the loop?). Perhaps \"related disciplines\" is a better phrase?\n\nThe list of extraction techniques provided in the OSF repository is extensive, but seems to be limited to relatively sophisticated techniques (e.g., machine learning, deep learning techniques and natural language processing). However, automated extraction tools (e.g., statcheck) perform quite well employing simpler techniques such as text search using regular expressions.\n\nThe word clouds are neat, but I'm not sure they add much beyond what is conveyed in the main text of the manuscript.\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? Not applicable",
"responses": [
{
"c_id": "9164",
"date": "27 Jan 2023",
"name": "Amanda Legate",
"role": "Author Response",
"response": "Comment This paper proposes a living review of papers that describe automated methods of data extraction in the social sciences that support meta analyses and other types of systematic reviews. This work is needed, as the number of tools of this type is increasing rapidly, and it is increasingly clear that they will play a prominent role in metascientific endeavors going forward. It is well written and clearly explicates the task at hand. Thank you, Dr. Rife, for offering your time and expertise for the improvement of our study protocol. We hope that we have been able to effectively address your concerns in the revised version of the protocol manuscript. Concern 1 I have two concerns: first, the paper has a unique task at hand, as it is describing an ongoing review of tools that themselves are used to conduct reviews. For reasons I'm not entirely aware of, when first reading the paper, I assumed that the proposed living review would itself be using automated tools (it wasn't until I reached the \"Search and updates\" section that I realized my error - at which point I had to go back and review the Introduction and Background. I'm not sure if this warrants any changes in the manuscript, but I thought it was worth pointing out. (I am reminded of this cartoon: https://xkcd.com/1447/.) Thank you for sharing this feedback. We hope that adjustments made to the revised version of protocol help to reduce confusion by more effectively describing the purpose, scope, and goals of the proposed study. We have also added a note explicitly stating that we do not intend to utilize automation tools for search, retrieval, or relevance decision tasks associated with this LSR. See section: “Objectives of this living review” – Footnote 1 Concern 2 Second, I worry that by focusing on published papers, this project will miss many programs of great interest. Tools for the automated analysis of scientific papers are often developed without any accompanying publication, at least initially (I am thinking here of projects such as Barzooka [https://github.com/quest-bih/barzooka] and Jetfighter [https://github.com/smsaladi/jetfighter]). Would it not be useful to also monitor code repositories such as GitHub and GitLab? We understand your concern. We first want to clarify that if tools/technologies are utilized for evidence synthesis, reviews, or otherwise applied in eligible studies, our review will capture this information as long as the author(s) reference the tool in their paper. There is no requirement that the research be conducted by or associated with the developer(s) of the tool/technology to be included in the review. We opted to employ a living review methodology to mitigate potential for overlooking newly developed tools or those currently under development. More specifically, if a tool does not appear in any published research (whether associated with the tool developers or otherwise reviewed, tested, and/or applied for evidence synthesis) during the base review, it can still be identified by later iterations of the search and retrieval stage. We have updated our methodological rationale to add clarity in this regard. See section: “Protocol” (Paragraph 1) Second, we agree with your assessment that monitoring code repositories would be useful. We feel that we can, within the scope of this study, support future research in this task by offering evidence surrounding the current (and evolving) state of automation endeavors across social science domains. To better support this aim and assist in alleviating some concern, we have added code repositories among our key items of interest in the revised protocol. See section: “Primary items of interest” (Number 5) Minor Notes I also have a few minor notes: Minor Notes – Bullet 1 The last two items in the \"Excluded papers\" section seem redundant with the criteria laid out in the preceding \"Included papers\" section (that is, the inclusion criteria should be enough to cover those instances.) Based on extant discourse related to SR screening behaviors, we incorporated these eligibility criteria to provide a coding framework for transparent documentation and reporting. We anticipate substantial variation in the level of detail included in article abstracts. Where a study may initially be considered for inclusion based on information available in the abstract, full-text review may ultimately result in a decision to exclude. In such cases, decisions to exclude articles based on full-text review must be coded accordingly. Thus, any one record may be coded based on both inclusion and exclusion criteria at difference stages of relevance screening. To help address your concern related to redundancy, we have revised the protocol manuscript to better describe the purpose for the exclusion criteria above and beyond the inclusion criteria. See section: “Eligibility criteria” (Paragraph 3) Minor Notes – Bullet 2 There are a number of references to \"tangent disciplines\" to social science. I've not heard this term previously (although perhaps I am just out of the loop?). Perhaps \"related disciplines\" is a better phrase? Thank you for this feedback. Both instances have been updated to “related disciplines” in the revised protocol. Minor Notes – Bullet 3 The list of extraction techniques provided in the OSF repository is extensive but seems to be limited to relatively sophisticated techniques (e.g., machine learning, deep learning techniques and natural language processing). However, automated extraction tools (e.g., statcheck) perform quite well employing simpler techniques such as text search using regular expressions. We greatly appreciate you taking the time to review our supplementary files and provide feedback. We agree that the list of techniques that may surface over the course of the review could be more inclusive. A revised document has been added to the OSF repository. The table is amended to include a more comprehensive list of components or architectures that may be identified by the proposed LSR. See section: “Extended data” - Filename “Extraction Techniques Revised.docx” Minor Notes – Bullet 4 The word clouds are neat, but I'm not sure they add much beyond what is conveyed in the main text of the manuscript. Thank you for bringing this to our attention. Figures 3 & 4 have been removed in the revised version of this protocol."
}
]
}
] | 1
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https://f1000research.com/articles/11-1036
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https://f1000research.com/articles/11-295/v1
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10 Mar 22
|
{
"type": "Research Article",
"title": "DNA barcoding detects resurrected taxon Giuris laglaizei (Sauvage 1880) in Sulawesi, Indonesia: Bolano Sau Lake payangka phylogeny, phenotypic characters and implications for Giuris spp. conservation",
"authors": [
"Samliok Ndobe",
"Muhammad Saleh Nurdin",
"Nur Hasanah",
"Aswad Eka Putra",
"Kasim Mansyur",
"Mohamad Nasir",
"Mashening L. Rabuna",
"Abigail Mary Moore",
"Muhammad Saleh Nurdin",
"Nur Hasanah",
"Aswad Eka Putra",
"Kasim Mansyur",
"Mohamad Nasir",
"Mashening L. Rabuna",
"Abigail Mary Moore"
],
"abstract": "Background: The freshwater ichthyofauna of Wallacea is diverse and understudied. A baseline survey of Bolano Sau Lake in Parigi Moutong District, Central Sulawesi Province, Indonesia in 2019 found an eleotrid goby (local name payangka) with characters conforming to the genus Giuris, long considered monophyletic as G. margaritacea/G. margaritaceus but recently found to comprise at least eight species. This study focused on the molecular (DNA barcoding) identification and phenotypic characters of the payangka. Methods: Payangka samples were collected from August to December 2019 in collaboration with local fishermen, weighed and measured, and preserved in 75% ethanol. Length, weight, sex (n=111) and seventeen morphometric characters/six meristic counts (n=42) were recorded. DNA barcoding was performed on a fin clipping preserved in 96% ethanol. Homologous nucleotide sequences were obtained from public (GenBank and BOLD) databases, analysis conducted in MEGA X, and phylogenetic trees edited in the Interactive Tree of Life (iToL). Results: Within the polyphyletic Giuris clade, the payangka sequence resolved into a sub-clade identified as Giuris laglaizei (Sauvage 1880), a recently resurrected taxon, based on a sequence provided by Philippe Keith. The length-weight relationship (L = 0.0087∙W3.162) indicated mildly allometric positive growth. Size distribution differed significantly between male and female fish with significantly larger mean size of males (13.56 cm) than females (11.62 cm). The meristic formula was: D VI-I,8 A I,8 P 13 V I,5 C15. Phylogenic analysis indicated four Giuris species in wetlands around Tomini Bay and five in Sulawesi. Conclusions: This first record of G. laglaizei in Indonesia advances knowledge of Wallacean and Indo-Pacific gobioid biogeography and highlights the need for a revision of the conservation status of the taxa currently grouped under Giuris margaritacea/G. margaritaceus in the IUCN Red List and FishBase databases. The data will inform biodiversity and fisheries management at local and regional levels.",
"keywords": [
"Eleotridae",
"Giuris margaritacea",
"amphidromy",
"phylogeny",
"meristic",
"morphometric",
"Tomini Bay",
"Wallacea"
],
"content": "Background\n\nIndonesian freshwater ichthyofauna is highly diverse, comprising primary freshwater and diadromous fishes.1 While the ichthyofauna of western Indonesia (Sundaland biogeographic province) is dominated by cyprinids (Cyprinidae), the gobies (Gobioidei) predominate in the Wallacea biogeographic province.1,2 The freshwater ichthyofauna of Sulawesi, the largest island in Wallacea, is characterised by endemic freshwater species flocks and diadromous (mostly amphidromous sensu3,4) taxa with marine larval stages.1 These include gobies (Gobioidei) of the Families Gobiidae and Eleotridae, the latter also known as sleepers or gudgeons.1,5–9 Although the number of diadromous (mostly amphidromous) gobies reported from the lakes, rivers and coastal waters around Sulawesi is increasing, with several recently described species and range extensions,10–18 the ichthyofauna of most Sulawesian waterbodies is still largely unstudied.9\n\nTypically multi-species shoals of amphidromous goby postlarvae, with local names including nike, penja and duwo, are heavily fished in coastal waters around Sulawesi as they migrate to freshwater habitats, both in their own right and as bycatch in anguillid glass eel fisheries.11,12,19–23 Goby postlarvae are also present and intensively fished in some inland waters, in particular Tondano Lake in North Sulawesi.10,24–28 The adults of some diadromous gobies are also locally important as food fish, including gudgeons (Eleotridae) generally known as payangka or (more rarely) payangga.10,29,30 Sulawesian payangka populations have been identified as northern mud gudgeon Ophiocara porocephala Valenciennes 183731–33 and snakehead gudgeon Giuris margaritacea Valenciennes 1837.25,26,34–36 Both taxa are thought to be amphidromous.37\n\nIn recent decades the Indonesian Government has promoted so-called “re-stocking” of inland waterbodies. These programs almost always involve the release of non-native (alien) species, often with negative impacts on native aquatic species in Indonesia38,39 including in Sulawesi.40–43 Increasing concern for native aquatic species has prompted surveys of inland waterbodies in Sulawesi, including those with a history of such introductions.\n\nBolano Sau Lake is one of a series of three small lakes close to the Tomini Bay coast of the northern arm of Sulawesi, in Bolano Subdistrict, Parigi Moutong District, Central Sulawesi Province. A baseline survey of Bolano Sau Lake in 2019 found an ichthyofauna dominated by introduced (alien) fish species.44,45 Three native species were caught during sampling, one of which was a gudgeon with the local name payangka, tentatively identified as Giuris margaritacea,45 the current valid name of the snakehead gudgeon in FishBase, the Global Database of Fishes. According to Kottelat (2013) the genus name Giuris is masculine in gender, and therefore the correct nomenclature is Giuris margaritaceus, the current organism name in the NCBI GenBank and BOLD nucleotide sequence databases.46\n\nWithin the Gobioidei, cryptic and morphologically similar species can complicate identification based on external morphology,46–49 and there have been many taxonomic revisions in the Gobiidae, including the Family Eleotridae. There are at least 10 “non valid” synonyms of G. margaritacea Valenciennes 1837 (originally Eleotris margaritacea Valenciennes 1837) listed in FishBase, including Ophieleotris aporos (originally Eleotris aporos Bleeker 1854) and junior synonyms under the genera Eleotris (n=7), Hypseleotris (n=1), and Ophieleotris (n=1). Ophieleotris aporos in particular is still commonly used,14,30,50–52 and a recent checklist of fishes from two Sulawesian islands13 lists G. margaritacea (from East and West Timor) and O. aporos (from lakes in North Sulawesi) as separate species, with the further addition of Ophieleotris aff. aporos (from Buton Island in Southeast Sulawesi). Recent research has demonstrated that G. margaritacea has been erroneously and confusingly applied to a taxonomic group comprising at least eight species.15,53\n\nSuch taxonomic uncertainty seriously complicates accurate species determination and the search for valid information on aspects such as species distribution, biology, ecology and status. As pointed out by,54 the ability to precisely identify the fish species in fisheries catches or waters is important for moving towards more sustainable exploitation of fish resources and better protection of fish diversity. An increasingly common molecular approach to species identification is DNA barcoding; this involves the sequencing of a fragment of DNA which is highly conserved within species but differs between species of the taxonomic group being studied.55 For vertebrates, including fishes, a subset or fragment of the mitochondrial cytochrome oxidase I (COI) gene is the most commonly used barcoding region.2,56 In addition to species identification, phenotypic traits are important for taxonomy and to support fisheries management.54,57,58\n\nFrom a biodiversity and responsible fisheries management point of view, it was considered important to determine the native species currently present in Bolano Sau Lake. This study combined molecular biology methods (DNA barcoding) to identify the payangka in Bolano Sau Lake with classic methods to describe phenotypic characters, in particular external morphology (morphometric and meristic characters) and growth pattern (length-weight relationship). The study will inform management of the payangka as well as contributing to knowledge of Giuris biogeography.\n\n\nMethods\n\nThis study complied with relevant ethical regulations in Indonesia and followed the ARRIVE guidelines. The use of the samples in this study did not require specific ethical approval for the following reasons:\n\n1. All fish specimens used were obtained under an ongoing collaboration between the Parigi Moutong District Marine and Fisheries Service (Dinas Kelautan dan Perikanan Kabupaten Parigi Moutong) and Universitas Tadulako following all applicable regulations.\n\n2. The fish were captured by local fishers operating legal fisheries using permitted artisanal fishing gears.\n\n3. All fish were euthanized following the standard guidelines in use for fish specimens at Universitas Tadulako. Based on standard internationally recognised protocols,59 the procedures used were designed to minimise any suffering experienced by the specimens (through anaesthetising the fish before pithing), and were performed by experienced personnel.\n\n4. The IUCN Red List assessment lists Giuris margaritacea (the only listed Giuris taxon) in the Least Concern category (not considered at risk of extinction).\n\n5. There was no experimental component.\n\nBolano Sau is the largest of a three-lake complex in the coastal plain along the north coast of Tomini Bay in Parigi Moutong District, Central Sulawesi Province, Indonesia. Batudako Lake is further inland and Laut Kecil Lake is closer to the coast. Bolano Sau Lake is situated just north of the equator in Bolano Barat Village, Bolano Subdistrict, between approximately 0° 27’ 12” to 0° 27’ 15” N and 120° 52’ 52” to 120° 53’ 49” E an elevation of 5 m above sea level with an area of around 76 Ha, a volume of around 762 m3, an average depth of around 4.26 m and a maximum depth of less than 10 m (Figure 1).\n\nPayangka specimens for morphometric and meristic analysis were collected from August to December 2019 in collaboration with local fishermen using a throw net with mesh size 3.5” (n=42). Field identification followed.6,60 Specimens were humanely euthanized (anaesthesia with 70% ethanol followed by pithing) following.59 Each fish was then weighed (electronic scales, precision 1 g), measured (Cadwell fish ruler, precision 0.5 mm), labelled and preserved in 70% alcohol.\n\nPrior to preservation, a fin clipping was taken from the right hand pectoral fin of a payangka specimen (female, total length (TL)=13.32 mm) and placed in a 1.5 mL Eppendorf tube filled with 96% absolute ethanol. The sample was dispatched to the BIONESIA laboratory in Denpasar for DNA barcoding. Genomic DNA was extracted from the sample using the Qiagen DNeasy Blood & Tissue Kit following manufacturer’s protocols. A fragment of mitochondrial DNA (mtDNA) from the cytochrome oxidase I (COI) gene was amplified through polymerase chain reaction (PCR) using Fish_F1 and Fish_R1 primers.61 The PCR profile comprised initial denaturation at 94 °C for 3 min; 35 cycles of 94 °C for 30 s, 50 °C for 30 s, and 72 °C for 60 s; and final extension at 72 °C for 2 min. The PCR product was visualized via electrophoresis on 1% agarose gel stained with Nucleic Acid Gel Stain (GelRed®). Sanger sequencing of the PCR product was performed by First Base. The forward and reverse sequences were trimmed, aligned and combined in MEGA X62 to produce a nucleotide sequence submitted to the NCBI GenBank repository as accession OM674613.63 The nucleotide composition (adenine, thymine, guanine, cytosine bases) of the payangka mitochondrial cytochrome C oxidase subunit I (COI) gene sequence was determined in MEGA X.62 The online BLASTn (Basic Local Alignment Search Tool-nucleotide) tool and the Barcode of Life Database (BOLD) Identification routine were used to provide an initial identification.\n\nHomologous nucleotide sequences with at least 90% coverage were obtained from the BLASTn results (Gobioid species in the 100 closest matches) and NCBI accession search using the terms Giuris margaritaceus, G. margaritacea, Ophieleotris aporos and Ophiocara porocephala, and from the BOLD Database using the keyword Giuris which yielded seven Barcode Index Numbers (BINs), with additional sequences obtained from the scientific literature (Table S1 – see Extended Data). The climbing perch Anabas testudineus was used as an outgroup: a sequence from Bolano Sau Lake, GenBank accession OM674614,63 and GenBank accession MG407353.64 All alignment, trimming and evolutionary analyses were conducted in MEGA X.62 Evolutionary relationships were inferred and phylogenetic trees constructed using the Maximum Likelihood method and Kimura 2-parameter model65 with default parameters, all codon positions, 100 × bootstrap test, and branch lengths representing the number of substitutions per site.\n\nThe first phylogenetic tree was constructed from an aligned dataset with 630 nucleotide positions containing 96 nucleotide sequences (GenBank accessions in Table S1). A second tree was constructed using all sequences in Table S1 with the genus level label Giuris (including BOLD records and non-deposited sequences) and other sequences nested within the Giuris clade in the first tree; there were 94 nucleotide sequences with 580 nucleotide positions in the aligned dataset. The payangka sequence was included in both analyses. The phylogenetic trees were exported from Mega X as Newick tree files and edited in the on-line interactive Tree of Life (iToL).66,67 Pairwise evolutionary distances (number of base substitutions per site) within the Giuris and an outgroup (Mogurnda adspersa) from the nearest Eleotridae clade were estimated using the Compute Pairwise Distances routine in Mega X, using the Maximum Composite Likelihood model.68\n\nMorphometric and meristic characters (Table 1) of the Bolano Sau Lake payangka (n=42) were measured or counted in the Aquatic Biology Laboratory, Universitas Tadulako, Palu.69 Morphometric characters (Figure 2) were measured using electronic callipers with a precision of 0.01 mm. Length, weight, sex and gonad maturity status data from a study on payangka reproductive biology (n=69; 25 females and 44 males) collected from Bolano Sau Lake in August and October 201945 were also included in some analyses. Data were tabulated in Microsoft Excel 2010 and analysed descriptively. The length-weight relation analysis (n=107) was performed in Microsoft Excel 2010 (RRID:SCR_016137) using the log10-transformed version of the formula W=a∙Lb, where W is total body weight (g); L is total length (cm); a is the antilog of the intercept and b is the slope of the linear regression of the Log10 transformed data. Analysis of mean size and size class distribution were implemented in R version 3.6.0 (RRID:SCR_001905)70 through the Rstudio version 1.1.456 interface (RRID:SCR_000432),71 using code from72 with a size class interval of 1 cm. Microsoft Excel spreadsheet algorithms based on72 were used to estimate mean size at first maturity (L50) and sex-ratio by size-class, also with a size class interval of 1 cm. The meristic formula was based on median values of the 6 meristic characters (dorsal fins D1 and D2, anal fin A, pectoral fin P, ventral fin V, caudal fin C) with spine counts given in Roman numerals and ray counts in Arabic numerals. Selected characters were compared with data on other Giuris spp. populations.\n\nQualitative data on biodiversity and fisheries in Bolano Sau Lake were collected during the payangka sample and environmental data collection. Secondary data were sourced from the baseline survey carried out from August to October 2019,44 scientific literature, and reputable on-line sources. Primary and secondary data were analysed with respect to implications for biodiversity, including taxon conservation status, and fisheries management.\n\n\nResults\n\nThe nucleotide composition (nitrogen bases) of the mitochondrial cytochrome C oxidase subunit I (COI) gene sequence was guanine 19.3%, cytosine 29.0%, adenine 23.9% and thymine 27.8%. The BLASTn and BOLD Identification routines assigned the goby or gudgeon, known locally as payangka, to the Gobioidei, Family Eleotridae, genus Giuris and taxonomic group labelled as Giuris margaritacea. Ten snakehead gudgeon Giuris margaritaceus sequences from Taal Lake, Luzon in the Philippines (accessions HQ654732-HQ654740) originally deposited as Ophieleotris aporos52 had a very high similarity (99.84%–99.85%) with the payangka sequence from Central Sulawesi, Indonesia, GenBank accession OM674613. The condensed tree in Figure 3 shows the payangka sequence (labelled BIOSUB77_03) nested within a G. margaritaceus sub-clade containing these sequences. Additional analyses using the Neighbor-Join option in MEGA X produced an equivalent structure. Seven other Philippine sequences had similarities of 98.45–99.38%, including accessions HQ682711 and HQ682712 from Laguna Lake, also in Luzon73 and accessions MG407388 to MG407392 from Lanao Lake in Mindanao.64\n\nThe Bolano Sau Lake payangka sequence is highlighted in yellow. Evolutionary relationships were estimated using the Maximum Likelihood routine in MEGA X.62 The analysis comprised 96 sequences with 630 nucleotide positions and 100 bootstrap replicates. The blue clade comprises sequences deposited in GenBank or BOLD databases as Giuris margaritacea and synonyms including Ophieleotris aporos. The length of the triangles is proportional to the number of sequences. The branch scale is in number of substitutions per site.\n\nThe analysis of the Giuris clade incorporating sequences from15 retrieved from the BOLD database (Figure 4) shows that the payangka from Bolano Sau Lake is not closely related to other Giuris specimens from Sulawesi or other regions in Indonesia. The number of base differences per site for representative sequences from each clade in Figure 4 (Table 2) shows that the genetic distance between the payangka and Giuris sp. from the Philippines was 0.002 to 0.016. Meanwhile the genetic distance between payangka and sequences from Indonesia in other Giuris clades was between 0.064 and 0.126, a range consonant with congeneric rather than conspecific relationships.\n\nThe Bolano Sau Lake payangka sequence is highlighted in yellow and the Giuris laglaizei sequence MNHN-14583 from Philippe Keith is highlighted in turquoise. The Maximum Likelihood analysis in MEGA X62 included 94 sequences with 580 positions and 100 bootstrap replicates. The red circles indicate node bootstrap values over 75%. The branch scale is in number of substitutions per site. Accession/Record details: see Table 1.\n\na Taxon: GS = Giuris sp.; GM = Giuris margaritaceus; GT = Giuris tolsoni; GV = Giuris viator; MA = Mogurnda adspersa (outgroup).\n\nb Origin: AUS = Australia; AUS/S = Australia or Sulawesi (actual site unknown); PH= Philippines; LU = Luzon (Lake Taal); M = Mindanao; P = Panay; Indonesia: CS= Central Sulawesi: A = Ampana; BS = Lake Bolano Sau; L = Luwuk; NS-T = North Sulawesi, Tondano Lake; SUL = Sulawesi, location unknown; BAL = Bali; LO = Lombok; MAL = Maluku; J-B = Java, Banten; J-E = East Java.\n\na Taxon: GS = Giuris sp.; GM = Giuris margaritaceus; GT = Giuris tolsoni; GV = Giuris viator; MA = Mogurnda adspersa (outgroup).\n\nb Origin: AUS = Australia; AUS/S = Australia or Sulawesi (actual site unknown); PH= Philippines; LU = Luzon (Lake Taal); M = Mindanao; P = Panay; Indonesia: CS= Central Sulawesi: A = Ampana; BS = Lake Bolano Sau; L = Luwuk; NS-T = North Sulawesi, Tondano Lake; SUL = Sulawesi, location unknown; BAL = Bali; LO = Lombok; MAL = Maluku; J-B = Java, Banten; J-E = East Java.\n\nThe TL range of Giuris sp. specimens (n=107) ranged from 7.9 cm to 16.3 cm, while weight ranged from 4.96 g to 61.0 g. The specimens in the morphometric and meristic study (n=42) ranged in size from 9.95 to 15.25 cm TL (mean 12.58 cm). In the sex-disaggregated length data set (n=69), variance was unequal between males and females (two-sample F-test, P < 0.01). The overall mean length was 12.95 cm. There was a highly significant (P < 0.001, two-tail t-test assuming unequal variance) difference in mean length between males (13.56 cm TL, n=44) and females (11.62 cm TL, n=25), with overlapping length distributions (Figure 5).\n\nDotted lines indicate mean TL for male (blue) and female (red) fish.\n\nMean length at maturity (L50) was 9.3 cm TL for females and 11.5 TL for males. Sex ratio was significantly (P < 0.05) different from 1:1 for all size classes except 12–13 cm TL, with female dominance below 12 cm TL and male dominance above 13 cm TL. The length-weight relationship was L=0.0087∙W3.162 (Figure 6), with a strong correlation (R2=0.901) and b > 3, indicating a mildly allometric positive growth pattern.\n\nA synopsis of the 17 morphometric characters measured for Giuris laglaizei from Bolano Sau Lake (Table 3) presents the data as absolute values (in mm) and as dimensionless ratios to TL. These data indicate considerable variability in most characters. The 6 meristic counts of Giuris laglaizei from Bolano Sau Lake (Table 4) yield a meristic formula based on median values of D VI-I,8 A I,8 P 13 V I,5 C15.\n\n* One specimen V.\n\nWater quality parameters tended to vary between sampling stations and times (Table 5). The ranges considered normal for Indonesian freshwater bodies used for fisheries (classes 2 and 3) according to Government Regulation No. 82/2001 (RI 2001) are also provided for the parameters covered under this regulation. During the collection of payangka samples and water quality data, qualitative data on environmental conditions were noted. These included visual records (photographs) of general conditions; for excerpts from the visual record see Figure 7. Originally Bolano Sau Lake was surrounded by lowland tropical rainforest and sago palm dominated wetlands. Observations showed considerable anthropogenic impacts, including extensive land-use change leading to erosion and sedimentation. Extensive areas around the lake had been converted for agriculture and human habitation (Figure 7a), and few sago palms remained in the riparian wetlands (Figure 7b).\n\n(Photographs taken by Samliok Ndobe).\n\nDuring the baseline survey,44 fish samples collected through experimental fishing in collaboration with local fishermen using 3½″ gillnets.45 Six species were reported: Nile tilapia Oreochromis niloticus (comprising nearly 77% of the experimental catch), payangka, striped snakehead (Channa striata), climbing perch (Anabas testudineus), gourami (Trichogaster sp.), a second gobioid fish, and the Mozambique tilapia (Oreochromis mossambicus). Local fishermen also reported catching common carp (Cyprinus carpio) and freshwater eels (Anguilla sp.) in the lake. This survey also revealed a predominantly sandy (67-73%) lake substrate with some silt (14-22%) and clay (11-13%). Phytoplankton concentration was 14,580/L, dominated by Cylindrospermopsis spp., Dinobryon spp., and Cyclotella spp. Mean zooplankton density was 28,890/L, dominated by unidentified larvae (Annelida, Crustacea (shrimps), Mollusca (bivalves) and fish) and Paramecia.\n\n\nDiscussion\n\nBarcode sequences (COI gene sequence fragments) over 600 bp are considered sufficient for differentiating between animal species, with 98-100% similarity generally indicating species identity.56 The BLASTn and BOLD Identity routine results place the specimen collected (GenBank accession OM674614) within the taxon named as Giuris margaritacea (Chordata, Actinopterygii, Perciformes, Gobiidae, Eleotridae) in these databases. Some unexpected sequence placements may have been due to errors in specimen identification, as might be expected within this taxonomic group.47,48 Examples include the nesting of Xenisthmus sp. from Australia (accession AF39137247) in the Mogurnda clade, Ophiocara porocephala from Bangladesh (accession MK57238974) in a Giuris margaritaceus sub-clade, and well-defined clades with a mixture of species names in the genera Eleotris and Gobiomorus. The nesting of O. porocephala from Bangladesh in the G. margaritacea clade lends credence to the possibility that some reports of payangka as O. porocephala may be similar cases, and point to a possible history of mistaken identity between two taxa which are not closely related genetically.\n\nFirst recorded and described from the Solomon Islands,75 the snakehead gudgeon G. margaritaceus has been thought to have a widespread distribution in the Indo-Pacific region.76 The gudgeon specimen examined by Valenciennes and named as Giuris margaritacea Valenciennes 1837, with the French common name éléotris perlé, was 6 inches long and collected from Vanikolo in the Solomon Islands by Quoy and Gaimard.75 G. margaritaceus is reported from Madagascar77 and the Indian sub-continent78 to Papua New Guinea and Pacific Islands,75,77,79–82 and from the Philippines52,83 to northern Queensland and north-eastern Australia.47,77,84,85 Considered native to Indonesia, it has been reported from Sumatra86 in the west to Papua51 in the east, including Sulawesi.6,14\n\nHistorically, the large number of G. margaritaceus synonyms appears related to the geographical distribution of this taxon. Original references (e.g. Cuvier and Valenciennes, 183775 and Sauvage, 188087) tend to give different species names to specimens collected from different islands or regions, even when they note a high level of similarity between morphological traits, with descriptions typically based on a small sample (in many cases just one specimen). Subsequent studies lead to a consensus view of the genus Giuris as monophyletic, with G. margaritacea or G. margaritaceus as the most senior (and hence valid) species name, as reflected in databases including the NCBI GenBank and BOLD, FishBase, the World Register of Marine Species (WoRMS), and Eschmeyer's Catalog of Fishes. However, Kottelat46 noted that: “The wide distribution and the observed variability of G. margaritaceus suggests that more than one species might be confused under this name”. The structure of the trees in this study (Figures 3 and 4) not only support the polyphyly of Giuris but also indicate widespread misidentification within Eleotridae and a need for taxonomic revision within other eleotrid taxa.\n\nThe deep divisions within the putative G. margaritaceus clade in Figure 3 are similar to the deep divisions in Glossogobius giuris from India.49 A study on the ichthyofauna of Java and Bali88 reported two BOLD BINs for Giuris margaritacea from this region, with a genetic distance of 12.56%, indicating more than one species in this region of Indonesia. Recent studies on the genus Giuris within the Indonesian Archipelago15 and other regions of the Indo-Pacific53 collectively resurrect and redescribe three species previously synonymised with G. margaritaceus (G. laglaizei Sauvage 1880; Giuris aporocephalus Macleay 1884; Giuris tolsoni Bleeker 1854), redescribe Giuris margaritaceus, and describe four new species (Giuris charpini Keith & Mennesson 2020; Giuris yahayai Keith & Mennesson 2020; Giuris caussei Keith, Mennesson & Lord 2020; and Giuris viator Keith, Mennesson, Lord, Hubert 2020). However, the analyses in this study indicate the range distributions for Giuris species in Keith et al. (2020) and Keith & Mennesson (2020)15,53 are still incomplete.\n\nIt is interesting that no Giuris sequence from Indonesia were closely related to the payangka from Bolano Sau Lake (Figure 4), and evolutionary relationships within Giuris do not necessarily seem to follow readily discernable patterns based on past or present geographical distance. For example, as in Ref. 53, Australian and Philippine clades (the latter including payangka from Bolano Sao Lake) seem more closely related to each other than to species found in areas lying between these two regions (Figure 4; Table 2), with one of the two lacustrine Giuris populations from the northern arm of Sulawesi (Bolano Sau and Tondano) belonging to each of these clades. The tree topography (Figure 4) and location of the closest matching sequences (Taal Lake, Luzon, Philippines) strongly suggested that the payangka, as well as the Philippine sequences within which it is nested, are in fact Giuris laglaizei Sauvage 1880 (originally Eleotris (Giuris) laglaizei). This species was first described from a specimen with the local name poi-poi collected near Manila in the Philippines.87 Unfortunately, sequences from Ref. 53 were not available in either GenBank or BOLD databases at the time of this study. However, Philippe Keith of the National Museum of Natural History of Paris kindly provided a sequence of G. laglaizei from the Philippines (Number 14583 in Ref. 53), which was not yet available in public databases. As expected, this sequence nested within the same Giuris clade as the payangka (Figure 4). The identity was 99.83% (one nucleotide difference in the aligned dataset) with a genetic distance of ≈ 0.00136. Based on this result, the Bolano Sau Lake payangka can be identified as G. laglaizei, a first record for Sulawesi and Indonesia, considerably extending the known distribution of this species.\n\nComparison with Ref. 15 and Ref. 53 strongly suggests that the Australian sister clade to that containing the payangka in Figure 4 is most likely Giuris aporocephalus Macleay 1884. The six specimens from Tondano Lake resolved within this clade. If indeed the Giuris in Tondano Lake are descended from introduced payangka sourced from Limboto Lake over 100 years ago, then it is likely that the payangka in Limboto Lake also belong to this clade, and are therefore not the same species as the payangka in Bolano Sau Lake, even though these two lakes are relatively close to each other. However homologous barcode (mtDNA COI) sequences for Limboto Lake payangka are not yet available, despite recent research using the Cyt-b genetic marker.36\n\nTable 6 shows the known and (strongly) suspected species identities and distributions of species within the genus Giuris. This study brings the number of Giuris species in Indonesia and Sulawesi to five, with four species in freshwater ecosystems around the coasts of Tomini Bay.\n\na Sources: No. 1-8: Ref. 53; No.1: inferred from Ref. 25 and Ref. 50; No. 4: this study; No. 5-7: Ref. 15; No. 7: Ref. 74.\n\nb O = Bolano Sau Lake (this study): A = Ampana; L = Luwuk; T = Tondano Lake, North Sulawesi (possibly also Limboto Lake in Gorontalo); S = Sulawesi, unknown site; M = Maluku; K = Lombok; B = Bali; J = Java; Grey shading and bold font = sites in Sulawesi.\n\nc P = Philippines; N = Papua New Guinea; A = Australia; C = Pacific islands; J = Taiwan and Japan (Okinawa); B = Bangladesh; M = Madagascar, Mayotte and Comoros.\n\nData on the length-weight relation of Giuris sp. appear to be limited and confined to Indonesia. Length-weight relation parameters and size ranges of payangka (Giuris laglaizei) from Bolano Sau Lake and other Giuris populations in Indonesia (Table 7) show a general tendency towards allometric positive growth patterns. The mildly allometric positive length-weight relation for Bolano Sau Giuris sp. is within the range reported for other populations of Giuris sp. The value of b (3.162) is slightly lower than that reported from Tondano Lake (Makmur et al. 2019) and Santani Lake in Papua and close to the lower limit of Giuris sp. from Limboto Lake. However, a value of b > 3 indicates that food availability is unlikely to be a limiting factor.\n\nThe length distribution of Giuris spp. specimens in this study was biased towards fish large enough to have potentially achieved sexual maturity. This is important because all samples were collected with gears (throw nets and gillnets) currently used by the Bolano Sau fishing community. With respect to the gillnet fishery, 67% of fish caught during the baseline survey of Bolano Sau Lake were found to be sexually mature, with a mean size at first maturity (both sexes combined) of 11.92 cm.45 Re-analysing the data disaggregated by sex (Figure 5), the mean size at capture was greater than the estimated size at sexual maturity for both sexes. This analysis indicates that the fishery is selective for males, and could explain the male bias previously reported for this population.45\n\nA study of Giuris spp. (most likely G. aporocephalus) in Tondano Lake, North Sulawesi10 also found a larger mean length in males (14.15 cm) than in females (13.75 cm), although the difference was less marked than for the Bolano Sau Lake payangka identified as G. laglaizei in this study. Furthermore, mean and maximum sizes sampled for both sexes in Tondano Lake were larger than in Bolano Sau Lake (Table 7). The generally smaller size of payangka in Bolano Sau Lake compared with Tondano Lake10 could be related to inter-specific differences and/or environmental factors. A comparison between selected morphometric characters of the Bolano Sau Lake payangka and eight Giuris species recently described or re-described is presented in Table 8 while Table 9 shows comparative data on meristic characters.\n\na Sources: No. 1: This study; No. 2-9: Ref. 15; No. 10: Ref. 10; Tondano Lake, 10a = males, 10b = females, mean values given.\n\nb CP = caudal peduncle; c One outlier each with 12% and 22%, remainder 15-20%.\n\na Sources: No. 1: This Study; No. 2-9: Ref. 53; No. 6-8: also Ref. 15; No. 10: Ref. 10; No. 11: http://www.fishbase.org.\n\nb D = dorsal fins (D1 = anterior; D2 = posterior); A = anal fin; P = pectoral fins; V = ventral (pelvic) fins; C = caudal fin.\n\nUnlike the genetic (DNA barcoding) data, a comparison between morphometric and meristic characters of the Bolano Sau Lake payangka and the eight Giuris species recently described or re-described15,53 in Tables 8 and 9 does not give a clear indication regarding the taxonomic identity of the Bolano Sau Lake Giuris population, although some characters are similar to the Philippine Giuris laglaizei. The wider range in Bolano Sau Lake payangka compared with most Giuris species for most of the characters could be related to the larger number of samples (42 compared with 2-12 fish). Although some morphometric characters have been used in discussing or determining the characteristics of species within the genus Giuris, in particular the resurrecting of synonymised species and the description of new species resulting in a total of eight now-recognised Giuris species,15,53 there are many similarities. All eight are described as having a body shape which is more ovoid than elongated, with G. yahayai also having a somewhat backed appearance. Other common features include sexual dimorphism and known or suspected amphidromy.\n\nAmphidromy as described by McDowall (2007) is characterised by “reproduction in fresh water, passage to sea by newly hatched larvae, a period of feeding and growing at sea usually a few months long, return to fresh water of well-grown juveniles, a further period of feeding and growing in fresh water, followed by reproduction there” and can be obligate or facultative.89 The presence of all life stages including adults (payangka) and larvae (nike) in Tondano Lake25 indicates that amphidromy is most likely facultative in at least some Giuris species. Mean length at first maturity in Tondano Lake payangka has been reported as 10.75 cm (females)10 and 13.4 cm (males)/13.7 cm (females).30 Reported values for fecundity range from 12,000 to 127,000, increasing with female size.10,28 Eggs fertilised in the morning hatch the following night and the larvae begin swimming after about 10 minutes, even though fins have not yet developed.28 Although in the past all or some of these larvae may have been carried to the sea and completed an amphidromous life-cycle, the Tondano Lake Giuris population seems to have adopted a fully freshwater lifecycle. It has been proposed that, although this non-migratory lifestyle may have evolved within the population over a more extended time, it may have become the prevailing mode of reproduction as an adaptation to the construction of three hydroelectric power plant dams preventing downstream and upstream migrations.25 Alternatively, if the payangka was indeed introduced in 1902 from Limboto Lake,34 then the adaptation may date from this introduction. The lack of genetic variation in the COI barcode for the six specimens sequenced by Pangemanan et al.25 (Figure 4) may be the result of a small founder population followed by such selection.\n\nWhether amphidromy is obligate or facultative is an important consideration with respect to the Bolano Sau Lake population. Despite its proximity to Tomini Bay, there is no permanent feature enabling fish to move between the lake and the sea. However, according to local fishermen seasonal flooding occurs at times during the raining season, creating a temporary connection. No larvae or small juveniles were found during the survey. While this may be an artefact of the collection methods used and/or the timing of the sampling, local fishermen do not catch nike in the lake, and did not report large schools of larvae. Further observations (monitoring) of Bolano Sau Lake payangka reproductive patterns and identification of early life stages in and/or near to the lake could shed light on this question.\n\nIf the payangka in Bolano Sau Lake is amphidromous and found in other waterbodies nearby, there is hope for natural recruitment from the wider Tomini Bay population to boost the population in the lake. The facilitation of such a process through the transport of migrating larvae (nike) is unlikely to be a wise move, as shoals of nike are typically multispecies, comprising several genera of Gobiidae and/or Eleotridae11,23,90 as well as other taxa such as glass eels of the genus Anguilla and crustacea.12,19–21 Therefore, shoals of nike are unlikely to be composed solely of Giuris laglaizei or indeed other species currently present in Bolano Sau Lake.\n\nIt is also possible that the payangka arrived in Bolano Sau Lake at some period(s) in the past when geological and hydrological features were more conducive to the migrations of diadromous fishes, and then adopted a fully freshwater life cycle, as seems to be the case for the payangka in Tondano Lake. In this case, it might be necessary to support recovery of the severely depleted Giuris population through well-planned release of captive bred fish. Initial steps towards captive breeding of the Tondano Lake payangka (Giuris sp.) have been taken, including ex-situ husbandry of larvae and juveniles.28 If indeed the Giuris sp. in Tondano Lake became established after the introduction of payangka from Limboto Lake in 1902,34,91 it would indicate that such an approach might be successful. However, any such moves should follow the national guidelines for re-stocking,92 in particular with respect to biosecurity (e.g. pests and disease), as well as ensuring the fish used for re-stocking are indeed the same species and ideally come from populations with similar genetic and other characteristics.\n\nFrom an ecological perspective, trophic relations are an important consideration. Species reported as preying on G. margaritacea and/or O. porocephala include the piscivorous goby Glossogobius giuris.93 The Giuris sp. in Tondano Lake is omnivorous but appears to undergo an ontogenetic shift in dietary preference, becoming increasingly carnivorous. Juveniles in the 12-30 mm TL range are reported as planktivorous, with the proportion of zooplankton relative to phytoplankton increasing as the fish grow; they begin to prey on Caradina shrimp at around 30 mm TL and on molluscs (Gastropods) and fish (including smaller conspecifics) at around 36-40 mm TL.31 However, such data are lacking for the payangka from Bolano Sau Lake, and indeed for the species G. laglaizei to which it most likely belongs.\n\nThe IUCN Red List of Threatened Species re-assessment of the snakehead gudgeon G. margaritacea in 201976 lists the species under the Least Concern (LC) category, with the rationale that the species is widespread and common in parts of its range and it is found in a wide variety of habitats. With respect to fisheries, the assessment mentions that this taxon is harvested for the international aquarium trade and in localised areas is also used for subsistence level consumption and as a bait fish, but levels of exploitation are unknown. The assessment also notes the need for further taxonomic work to determine if the Western Pacific and Western Indian Ocean subpopulations are conspecific. Recent genetic evidence validates this concern as the newly described Giuris yahayai appears to be limited to the Indian Ocean,53 while seven species have been identified in the Indo-West Pacific with at least three species present in eastern Central Sulawesi, the Moluccas, and the Philippines.15,53 The boundaries of each species cannot as yet be determined with certainty; however, the known ranges of several species vary in extent and in some cases overlap.53 Together with the identification of the payangka from Bolano Sau Lake as G. laglaizei, the reanalysis of Giuris sequences from Tondano Lake in Pangemanan et al., (2020) as belonging to a different clade from all other Sulawesian Giuris sequences (most likely G. aporocephalus) means that at least five Giuris species are present in Sulawesi, with four species found in Tomini Bay watersheds. Future barcoding efforts may further increase the known range of one or several Giuris species.\n\nThe polyphyly of Giuris calls into question the validity of the LC status76 for at least some of the species in this genus. The fragmented nature and uneven size of known distributions indicate that some of the eight species currently apparent within this genus could be at risk from serial extirpation and even extinction. At least one Giuris population (species unknown) from the Proserpine River in Australia appears to have been lost.76,85 It may never be known if this was a now extinct species or an extirpated population of a widespread species.\n\nThe principal threats mentioned in the Red List assessment76 are subsistence and ornamental fisheries. However, alien or exotic invasive species introductions are considered a major threat to freshwater fish biodiversity worldwide.94 In particular, wild Nile tilapia populations are increasingly widespread across Indonesia39–42,95–97 and have been implicated in the decline of native species in many inland waters across the Indonesian Archipelago.39,40,97–99 Mechanisms through which introduced species, including the Nile tilapia, could affect the payangka and other native fishes include competition for food and habitat; the introduction and transmission of parasites and disease; predation, especially on eggs and larvae or juveniles; and behaviour leading to habitat degradation39,41,97,100–102\n\nThe majority of data on Giuris fisheries are from Tondano Lake in North Sulawesi, approximately 500 km east of Bolano Sau Lake. Payangka has historically been the main fisheries species in Tondano Lake, comprising 35% of the total production volume in 1980.28,100 All sizes from 9 mm to 200 mm are reported in fisheries catch28,31; however the nike fisheries target postlarvae and fingerlings in the 12-30 mm TL range, while payangka catches were dominated by the size range 105-135 mm TL, with few larger individuals. While the nike fishery is economically viable, with relatively high income and profit margins,27 concerns have been expressed regarding the aggregate ecological sustainability of the fisheries targeting payangka in the lake.30 Strong indications of overfishing were already apparent around 30 years ago, with annual catch volume reduced to 25% of that in 1980-1985 by 1990.31 The introduction of alien species has been implicated as a causal factor of declining Giuris catches and abundance. In North Sulawesi, with catfish (Clarias sp.) is reported to have had negative impacts on payangka stocks in Tondano Lake.100 However, it seems the payangka itself may be an introduced species in this waterbody.34\n\nWith respect to the Bolano Sau Lake payangka, this once common and popular food fish has become increasingly rare since the introduction of alien species under government programs intended to increase fisheries production, although overfishing is also suspected as a factor.45 In Bolano Sau Lake, government-supported “re-stocking” has occurred in the lake over several decades.35 The most abundant alien species in 2019 was the Nile tilapia (Oreochromis niloticus), while other introduced alien species included the Mozambique tilapia (Oreochromis mossambicus) and gourami (Trichogaster sp.). Two other species, the striped snakehead Channa striata and climbing perch Anabas testudineus are widely considered as native fishes by Sulawesians and figure in many traditional dishes, although they may have been introduced to Sulawesi, possibly in prehistoric times.6,103,104 With respect to introduced species, it is interesting to note that not all species introduced to Bolano Sau Lake have become established or invasive. For example, the common carp (Cyprinus carpio) had been repeatedly introduced prior to 2016,35 but none were seen during the surveys in 2019. Fishermen reported that after the introduction they did catch carp; but the numbers dwindled over time, in contrast to the Nile tilapia (O. niloticus) which quickly became the dominant species in the lake.\n\nThe IUCN Red List assessment76 describes the habitat of G. margaritaceus as streams, while in Northern Australia the most common habitat is described as small rainforest creeks and wetlands located close to the river mouth85; lacustrine habitat is not mentioned. However, Giuris species have been found in both coastal streams and lakes, and would seem that lakes are a key habitat for at least some Giuris species in Indonesia, and specifically in Sulawesi, as well as in the Philippines and Papua New Guinea.15,52,53,105 It would seem likely that G. laglaizei may be a predominantly lacustrine species, as the known Philippine populations are all lacustrine, as is the Sulawesi population in this study.\n\nAs in many regions worldwide,94 lakes in this region are typically subject to significant anthropogenic disturbance leading to habitat alteration and degradation.40,41,106,107 This includes lakes known to have Giuris populations such as Limboto and Tondano,100,108 with negative impacts on payangka stocks including changes in condition factor.100 Quantitative data (Table 5) and qualitative observations indicate potential threats to the Bolano Sau Lake environment as a habitat for fish. Parameters of concern include temperature, consistently above 31°C with a maximum in excess of 33°C, and dissolved oxygen (DO). The latter was consistently below 4 mg/L and sometimes below 3 mg/L, the lower limit considered acceptable by Government Regulation No. 82/2001.109 The low levels of DO may be related to the elevated temperature, as the capacity to retain oxygen is inversely correlated with water temperature.110 The gill oxygen limitation theory (GOLT) proposed by Pauly111 posits that fish growth and size are limited by the availability of oxygen; higher temperatures increase metabolic rates, lowering the size at which the limitation will be reached. Thus, the high temperature and low DO values recorded in Bolano Sau Lake could be a contributing factor to the relatively small maximum size of the payangka. Locally high levels of nitrate (NO3-N) may be due to sewage and/or fertiliser run-off, and could and act in synergy with the temperature and low oxygen conditions, especially as toxicity increases with temperature.110 Combined with the observed land use/land cover changes, these data call for integrated watershed management.\n\n\nConclusion\n\nThe COI barcoding approach identified a payangka from Bolano Sau Lake in Central Sulawesi Indonesia as the recently resurrected Giuris laglaizei. This represents the first record of G. laglaizei in Indonesia and indeed the first outside the Philippines. However, the phenotypic characters measured or counted in this study could not enable a definitive identification of the Giuris sp. in Bolano Sau Lake to species level. In addition, other characteristics noted during this study and other visits to the study site are ambiguous in terms of taxonomic identification. For example, both colour and general appearance vary between sexes, stage of the reproductive cycle, and even habitat characteristics within the lake. These results and considerations strongly indicate the advisability of further research using molecular biology methods to resolve the taxonomic identity of other Giuris sp. populations throughout the distribution of this genus.\n\nThe phylogenetic analysis of Giuris highlights the complex biogeography of this genus in Indonesia, with at least four Giuris species present in the coastal regions around Tomini Bay and five in Sulawesi. These findings call into question the IUCN Red List Least Concern status of the taxonomic unit, until recently named Giuris margaritacea, now revealed as a genus comprising at least eight species. While identifying the species present is a first step towards managing and preserving fish biodiversity in inland waters, this needs to be followed by appropriate management. The threats to and sharp decline of the Bolano Sau Lake payangka population are reflected in similar threats and/or trends reported for other Giuris spp. populations, and could result in serial extirpations if unchecked. From both biodiversity and fisheries perspectives, there is a need to manage freshwater fisheries resources to conserve native fish species still present, including the Bolano Sau Lake payangka.\n\n\nData availability\n\nHarvard Dataverse: Bolano Sau Lake Fish Data https://doi.org/10.7910/DVN/JL5JP9.69\n\nThis project contains the following underlying data:\n\n• Giuris_payangka_data_2019.tab (dataset)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nNCBI Metazoan Mitochondrial COX1 SUB1096094963:\n\n• The partial Cytochrome C Oxidase subunit I gene mitochondrial DNA sequence of Giuris laglaizei, Accession OM674613 https://www.ncbi.nlm.nih.gov/nuccore/OM674613\n\n• The partial Cytochrome C Oxidase subunit I gene mitochondrial DNA sequence of Anabas testudineus, Accession OM674614 https://www.ncbi.nlm.nih.gov/nuccore/OM674614\n\nHarvard Dataverse: GenBank Accessions, BOLD Records (mitochondrial COI gene sequences) and other nucleotide sequences used for phylogenetic analyses of Eleotridae and Giuris spp. https://doi.org/10.7910/DVN/WMDHOJ.112\n\nThis project contains the following extended data:\n\n• Table S1_mtDNA_COI_sequence_references.pdf (Table S1)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nHarvard Dataverse: ARRIVE checklist for ‘DNA barcoding detects resurrected taxon Giuris laglaizei (Sauvage 1880) in Sulawesi, Indonesia: Bolano Sau Lake payangka phylogeny, phenotypic characters and implications for Giuris spp. conservation’ https://doi.org/10.7910/DVN/JL5JP9.69\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\nThe authors gratefully acknowledge a vital contribution from Philippe Keith of the National Museum of Natural History, Paris in the form of a Giuris laglaizei COI nucleotide sequence which was not yet available through public databases. The authors also wish to thank the Parigi Moutong District Marine and Fisheries Service, Central Sulawesi and the Faculty of Animal Husbandry and Fisheries, Tadulako University, Palu for support during this research.\n\n\nReferences\n\nHutama AA, Hadiaty RK, Hubert N: Biogeography of Indonesian Freshwater Fishes: Current Progress. Treubia. 2016; 43: 17–30. Reference Source\n\nHubert N, Kadarusman WA, Busson F, et al.: DNA Barcoding Indonesian freshwater fishes: challenges and prospects. DNA Barcodes. 2015; 3(1): 144–169. Publisher Full Text\n\nKeith P: Biology and ecology of amphidromous Gobiidae of the Indo-Pacific and the Caribbean regions. J Fish Biol. 2003 Oct; 63(4): 831–847. 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Publisher Full Text\n\nPieter S, Pangemanan JF, Dien CR: Analisis kelayakan usaha penangkapan ikan nike (Ophieleotris aporos) di Danau Tondano Desa Kaima Kecamatan Remboken Kabupaten Minahasa. Akulturasi. 2019; 7(2): 1365–1372. Reference Source\n\nSusanto MK, Bataragoa NE, Moningkey RD: Size Distribution and Growth of young Payangka Fish, Ophieleotris aporos (Bleeker) from Lake Tondano. J Ilm Platax. 2017; 5(2): 189–197. Publisher Full Text\n\nRostitawati T, Wahyuddin NI, Obie M: The Poverty Puddles of the Cage Fishing Community at Limboto Lake Coast, Indonesia. J Sustain Dev. 2019; 12(3): 82–90. Publisher Full Text\n\nMamangkey JJ, Rogahang FHN, Adil E: Analisis struktur populasi dan tingkat kemantangan gonad ikan payangka (Ophieleotris aporos) di Danau Tondano Sulawesi Utara. Front J Sains dan Teknol. 2019; 2(3): 211–219. Reference Source\n\nSatria H, Kartamihardja ES: Distribusi panjang total dan kebiasaan makan yuwana ikan payangka (Ophiocara porocephala). 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}
|
[
{
"id": "135393",
"date": "23 May 2022",
"name": "Jonas P. Quilang",
"expertise": [
"Reviewer Expertise Population genetics",
"molecular genetics and phylogenetics",
"fish 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 authors collected Payangka specimens from August to December 2019 in Bolano Sau Lake in Parigi Moutong District, Central Sulawesi Province, Indonesia. They recorded the length, weight and sex of 111 specimens and obtained data for 17 morphometric and six meristic characters from 42 specimens. These morphometric and meristic data were used for morphological analysis and determination of length-weight relationship. In addition, the authors obtained the mitochondrial cytochrome c oxidase I (COI) sequence from a single specimen for molecular identification via DNA barcoding. Additional COI sequences were obtained from public databases for phylogenetic analysis. DNA barcoding revealed that the specimen matched with Giuris laglaizei in public databases.\nThe study is interesting because this is the first record for this species outside of its known distribution (Philippines). However, it could have been better if additional specimens were sequenced for their COI so as to have replication and also to be able to compute for intra-species genetic distance and to determine if there is genetic differentiation within the species. COI sequencing of additional specimens may reveal not only genetic differentiation but also presence of cryptic species.\nCOI is an established marker in fishes and other animals for DNA barcoding, that is, for species identification and delineation. However, for phylogenetic studies additional molecular mitochondrial and nuclear markers have to be used and so caution should be observed when using the terms phylogenetic and polyphyletic in the manuscript. A more comprehensive phylogenetic analysis which should include all species under the genus Giuris and other genera under Eleotridae and using not just a single molecular marker (COI) should be done before one can conclude that Giuris is indeed polyphyletic and not monophyletic or paraphyletic; hence, the authors should avoid using the term polyphyletic.\nLastly, the colon in the title is usually used to separate the main part (which is broader in scope) from the subtitle or explanatory part. It seems that the use of the colon in the title is inappropriate. The first part of the title is declarative while the second part (to the right of the colon, which is supposedly the subtopic), is descriptive and so there is a disconnect. I suggest that the title be made more specific and more reflective of what was done in the study. The bulk of the study is on morphological analysis, hence, this should be given more emphasis in the title. Only a single DNA sequence was generated in this study, which was used for the DNA barcoding and phylogenetics aspects of the study.\nPlease see additional comments and corrections in the attached copy of the manuscript.\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? Yes",
"responses": [
{
"c_id": "9248",
"date": "26 Jan 2023",
"name": "Samliok Ndobe",
"role": "Author Response",
"response": "Thank you very much for your thoughful input. Dey=tailed responses are given below. The study is interesting because this is the first record for this species outside of its known distribution (Philippines). However, it could have been better if additional specimens were sequenced for their COI so as to have replication and also to be able to compute for intra-species genetic distance and to determine if there is genetic differentiation within the species. COI sequencing of additional specimens may reveal not only genetic differentiation but also presence of cryptic species. Response: we also consider that this additional work would be worthwhile. We are exploring the possibility of a more detailed study on payangka (possibly focused on more than one lake) in order to address such additional research questions, which were not within the scope of the research reported here. COI is an established marker in fishes and other animals for DNA barcoding, that is, for species identification and delineation. However, for phylogenetic studies additional molecular mitochondrial and nuclear markers have to be used and so caution should be observed when using the terms phylogenetic and polyphyletic in the manuscript. A more comprehensive phylogenetic analysis which should include all species under the genus Giuris and other genera under Eleotridae and using not just a single molecular marker (COI) should be done before one can conclude that Giuris is indeed polyphyletic and not monophyletic or paraphyletic; hence, the authors should avoid using the term polyphyletic. Response: thank you for this advice. We accept the point you are making and have removed all occurrences of the term polyphyletic, using expressions which we consider reflect the results we can consider as robust. With respect to the term phylogenetic, we consider that we have used this term sparingly, in two ways. Firstly, as a description of what we did (construction of phylogenetic trees), and secondly referring to the interpretation (phylogenetic analysis) of results from both our study (in particular the phylogenetic trees) and other studies. With respect to other markers, again that is outside the scope of this study. However, we fully agree that further research is needed, and indeed the need for such research is one of our conclusions. In the revised version we have explicitly stated the need for additional molecular markers in the conclusion. Lastly, the colon in the title is usually used to separate the main part (which is broader in scope) from the subtitle or explanatory part. It seems that the use of the colon in the title is inappropriate. The first part of the title is declarative while the second part (to the right of the colon, which is supposedly the subtopic), is descriptive and so there is a disconnect. I suggest that the title be made more specific and more reflective of what was done in the study. The bulk of the study is on morphological analysis, hence, this should be given more emphasis in the title. Only a single DNA sequence was generated in this study, which was used for the DNA barcoding and phylogenetics aspects of the study. Response: thank you for this input, which we will certainly consider for the future. We have not edited the title in this revised version because of the publishing model of F1000 Research; as the paper was published on-line before review, we consider this could cause confusion. Additionally, the Editor and Reviewer 2 have not requested a change of title. Please see additional comments and corrections in the attached copy of the manuscript. Response: Thank you, we have addressed these points in the revised manuscript. We also made an annotated version of the pdf copy you kindly supplied, giving more detail on our edits in response to your suggestions and comments. We will endeavor to share this file if it is possible."
}
]
},
{
"id": "137863",
"date": "18 Jul 2022",
"name": "Aurycéia Guimarães-Costa",
"expertise": [
"Reviewer Expertise Evolution",
"DNA Barcoding",
"phylogeny"
],
"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 by Ndobe et al. brings up taxonomic information about a group of species that have many difficulties in morphological identification, which are members of the Eleotridae family. The authors presented a brief history of the revisions of the taxonomic nomenclatures that the species of Giuris passed, showing that there are still confusions in the delimitation of the species.\nIn the work, the authors used the DNA Barcoding methodology to show that specimens regularly identified as G. margaritacea/G. margaritaceus are actually Giuris laglaizei, in addition to identifying the first occurrence of this species in Indonesia.\nOverall, I liked the manuscript. The objectives were achieved based on the DNA Barcoding methodology. Although this methodology is very direct and objective, the authors also elucidated other questions related to the taxonomy of the group, such as, for example, the elucidation of a species complex (Giuris margaritacea) that may comprise at least eight species. This evidence is extremely important for the delimitation of conservation care for the correct species.\nThus, this study, which integrated morphology and molecular, needs to be disseminated to science and, mainly, to researchers interested in the evolutionary relationships of the Eleotridae family.\nMinor revisions\nBackground: change “seventeen\" to “17”\n\nI suggest changing all mentions of the name \"Payangka\" that are in italic font to regular font, as even mentioned in the text as a popular name for the species, an italicized name can be confused with the genus.\n\nI think the tree in Figure 4 is not didactic for visualizing Giuris' clusters. I strongly advise rendering the tree to a linear topology, so that the reader does not have a hard time seeing the formation of the groups and the names of the species.\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": "9247",
"date": "26 Jan 2023",
"name": "Samliok Ndobe",
"role": "Author Response",
"response": "Thank you very much for your input and approval. Please see below detailed response to your suggestions for Minor revisions 1. Background: change “seventeen\" to “17” Response: Thank you, we have made this change. 2. I suggest changing all mentions of the name \"Payangka\" that are in italic font to regular font, as even mentioned in the text as a popular name for the species, an italicized name can be confused with the genus. Response: Thank you, we have made this change. 3. I think the tree in Figure 4 is not didactic for visualizing Giuris' clusters. I strongly advise rendering the tree to a linear topology, so that the reader does not have a hard time seeing the formation of the groups and the names of the species. Response: Thank you for the suggestion, but we have not made this suggested change. Using a linear topology makes the tree too long to fit (at a readable size) on a standard page or on a laptop screen. We could produce the tree in a linear format and add it to the \"Extended Data\" deposited in the on-line repository. Please advise if you think that would be a good idea."
}
]
}
] | 1
|
https://f1000research.com/articles/11-295
|
https://f1000research.com/articles/12-91/v1
|
24 Jan 23
|
{
"type": "Research Article",
"title": "Awareness of interventional radiology among medical students at KFU in Al-Hasa province",
"authors": [
"Rahaf Al Mutairi",
"Mohammed Al Mulhim",
"Linah Bin mutreb",
"Mohammed Al Mutairi",
"Mohammed Hazem",
"Rahaf Al Mutairi",
"Mohammed Al Mulhim",
"Mohammed Al Mutairi",
"Mohammed Hazem"
],
"abstract": "Background: Interventional radiology (IR) is a branch of diagnostic radiology that performs minimally invasive procedure using image guided radiological techniques. Methods: To measure the awareness of IR between clinical-year medical students and medical interns at King Faisal University (KFU) in Al-Hasa province and the likelihood of medical students to enter IR in the future, a cross-sectional study was performed between year 4 and 5 medical students (clinical year students) and medical interns at KFU, Al-Hasa with the use of validated electronic questionnaire. Results: A total of 246 participants fulfilled the inclusion criteria of this study. The students were in clinical years: 54.9% were in their fourth year, 34.6% were in their fifth year, and 10.6% were interns. Approximately half of the responders (46.9%) think their knowledge regarding IR is poor. Lectures were the most frequently identified information source (33.3%). Around 48% of the participants had a satisfactory level of knowledge on interventional radiology. Conclusion: This study showed relatively poor awareness and knowledge toward IR among medical interns and clinical years medical students. To solve this issue, a number of strategies can be implemented, such as early inclusion of an interventional radiology course in the curriculum, IR symposiums, and IR awareness campaigns.",
"keywords": [
"interventional radiology",
"medical students",
"medical interns",
"medical curriculum",
"Al-Hasa"
],
"content": "Introduction\n\nInterventional radiology (IR) is a subspecialty of diagnostic radiology that uses image-guided radiological techniques to perform minimally invasive procedures that substitute some major open surgical procedures. Furthermore, an interventional radiologist uses needles, fine catheter tubes and wires to reach the target area. Benefits of interventional radiology can range from shorter hospital stays, faster return to work and reduced risks.1,2 With the development of medicine in recent years, IR became involved with multiple systems in regard to the diagnosis and treatments such as angioplasty, drainage, embolization, stent insertion and ablation treatment of thrombus.3–5 However, there is an overlap between other specialties for procedures and IR. This may lead to an unclear perception among medical students about the tasks of an interventional radiologist.6 There are a few studies that evaluate medical students' knowledge of IR in the literature. Particularly, there is no research that has been published in the eastern part of Saudi Arabia. As a result, our goal is to assess how well-aware medical interns and medical students enrolled in clinical years at KFU in Al-Hasa region are of the value and necessity of IR.\n\n\nMethods\n\nMedical interns and clinical-year medical students at KFU in the province of Al-Hasa participated in this cross-sectional study conducted in eight months between 24/01/2021 to 09/09/2021. This study included 246 participants in all. An online survey that was delivered to the target demographic contained a self-administered questionnaire.7 The only participants in this study at KFU were clinical medical students and interns. Incomplete surveys, KFU preclinical medical students, medical students from other universities, and the general population were disqualified. Microsoft Excel was used to tabulate and arrange the data in a neat and straightforward manner (Microsoft Corporation, Redmond, WA).\n\nThe SPSS (Statistical Package for Social Sciences) software for Windows, version 26, URL: https://www.ibm.com/products/spss-statistics, IBM SPSS statistics, RRID:SCR_016479 was used for data administration and analysis (IBM Corp., Armonk, NY, USA). In order to quantify both continuous and categorical study variables, descriptive statistics were reported using mean, standard deviation, frequencies, and percentages as needed. A Chi-squared test was employed to compare the attitude and satisfaction levels in relation to the research variables. A p-value was less than 0.05 was considered statistically significant.\n\n\nResults\n\nA total of 246 participants fulfilled our study inclusion criteria and completed the study questionnaire. A total of 134 (54.5%) students were males. As for students’ clinical grade, 135 (54.9%) were in their fourth year, 85 (34.6%) were in their fifth year, and 26 (10.6%) were interns. Around 115 (46.7%) students think their knowledge regarding interventional radiology is poor as compared to other subjects, while 110 (44.7%) think that they had adequate to excellent knowledge. Furthermore, 67 (27.2%) students said they had taken or planned to finish a radiology elective rotation. Only 62 (25.2%) of the students said they would contemplate diagnostic radiology as a job in terms of their future plans. For those who would not consider the specialty, the most reported causes were lack of information regarding the specialty 75 (40.3%), followed by being not an interesting specialty 72 (38.7%), unsuitable lifestyle 26 (14%), and fear of radiation exposure 13 (7%). Around 50 (20.3%) students reported that they had seen patients who were managed by an interventional radiologist (Table 1).\n\nThis survey found that exactly 91 (37%) participants at KFU in the Al-Hasa region were aware of interventional radiology and understood that interventional radiologists should complete their training in the radiology specialty. A total of 114 (46.3%) participants believe interventional radiologists have separate outpatient clinics, while 130 (52.8%) believe they attend ward rounds in hospitals. However, 112 (45.5%) of the students believe that interventional radiologists shouldn't be allowed to admit patients to hospitals. A total of 209 (85%) students agree that interventional radiologists treat people with major diseases while only 101 (41.1%) think that they treat minor illnesses as well. Only 40 (16.3%) presumed interventional radiologists don’t treat patients at all. Regarding procedures that can be done by interventional radiologist, 205 (83.3%) of the students correctly reported lower limb angioplasty and stenting, followed by 192 (78%) uterine artery embolization for fibroids, 173 (70.3%) venous access procedures, and 137 (55.7%) arteriovenous fistulas for dialysis (Table 2).\n\nOn the other hand, all the data regarding the perception of medical intern and clinical-year medical students at KFU in Al-Hasa province for interventional radiology are mentioned in Table 3. Around 182 (74%) students were familiar with a procedure called angioplasty. The most reported source of knowledge for that procedure was from a vascular surgeon (59.9%), followed by cardiologist (59.3%), interventional radiologist (30.2%) while 6.6% reported - other - as the source of their knowledge. If a 2-week elective rotation in interventional radiology is made available during the internship's 3-month surgery rotation, a total of 146 students (59.3%) expressed interest in attending.\n\nIn relation to the information sources for interventional radiology, lectures were the most often cited information source 82 (33.3%), followed by radiology elective rotations 59 (24%), self-directed research 45 (18.3%), problem-based learning tutorials 36 (14.6%), ward rounds 30 (12.2%), meetings 24 (9.8%), and colleges 5 (2%). About 104 (42.3%) students mentioned that they had had no exposure to interventional radiology (Figure 1).\n\nSimilarly, overall awareness level regarding IR amidst medical intern and clinical-year medical students at KFU in Al-Hasa province is shown in Figure 2. Around 118 (48%) students had good awareness level while 128 (52%) had poor awareness regarding interventional radiology.\n\nFinally, all the data in relation to the distribution of medical students and interns’ awareness regarding interventional radiology by their personal data and perception are reported in Table 4. Amongst participants with a good level of IR awareness, 35 (56.5%) students consider a career in diagnostic radiology compared to 25 (37.3%) students who are not sure about that with detected statistical significance (P=0.048). Additionally, a good degree of perception was detected in 22 (84.6%) of medical interns in contrast to 51 (37.8%) of fourth year students and 45 (52.9%) of fifth year group with statistical significance (P=0.001). Also, 59 (64.6%) of the students and interns who consider a career in interventional radiology had high degree of awareness level regarding the specialty versus 97 (35.4%) of those who are not sure (P=0.009). When it came to the participating students who had a high level of awareness of IR, 96 (52.7%) were familiar with the procedure called ‘angioplasty’ compared to 22 (34.4%) who were not (P=0.011).\n\n$ Exact probability test.\n\n* P<0.05 (significant).\n\n\nDiscussion\n\nRecent studies have suggested that interventional radiology (IR) is a radiology sub-specialty with components for IR-based education that have not been included in the undergraduate medical curriculum.8 Interventional specialties are expanding swiftly and are influencing various surgical and medical fields.9 The rapid advancement in the field has encouraged the improvement of imaging modalities, which are now crucial in the diagnosis and treatment of various illnesses in a variety of unrelated disciplines.10 This advancement has made it possible to develop a less intrusive therapy and offered interventional specialty practitioners in the fields of surgery and medicine access to new opportunities.11 The current study intended to evaluate the awareness of IR among medical intern and clinical-year medical students at KFU in Al-Hasa province.\n\nThe outcome indicated that almost half of the students (48%) had good awareness level regarding interventional radiology in total. In more detail, about one-third of the students understand that radiology training is necessary for becoming an interventional radiologist. In addition, more than half of the students (52.8%) think that interventional radiologists attend the hospital's wards but less than half (46.3%) believe that interventional radiologists have outpatient clinics. As for interventional radiologist role in treating patients, the vast majority of students (85%) think that interventional radiologists treat patients with major diseases but about 41.1% think that interventional radiologists attend to patients with minor diseases. Furthermore, only about 16.3% of students believed that interventional radiologists do not provide any patient care at all, and less than half of students (45.5%) believe that interventional radiologists should not admit patients to hospitals. Regarding procedures that can be done by an interventional radiologist, 83.3% of the students correctly reported lower limb angioplasty and stenting, followed by 78% uterine artery embolization for fibroids, 70.3% venous access procedures, and 55.7% arteriovenous fistulas for dialysis. This average level of awareness may be explained by many factors. First, about 42% of the students had no previous exposure to intervention radiology while only one-third of them (33.3%) had information from lectures. Second, only 27% of the students finished, or did plan to complete an elective rotation in radiology, which may play a role in providing them with information regarding the specialty. Third, only one-quarter of the students will consider diagnostic and interventional radiology for their future careers, which lessens their motive to know more about the specialty. Fourth, only one-fifth claimed to have observed patients who received care from an interventional radiologist. This clearly declares a vague picture regarding this new specialty.\n\nMany studies found that medical students reported poor knowledge of IR as a result of suboptimal teaching and exposure levels. Agrawal D et al.12 reported that 60% of medical students knew very little or nothing about IR. Remarkably, 91.5% of students expressed interest in obtaining IR-based instruction as part of their undergraduate bachelor degree, which is significantly more than the amount assumed in the present study. In Canada, O'Malley L et al.13 found that more than half of the participants (53%) had “poor” knowledge of IR and only 18% reported that they would contemplate a career in IR. Lack of understanding (48%) or lack of interest (43%) are the main factors keeping them from considering IR as a career, which is consistent with our study findings. Additionally, 74% of students reported that a compulsory 2-week radiology rotation throughout clerkship would be helpful, and 71% said that a 2-week elective IR rotation during their required core surgery rotation would be intriguing. In England, a higher awareness level among medical students has shown that 75.9% knew that interventional radiologists performed angioplasty and stenting of arteries as reported by Atiiga PA et al.14 More than half (54.5%) thought cardiac procedures are done by IR. Also, 31.4% of the students knew IR procedures included the treatment of tumors. In Saudi Arabia, similar findings were reported by Alshumrani GA et al.15 where 52% of final-year students had poor knowledge of IR. Only 40% of the participants either finished or are planning to complete an elective rotation in radiology. A career in IR was something that roughly 38% of students were willing to consider. The most frequent excuse given for not contemplating a career in IR was not having enough knowledge (43%). Only 33% correctly acknowledged the method of training of interventional radiologists. Another study in Riyadh6 found that only 16 participants thought they understood IR well, whereas 83% said they knew very little. Half of the participants believe that interventional radiologists (IRs) must complete training in radiology. However, 42% believed that radiology and surgery were the correct paths of training for IRs. 71% and 73% of the final-year medical students correctly acknowledged that both uterine artery embolization and lower limb angioplasty are performed by IRs, respectively. There are many studies which confirm the lack of knowledge regarding IR among medical students and interns.16–18 The scope of this study is limited by the sample size as well as its restriction to one university in one region and should preferably be applied to various universities in the kingdom or in a larger view the middle east to improve the policy regarding IR education in universities.\n\n\nConclusion\n\nThe current study found that final-year medical students and medical interns had relatively poor awareness and knowledge toward IR. There are several methods that can be used to address this problem, including early introduction of IR course into the curriculum, launching IR awareness campaigns, and IR symposiums. This will contribute to better understanding of this important medical specialty that is of great advantage to healthcare.\n\n\nEthical approval\n\nThe 1975 Helsinki Declaration and its later amendments or comparable ethical standards were followed in all procedures involving human subjects, as well as the ethical requirements of the institutional and/or national research committee. King Faisal University granted the ethical endorsement (reference number: KFU-REC-2022-SEP–ETHICS171).\n\n\nInformed consent statement\n\nAll participants in the study provided their informed permission.",
"appendix": "Data availability\n\nZenodo: Awareness of interventional radiology among medical students at KFU in Al-Hasa province, DOI: 10.5281/zenodo.7442904. 19\n\nThis project contains the following underlying data:\n\n• IR - Responses-.xlsx (dataset)\n\n• Questionnaire (copy of questionnaire used in this study)\n\nZenodo: STROBE checklist for [Awareness of interventional radiology among medical students at KFU in Al-Hasa province], DOI: 10.5281/zenodo.7451599. 20\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 Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia, financed this work through the Annual Funding track [Grant No. GRANT1609]. Their permission was obtained for the acknowledgment.\n\n\nReferences\n\nTrainee: Saudi Commission for health specialties:n.d. Retrieved November 14, 2020.Reference Source\n\nKessel D: What is interventional radiology? BSIR;n.d. Retrieved November 14, 2020.Reference Source\n\nBelli A, Markose G, Morgan R: The Role of Interventional Radiology in the Management of Abdominal Visceral Artery Aneurysms. Cardiovasc. Intervent. Radiol. 2011; 35(2): 234–243. Publisher Full Text\n\nBaker T, Aaron J, Borge M, et al.: Role of interventional radiology in the management of complications after pancreaticoduodenectomy. Am. J. Surg. 2008; 195(3): 386–390. Publisher Full Text\n\nAmerican Board of Radiology|An ABMS Member Board:2020 [cited 14 November 2020].Reference SourceReference Source\n\nAl Zahrani Y, Abohimed A, Arabi M: Interventional radiology awareness among the final-year medical students in Riyadh. Arab J. Intervent. Radiol. 2020; 4(1): 32–37. Publisher Full Text\n\nAlbaqawi R, Alreshidi M, Alshubrami D, et al.: Awareness of interventional radiology among clinical years' medical students and medical interns at University of Hail. The Arab Journal of Interventional Radiology. 2019; 3(2): 58–64. Publisher Full Text\n\nEmin EI, Ruhomauly Z, Theodoulou I, et al.: Are interventional radiology and allied specialities neglected in undergraduate medical education? A systematic review. Ann. Med. Surg. 2019; 40(40): 22–30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAggarwal R, Mishra A: Surgical technical skills. Essential Simulation in Clinical Education. 2013; 7: 111–130. Publisher Full Text\n\nMaingard J, Kok HK, Ranatunga D, et al.: The future of interventional and neurointerventional radiology: learning lessons from the past. Br. J. Radiol. 2017; 90: 20170473. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBaum S, Pentecost M: Abrams' angiography. 2nd ed.Philadelphia:Lippincott;2005.\n\nAgrawal D, Renfrew MA, Singhal S, et al.: Awareness and knowledge of interventional radiology among medical students at an Indian institution. CVIR Endovascular. 2019; 2(1): 45–47. PubMed Abstract | Publisher Full Text | Free Full Text\n\nO'Malley L, Athreya S: Awareness and level of knowledge of interventional radiology among medical students at a Canadian institution. Acad. Radiol. 2012 1; 19(7): 894–901. PubMed Abstract | Publisher Full Text\n\nAtiiga PA, Drozd M, Veettil R: Awareness, knowledge, and interest in interventional radiology among final year medical students in England. Clin. Radiol. 2017 1; 72(9): 795.e7–795.e12. PubMed Abstract | Publisher Full Text\n\nAlshumrani GA: Awareness of interventional radiology among final-year medical students and medical interns at a university in Southwestern Saudi Arabia. Saudi Med. J. 2013 Aug 1; 34(8): 841–847. PubMed Abstract\n\nLeong S, Keeling AN, Lee MJ: A survey of interventional radiology awareness among final-year medical students in a European country. Cardiovasc. Intervent. Radiol. 2009 Jul 1; 32(4): 623–629. PubMed Abstract | Publisher Full Text\n\nde Gregorio MA , Guirola JA, Sierre S, et al.: Interventional radiology and Spanish medical students: a survey of knowledge and interests in preclinical and clinical courses. Cardiovasc. Intervent. Radiol. 2018; 41(10): 1590–1598. PubMed Abstract | Publisher Full Text\n\nKattapuram TM, Sheth RA, Ganguli S, et al.: Interventional radiology symposium for medical students: raising awareness, understanding, and interest. J. Am. Coll. Radiol. 2015 1; 12(9): 968–971. PubMed Abstract | Publisher Full Text\n\nAlmotreb LK: Awareness of interventional radiology among medical students at KFU in Al-Hasa province. Zenodo. 15 Dec 2022. Web. Publisher Full Text\n\nAlmotreb LK: STROBE checklist. Zenodo. 17 Dec 2022. Web.Publisher Full Text"
}
|
[
{
"id": "201211",
"date": "04 Sep 2023",
"name": "Lorenzo Faggioni",
"expertise": [
"Reviewer Expertise Radiology",
"Radiation protection",
"Radiology education",
"Imaging 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\nI have the following comments:\nIn the Abstract, it would be important to add the most relevant proportions and p-values reported in Table 4 to the Results section.\n\nIn the Introduction, please briefly summarize the findings from the \"few studies\" (which ones?) evaluating the IR knowledge of medical students.\n\nIn the Discussion, the paragraph \"The outcome indicated ... new specialty\" largely repeats the study results without making comparisons to the existing literature. Could you please address this? This part could perhaps be more integrated / partially merged with the following paragraph (\"Many studies...\").\nMoreover, please describe in more detail the findings of refs 16-18 mentioned near the end of the Discussion section.\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": []
}
] | 1
|
https://f1000research.com/articles/12-91
|
https://f1000research.com/articles/12-89/v1
|
23 Jan 23
|
{
"type": "Research Article",
"title": "Multimorbidity in Sudanese women newly diagnosed with breast cancer: a retrospective cross-sectional study",
"authors": [
"Mohammed Alorini",
"Saeed Omar",
"Mutasim Abubaker",
"Ishag Adam",
"Mohammed Alorini",
"Saeed Omar",
"Mutasim Abubaker"
],
"abstract": "Background: The association between multimorbidity and breast cancer is not yet fully understood. Few studies have published data on the association between multimorbidity and breast cancer in Africa, and none of them were conducted in Sudan. This study was conducted to estimate the prevalence and associated factors for multimorbidity (obesity, hypertension, diabetes, cardiovascular disease, asthma and tuberculosis, and HIV) and their association with breast cancer stage in women newly diagnosed with breast cancer in eastern Sudan. Methods: A retrospective cross -sectional study was conducted at East Oncology Center in Gadarif, eastern Sudan, from January to October 2021. Medical files were reviewed and sociodemographic, clinical data (comorbidities of hypertension, diabetes, cardiovascular disease, asthma, tuberculosis, and HIV) were retrieved. Logistics regression analysis was performed. Results: Medical files of 384 women who had newly diagnosed breast cancer were reviewed and included in this analysis. The median (interquartile) of their age was 50.0 (39.0‒60.0) years. Sixty-five women (16.9%) had multimorbidity. Obesity (77, 20.1%), hypertension (66, 17.20%), and diabetes mellitus (50, 13.0%) were the most common forms of morbidity among these women. Multivariate analysis showed that age was positively associated with multimorbidity (adjusted odds ratio [AOR] = 1.04, 95% confidence interval [CI] = 1.02‒1.07). Women with a lower level of education (AOR = 3.23, 95 % CI = 1.73‒6.04) and residing in urban areas (AOR = 2.22, 95% CI = 1.14‒4.34) were at higher risk for multimorbidity. Multivariate analysis showed that women with multimorbidity were at higher risk for presenting with newly diagnosed advanced breast cancer (AOR = 3.36, 95% CI = 1.85‒6.08). Conclusion: In eastern Sudan, older women, women with less education, and women residing in urban areas are at higher risk for multimorbidity associated with advanced newly diagnosed breast cancer.",
"keywords": [
"multimorbidity",
"breast cancer",
"newly diagnosed",
"risk factors",
"Sudan"
],
"content": "Introduction\n\nBreast cancer is the commonest cancer in women and the leading cause of cancer-related death globally.1 It is the commonest cancer in sub-Saharan Africa women.1 Factors such as geography, age,2 family history,3 menstrual history, nulliparous,4 and existing benign breast disease5 are identified as risk factors for breast cancer. Patients, and especially those who are elderly, may have comorbidities when they are diagnosed with cancer.6 Previous studies have shown that 20–35% of women with breast cancer have one or more comorbidities at the time of breast cancer diagnosis.6 The presence of comorbidities at the time of diagnosis of breast cancer poses an additional challenge for the management of the disease.7 Communicable disease, urbanization, and cardiovascular disease are risk factors for breast cancer.8 Bensken et al. recently reported that women with multimorbidity and breast cancer are at increased risk of death.9 Investigating the presence of comorbidities along with breast cancer is very important not only because they are potential risk factors for breast cancer but also because they can affect the stage of the disease at diagnosis, the treatment modality, and the prognosis of the disease.6,9\n\nBreast cancer is the most frequent hospital-treated malignancy in Sudan. Its incidence and mortality in the country have been estimated at 22.5 and 16.6 per 100,000 women (among hospital treated malignancy), respectively.10 Risk factors for breast cancer among Sudanese patients include past history of benign breast disease, pesticide exposure, overweight, physical inactivity, and being unmarried.11 The country’s epidemiological transition, through enhanced control of communicable diseases, increased life expectancy, urbanization, and lifestyle modifications, has led to a rise in the prevalence of risk factors for non-communicable disease.12 Increased life expectancy also results in multimorbidity (coexisting diseases) at the personal level, including in breast cancer patients.6 The aim of this study is to estimate the prevalence and associated factors for multimorbidity (hypertension, obesity, diabetes, cardiovascular disease, asthma, tuberculosis, and HIV) and their association with breast cancer stage in women newly diagnosed with breast cancer in eastern Sudan.\n\n\nMethods\n\nThe study followed the “Strengthening the Reporting of Observational studies in Epidemiology (STROBE) Statement standard checklists.13 A retrospective study was conducted at East Oncology Center in eastern Sudan, from) 03/01/2021 to 31/10/2021. The center is located in Gadarif city, which has a population of 1,727,401 residents and is located on the Ethiopian border, 400 km from the capital, Khartoum. Although East Oncology Center is located in Gadarif, its catchment covers the eastern part of Sudan (Gadarif, Kassala, and Port Sudan), from where patients are treated for free. The main services provided in the centre are diagnostic services, endocrine treatment, surgery, chemotherapy, as well as radiation therapy.\n\nOutcome measures\n\nThe main outcome measures were to estimate the prevalence and associated factors for the most common comorbidities (hypertension, obesity, diabetes, cardiovascular disease, asthma, obesity, tuberculosis, and HIV) in women newly diagnosed with breast cancer in eastern Sudan and the associated stage of their cancer.\n\nSample size\n\nThe sample size (384) was calculated using the formula of the sample size for proportion; (n) for this study was calculated by using a single proportional formula (n = Z2pq/d2). Where p was the expected prevalence of multimorbidity among women with breast cancer (50%), based on a similar study from Africa6=, q = (1-p), Z1-α = confidence interval of 95% =1.96, d = margin of error of 5%= 0.05. OpenEpi was used to calculate the sample size.14\n\nThis study included consecutive files of women newly diagnosed with breast cancer.\n\nWomen with a previous cancer diagnosis, who had previously received treatment (radiotherapy, chemotherapy, or any endocrine therapy), or who were unable to give informed consent were excluded.\n\nData were retrieved from the medical files (papers) and a questionnaire used to collect data from these files of women who had newly diagnosed breast cancer, which had been confirmed by histopathological analysis. Data extracted were about age and comorbidities (hypertension, diabetes, cardiovascular disease, asthma, cerebrovascular accident, thyroid disorders, tuberculosis, and HIV). Body height and weight were recorded to compute body mass index (BMI).\n\nWomen were grouped by stage at diagnosis as early (I–II) or advanced (III–IV), as per the guidelines outlined in the American Joint Committee on Cancer’s staging system.15\n\nThe data were analyzed using Statistical Package for the Social Sciences (SPSS, RRID:SCR_002865) software for Windows, version 22.0 (IBM, Armonk, NY, USA). Continuous data were checked for normality using the Shapiro–Wilk test; those found to be not normally distributed were expressed as a median (interquartile [IQR]), while the categorized data were expressed as frequency (proportion). Univariate analyses were performed with multimorbidity and newly diagnosed advanced breast cancer (stages III–IV) as the dependent variable and sociodemographic and clinical factors (multimorbidity for advanced breast cancer) as the independent variables. Multicollinearity was initially evaluated (by the presence of high correlation between the variables (r ≥0.9) or if the variance inflation factor was more than 4. Multicollinearity was not detected between the variables. Then variables with p <0.200 were shifted to build multivariable analysis, and the “backward likelihood ratio (LR) was used to evaluate the independent effects of each covariate by controlling the effects of other variables. The adjusted odds ratios (AOR) and 95% confidence intervals (CI) were computed”. A p-value less than 0.05 was considered statistically significant.\n\n\nResults\n\nIn this study, a total of 384 files of women with newly diagnosed breast cancer were included in the analysis. The median (IQR) of their age and parity (number of deliveries) were 50.0 (39.0–60.0) and 5.0 (2.0–7.0), respectively. The majority (88.5%) of women were housewives. Around two-thirds (68.2%) of women had less than secondary school education. Of the women, 239 (62.2%) were from urban areas (Table 1).\n\n65 women (16.9%) had multimorbidity. Obesity (n=77, 20.1%), hypertension (n=66, 17.20%), diabetes mellites (n=50, 13.0%), asthma (n=5, 1.3%), tuberculosis and HIV (n=6, 1.6%), cerebrovascular accident (n=5, 1.3%), and thyroid disease (n=2, 0.5%) were morbidities encountered among these women.\n\nThe median (IQR) of age was significantly higher in women with multimorbidity, who also tended to have a lower level of education and resided in urban areas. There was no significant difference in parity, marital status, and menopause between women with multimorbidity compared with those without (Table 1).\n\nMultivariate analysis showed that age was positively associated with multimorbidity (AOR = 1.04, 95% CI = 1.02–1.07). Women with a lower level of education (AOR = 3.23, 95% CI = 1.73–6.04) and who resided in urban areas (AOR = 2.22, 95% CI = 1.14–4.34) were at higher risk for multimorbidity (Table 2).\n\nThere was no significant difference in age, parity, education level, residency, or menopause between women with a new diagnosis of early breast cancer compared with those with a new diagnosis of advanced breast cancer (Table 3).\n\nMultivariate analysis showed that women with multimorbidity were at higher risk of presenting with newly diagnosed advanced breast cancer (AOR = 3.36, 95% CI = 1.85–6.08) (Table 4).\n\n\nDiscussion\n\nIn the current study, we observed that 16.9% of the women with newly diagnosed breast cancer had multimorbidity. Obesity was detected in 20.1% of the women, and 17.20% had hypertension. It was recently reported that 36.6% of adult females in eastern Sudan are obese16 and 40.9% have hypertension.17 The low prevalence of hypertension among the women with newly diagnosed breast cancer in this study could be explained by the method followed in the current study (retrospective and self-reported by the patient). Our results for the prevalence of obesity and hypertension among women newly diagnosed with breast cancer was significantly lower than the reported prevalence of obesity (35%) and hypertension (32%) that had recently been reported among women newly diagnosed with breast cancer in other African countries.6 Our results indicate that multimorbidity in women with newly diagnosed breast cancer was positively associated with age. We previously reported that age was positively associated with hypertension in a community-based study in the same setting (Gadarif).17 This aligns with a recent report that showed that age is positively associated with multimorbidity in women with breast cancer in Africa.6 Moreover, Gurney et al. reported that patients with various cancers (breast, colon, rectal, liver, stomach, ovarian, uterine, bladder, or kidney) and comorbidity are older.18 It is well accepted that multimorbidity is associated with increasing age, due to age-related chronic health conditions, and may be explained by the increased stiffness of the arteries (mainly aorta) as a result of the ageing process.\n\nThe current study showed that women with multimorbidity were at 3.36 higher risk of presenting with advanced breast cancer. Interestingly, a large cohort study in several African countries showed multimorbidity not to be associated with stage at diagnosis, although it was associated with earlier stage in obese and hypertensive women alone.6 It is worth mentioning that our results should be compared cautiously with those of the later study because of different sociodemographic characteristics and the prevalence of HIV (higher in the later study).6 Moreover, it has been shown that patients with various cancers and comorbidity are at increased risk of being diagnosed with distant metastases and present late for diagnosis.18 Likewise, Sarfati et al., showed that patients with comorbidity with colon cancer have an increased risk of being diagnosed with distant metastases than patients with no comorbidity burden.19 It should be noted that comorbidity may distract both the patient as well the physician from early signs and symptoms of cancer and hence lead to delay in the cancer diagnosis. On the other hand, the presence of comorbidity can increase patients’ contact with health services, which may lead to earlier diagnosis of the cancer.\n\nOur study was retrospective one and it was designed to assess multimorbidity and not each comorbidity independent from each other. Moreover, the low prevalence of some individual disease comorbidities, such as HIV, could have influenced the ability to detect significant differences for such disease.\n\n\nConclusion\n\nIn eastern Sudan, older women, women with less education, and those who reside in urban areas are at higher risk for multimorbidity associated with advanced newly diagnosed breast cancer.\n\n\nEthical approval\n\nEthical approval was received from the Ethics Committee at the Faculty of Medicine, Gadarif University, Sudan (reference number: 2021/08). Files were analyzed unanimously.",
"appendix": "Data availability\n\nFigshare: Multimorbidity in Sudanese women newly diagnosed with breast cancer: a retrospective cross-sectional study. https://doi.org/10.17605/OSF.IO/ZUY2K.\n\nThe project contains the following underlying data:\n\n- Supplementary File 1.\n\n- Questionnaire.\n\nFigshare: STROBE checklist for ‘Multimorbidity in Sudanese women newly diagnosed with breast cancer: a retrospective cross-sectional study’. https://doi.org/10.17605/OSF.IO/ZUY2K\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\nFeng RM, Zong YN, Cao SM, et al.: Current cancer situation in China: Good or bad news from the 2018 Global Cancer Statistics? Cancer Commun. 2019; 39: 1–12.\n\nHolm J, Eriksson L, Ploner A, et al.: Assessment of breast cancer risk factors reveals subtype heterogeneity. Cancer Res. 2017; 77: 3708–3717. PubMed Abstract | Publisher Full Text\n\nMomenimovahed Z, Salehiniya H: Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer Targets Ther. 2019; Volume 11: 151–164. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJohn EM, Hines LM, Phipps AI, et al.: Reproductive history, breast-feeding and risk of triple negative breast cancer: The Breast Cancer Etiology in Minorities (BEM) study. Int. J. Cancer. 2018; 142: 2273–2285. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRehman S, Husnain SM: A probable risk factor of female breast cancer: Study on benign and malignant breast tissue samples. Biol. Trace Elem. Res. 2014; 157: 24–29. PubMed Abstract | Publisher Full Text\n\nAyeni OA, Norris SA, Joffe M, et al.: Preexisting morbidity profile of women newly diagnosed with breast cancer in sub-Saharan Africa: African Breast Cancer-Disparities in Outcomes study. Int. J. cancer. 2021 [cited 2022 Aug 25]; 148: 2158–70. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJakobsen M, Kolodziejczyk C, Jensen MS, et al.: Cardiovascular disease in women with breast cancer - a nationwide cohort study. BMC Cancer. 2021 [cited 2022 Aug 25]; 21.Reference Source\n\nCheng JS, Chen TC, Chen TD, et al.: Association between breast cancer and hepatitis C: A joint study of hospitalized patients and nationwide cohorts. Transl. Res. 2022 [cited 2022 Aug 28]; 245: 117–129. PubMed Abstract | Publisher Full Text\n\nBensken WP, Schiltz NK, Warner DF, et al.: Comparing the association between multiple chronic conditions, multimorbidity, frailty, and survival among older cancer patients. J. Geriatr. Oncol. 2022 [cited 2022 Aug 30]; 13: 1244–1252. PubMed Abstract | Publisher Full Text\n\nElamin A, Ibrahim ME, Abuidris D, et al.: Part I: cancer in Sudan—burden, distribution, and trends breast, gynecological, and prostate cancers. Cancer Med. 2015 [cited 2021 Dec 15]; 4: 447–456. PubMed Abstract | Publisher Full Text | Free Full Text\n\nElbasheer MMA, Alkhidir AGA, Mohammed SMA, et al.: Spatial distribution of breast cancer in Sudan 2010-2016. PLoS One. Public Library of Science. 2019; 14: e0211085. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOmar SM, Osman OS, Gasim GI, et al.: Pattern and Trends in Adult Hospitalization/Admission and Mortality Among Medical Ward Inpatients at Gadarif Hospital in Eastern Sudan: A Four-Year Retrospective Study. Int. J. Gen. Med. 2022 [cited 2022 Sep 4]; 15: 5879–5889. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCuschieri S: The STROBE guidelines. Saudi J Anaesth. Wolters Kluwer -- Medknow Publications;2019; vol. 13. : S31.\n\nOpenEpi Menu:[cited 2022 Jan 1].Reference Source\n\nEdge SB, Compton CC: The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann. Surg. Oncol. 2010 [cited 2022 Aug 29]; 17: 1471–1474. PubMed Abstract | Publisher Full Text\n\nOmar SM, Taha Z, Hassan AA, et al.: Prevalence and factors associated with overweight and central obesity among adults in the Eastern Sudan. PLoS One. Public Library of Science. 2020; 15: e0232624.\n\nOmar SM, Musa IR, Osman OE, et al.: Prevalence and associated factors of hypertension among adults in Gadarif in eastern Sudan: a community-based study. BMC Public Health. 2020; 20: 291. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGurney J, Sarfati D, Stanley J: The impact of patient comorbidity on cancer stage at diagnosis. Br. J. Cancer. 2015 [cited 2022 Sep 4]; 113: 1375–1380. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSarfati D, Tan L, Blakely TPN: Comorbidity among patients with colon cancer in New Zealand. N. Z. Med. J. 2011 [cited 2022 Sep 4]; 124: 76–88. PubMed Abstract"
}
|
[
{
"id": "308923",
"date": "13 Aug 2024",
"name": "Phumudzo Ndwambi",
"expertise": [
"Reviewer Expertise Breast Cancer"
],
"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 very relevant topic and is should be considered with a lot more precision for reproducibility.\n1. Most of the references are from the past 5 years ( after 2019) but there are some outdated references dating to 2010 that may potentially have more recent data and this should be looked into.\n\n2. A Clear definition of diagnostic parameters should be provided, in the form of universal reference ranges for each comorbidity as well as for the definition of locally advanced breast cancer. It should also be stated whether these diagnoses encompass poorly vs well controlled patients and the definitions thereof. The term cerebrovascular accidents and thyroid disorders are too vague. There needs to be clear inclusion and exclusion criteria of which pathologies in these terms were included. It also needs to be specified if the presence of Tuberculosis is seen in the current form or a previous history, followed by whether the TB is on active or maintenance phase of treatment.\nI was unable to retrieve the questionnaire and this may potentially address these issues\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?\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? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/12-89
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https://f1000research.com/articles/12-86/v1
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23 Jan 23
|
{
"type": "Case Report",
"title": "Case Report: Managing Bardet-Biedl syndrome at a tertiary care centre",
"authors": [
"Sandip Ghimire",
"Prativa Sangroula",
"Ujwal Thokar",
"Prativa Sangroula",
"Ujwal Thokar"
],
"abstract": "Bardet-Biedl syndrome (BBS), a rare ciliopathy, is a genetic disease with autosomal recessive inheritance which presents with multiple organ system involvement. It usually presents with renal dysfunction, dystrophy of rods and cones, obesity, hypogonadism, post-axial polydactyly, learning difficulties and other minor features. The treatment of this condition is primarily symptomatic and involves a multidisciplinary approach. We here present a case report of 42-year-old male patient presenting in the medicine department with renal impairment, metabolic syndrome, blindness, polydactyly, diabetes mellitus, and a learning disability. He was managed for renal impairment, hypertension and metabolic syndrome using the various approaches including medicines, dietary modifications including diabetic and renal diet, and lifestyle modifications. His renal function improved after the treatment, and he was able to lose weight which improved his diabetes control, cholesterol levels, and liver enzymes. This case underscores the importance of a multidisciplinary and wholistic approach while managing a case with BBS.",
"keywords": [
"Bardet-Biedl syndrome",
"renal impairment",
"polydactyly",
"metabolic syndrome",
"retinitis pigmentosa"
],
"content": "Introduction\n\nBardet–Biedl syndrome (BBS) is a rare ciliopathy with autosomal recessive inheritance.1 BBS is prevalent all over the world in varying frequencies. Its prevalence in North America and Europe ranges from the 1:140000 to 1:160000 live births.2 BBS is characterized by renal dysfunction, dystrophy of rods and cones, obesity, hypogonadism, post-axial polydactyly, learning difficulties and other minor features. Coexistence of clinical findings itself can consolidate the diagnosis of BBS. However, for the definitive diagnosis, sequencing of known disease-causing genes is needed.1 Till date, about 21 BBS genes responsible for BBS have been identified including BBS1 - BBS20 and NPHP1 genes. The number of known BBS genes is likely to increase with the advancement in the genetic analysis via exome sequencing, and the study of more people in this population.3 Despite advancement in the diagnosis of BBS, the management of this syndrome is largely limited to the symptomatic treatment.3\n\nHere, a patient with clinically diagnosed BBS who presented with complications including renal impairment, metabolic syndrome and blindness is described. His complications i.e., renal impairment and metabolic syndrome, and quality of life improved after starting him on the treatment and lifestyle modification. This case highlights the importance of timely diagnosis and treatment of clinical features and complication to improve the outcomes in patients with BBS.\n\n\nCase report\n\nA 42-year-old, unemployed South Asian man from Palpa District, Western Nepal came to our attention in medical outpatient department when he presented for his routine follow up for type 2 diabetes mellitus in November 2021. He was assisted by his mother as he was completely blind. His blood reports showed impaired renal function test. He was then further evaluated for his renal derangement. He was the eldest son among three siblings in the family. His mother denied the history of consanguinity. The mother said the patient had delayed development compared to other two siblings; he could speak monosyllables at the age of eighteen months, and two to three words at the age of three years which was delayed in comparison to other children of this age. He was found to have decreased vision when he was about four years of age, which was painless and progressive, and he was completely blind by the age of 10. He was admitted in school but could not continue his formal education beyond grade five, at the age of 11, because of his learning difficulties and vision problem. At the time of history taking, his visual acuity in both eyes was perception of light. He married at the age of 20 years and has two male children of 21 years and 20 years. Both of the children are doing well in college without any physical or mental impairment.\n\nOne year prior to this appointment, he visited a nearby clinic with the complaints of increased urinary frequency where he was diagnosed with type 2 diabetes mellitus and hypertension, and was started on oral hypoglycemic agent (tablet metformin 500mg per oral twice a day) and antihypertensive medication (tablet amlodipine 5mg per oral once a day).\n\nOn physical examination, his vital parameters were stable. He had central obesity and his waist circumference was 98 centimeters. His height was 152cm, weight was 74kg, and body mass index (BMI) was 32.0 kg/m2. He had a moon shaped face, polydactyly on both feet, and right hand with history of amputation of the extra finger of the left hand during childhood at home by mother (Figures 1,2). His fundus examination showed the features of advanced retinitis pigmentosa with no evidence of diabetic retinopathy and hypertensive retinopathy.\n\nThere is one extra finger in the right hand (red arrow).\n\nThere are extra toes in both feet (red arrows).\n\nOn laboratory reports, his blood counts and thyroid function test were within normal limits. His blood urea level was 54.6 mg/dl (15-45 mg/dl), serum creatinine level was 1.8 mg/dl (0.5-1.4 mg/dl), fasting blood glucose was 97 mg/dl (60-105 mg/dl), post prandial glucose was 156 mg/dl (70-140 mg/dl), and glycated hemoglobin level of 6.2% (3.8-5.8%). His urine microscopic examination was normal with spot protein creatinine ratio of 0.1 mg/mg. His intact parathyroid hormone level was raised i.e., 289.5 pg/mL (10-65 pg/mL) and serum uric acid level was 9.4 mg/dl (3.4-7.0 mg/dl). However, his serum calcium, phosphorous, albumin, sodium, potassium and vitamin D level were within normal limits. His liver function test showed aspartate transaminase level of 48 IU/L (0-46 IU/L), alanine transaminase level of 87 IU/L (0-40 IU/L) and alkaline phosphatase level of 168 U/L (30-120 U/L). In lipid profile plasma cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol were 180 mg/dl, 240 mg/dl, 40 mg/dl, 92 mg/dl, and 48 mg/dl respectively. His estimated glomerular filtration rate (eGFR) was 48 ml/min/1.73m2.\n\nOn imaging studies, ultrasound of the abdomen and pelvis showed: fatty changes in liver grade-1 with normal liver size, loss of corticomedullary differentiation of bilateral kidneys with right kidney measuring 9.3x4.1 cm and left kidney measuring 8.9x5.0 cm, simple left renal cyst, and non-obstructing left nephrolithiasis (Figures 3,4). Two-dimension echocardiogram showed: mild enlarged left atrium of 42mm, normal left ventricle systolic function with ejection fraction of 65%, normal left ventricle diastolic function, no regional wall motion abnormalities, normal valves, and no intracardiac mass, thrombus, vegetation, pericardial effusion.\n\nRK: Right kidney\n\nLK: Left kidney\n\nA diagnosis of the Bardet-Biedl syndrome was made based on the modified diagnostic criteria for BBS (Table 1).4 The patient and his family members were counselled about the disease and the patient was started on supportive care. He was started on oral hypoglycemic agent (tablet linagliptin 5mg PO OD), angiotensin receptor blocker (tablet telmisartan 40mg PO HS), calcium channel blocker (tablet amlodipine 2.5mg PO OD), xanthine oxidase inhibitors (tablet febuxostat 40mg PO OD), HMG-CoA reductase inhibitors (tablet atorvastatin 10mg PO HS), oral N-acetylcysteine (600 mg PO BD), and cholecalciferol (60000 IU once a week). As he met the criteria of metabolic syndrome, he was advised to perform daily exercises and consume low calorie diet for reducing his BMI. He was advised to follow a renal diet and asked to avoid over the counter medications. He was followed every two months and danger signs of renal failure were explained. After receiving treatment and adhering to the lifestyle modification for six months, he lost four kilograms of bodyweight. His laboratory parameters improved to blood urea level of 21 mg/dl, serum creatinine level of 1.2 mg/dl, serum uric acid level of 6.0 mg/dl and normal range of liver enzymes.\n\n\nDiscussion\n\nCiliopathies refer to shared disorders due to loss of cilia and/or its dysfunction leading to various systemic manifestations in humans, BBS being one of them. Ciliopathies affects the various ciliated organ system causing a wide range of manifestations. Among the 21 recognized BBS genes, BBS1 and BBS10 are the two main genes that are involved in more than 20% of the cases. Bardet–Biedl genes encode BBSomes, proteins that aid in generation and function of primary cilia.5\n\nDiagnosis of BBS is done on the basis of phenotypic presentation of the disease and the disease manifestation varies among the patients remarkably. There are multiple primary and secondary features of BBS which have been summarized among patients of various age groups.3 The primary features of BBS include retinal abnormalities, obesity, polydactyly, hypogonadism, renal anomalies, and learning difficulties.1 Secondary features include speech disorder/delay, strabismus/cataracts/astigmatism, brachydactyly/syndactyly, developmental delay, polyuria/polydipsia (nephrogenic diabetes insipidus), ataxia/poor coordination/imbalance, mild spasticity (especially lower limb), diabetes mellitus, dental crowding/hypodontia/small roots/high arched palate, left ventricular hypertrophy/congenital heart disease, hepatic fibrosis.1 Many patients at birth have only polydactyly and other clinical features arise as the patient grows.3\n\nIn BBS the major cause of morbidity and mortality is renal failure causing 25% mortality by the age of 44 years.5 Renal disease is prevalent among 53-82% of patient with BBS. Spectrum of the renal anomalies varies from polycystic kidney disease (most common), renal dysplasia, hydronephrosis, scarred or atrophic kidneys, loss of corticomedullary function, and renal involvement secondary to metabolic syndrome.6 The main management of BBS currently focuses on the symptomatic treatment of the patient to reduce the harmful effects of various manifestations on the organ systems of the patient, especially on the kidneys and eyes.3,6 Renal failure in BBS is managed as in other situations with the use of supportive therapy and renal replacement therapy if necessary.5 In our case, we managed the deranged renal function of the patient using the same multidisciplinary approach as we do in other cases of renal impairment.\n\nEarly detection of this pleiotropic disease plays an indispensable role in its management. Patients with BBS need a multidisciplinary approach by a team of pediatricians, nephrologists, orthopedic surgeons, endocrinologists, psychologists, cardiologists, ophthalmologists, dental specialists, speech and language therapists, dietitians, geneticists and patient support group representatives. This multifaceted approach with annual review of the patient can provide a plan to individualize risk stratification for particular system like renal and endocrine system. In addition, genetic assessment gives the chance to secernate patients according to genotype, hence the need to follow up according to the natural progression of BBS can be insisted.5,6 Moreover, the affected individual and their family members can benefit from the genetic counseling.7,8\n\nIn future, genetic therapies will foresee considerable obstacles and challenges due to numerous disease-causing genes and private mutations seen in a particular single family. Potential genetic therapies for the management of BBS in the near future might include gene therapy, readthrough therapy, exon skipping therapy and genome editing. Other non-genomic therapies that can be available in future encompasses targeted drug therapy and drug repurposing.6 Despite extensive research in gene therapies, early diagnosis and symptomatic treatment remains the mainstay of the management of BBS for now.\n\nThis case highlights the importance of identifying patients with BBS and screening them for the possible complications including renal dysfunction, metabolic syndrome, and retinitis pigmentosa. Early identification and proper management of complications can halt the progression of complications and can improve the quality of life of patient, as in this case.\n\nHowever, in this case, we couldn’t perform genetic analysis to find the responsible gene because of the unavailability of the resources. In addition to this, as BBS is associated with many gene mutations, has various clinical features, and many complications, a result from this single case report might not be applicable to all patients with BBS. Hence an individualized approach might be necessary for the optimal management of BBS patients.\n\n\nConclusion\n\nBardet-Biedl syndrome is a rare genetic disease with various clinical manifestations. As this condition is rare, diagnosis can be easily overlooked by medical professionals. Management of BBS is symptomatic and requires a multidisciplinary approach. Gene therapy, which is evolving swiftly as a treatment modality in BBS, is challenging owing to the complexity and variability of the genes involved. As renal manifestations including renal failure are the major causes of morbidity and mortality in BBS, they should be screened for early diagnosis and managed accordingly. Hence, timely identification and proper treatment of people with BBS can improve their survival and quality of life.\n\n\nConsent\n\nVerbal informed consent was taken from patient and written informed consent was taken from his mother for the publication of the article and associated images.",
"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\nForsythe E, Beales PL: Bardet-Biedl syndrome. Eur. J. Hum. Genet. 2013; 21(1): 8–13. Epub 2012/06/21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKatsanis N, Lupski JR, Beales PL: Exploring the molecular basis of Bardet–Biedl syndrome. Hum. Mol. Genet. 2001; 10(20): 2293–9. Publisher Full Text\n\nSuspitsin EN, Imyanitov EN: Bardet-Biedl Syndrome. Mol Syndromol. 2016; 7(2): 62–71. Epub 2016/07/08. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBeales PL, Elcioglu N, Woolf AS, et al.: New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J. Med. Genet. 1999; 36(6): 437–446. PubMed Abstract | Publisher Full Text | Free Full Text\n\nElawad OAMA, Dafallah MA, Ahmed MMM, et al.: Bardet–Biedl syndrome: a case series. J. Med. Case Rep. 2022; 16(1): 169. PubMed Abstract | Publisher Full Text | Free Full Text\n\nForsythe E, Kenny J, Bacchelli C, et al.: Managing Bardet–Biedl Syndrome—Now and in the Future. Front. Pediatr. 2018; 6: 6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhan BA, Shahid A, Bin Nazir M, et al.: Laurence-Moon-Bardet-Biedl Syndrome: A Case Report. Cureus. 2019; 11(9): e5618. Epub 2019/11/07. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhan PA, Nishaat J, Noor S, et al.: Laurence Moon Bardet Biedl Syndrome: A Rare Case Report in A Tertiary Care Teaching Hospital, Hyderabad, Telangana, India. Int. J. Med. Public Health. 2017; 7: 68–71. Publisher Full Text"
}
|
[
{
"id": "161292",
"date": "02 Mar 2023",
"name": "Miriam Zacchia",
"expertise": [
"Reviewer Expertise Nephrology"
],
"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 describes a case of BBS, which is interesting to be added to the literature given the rarity of the disease. One of the most interesting pieces of information provided is the fact that the patient had two children, an interesting piece of info given the common idea that the syndrome is associated with infertility; moreover, lifestyle changes, diet and drugs to control metabolic syndrome improved renal function.\n\nBelow are my suggestions:\n\nIn the introduction, please explain the reason for a need for an additional case report in the literature: the phenotype of BBS patients is highly variable, ranging from patients with complete-multi-system disease and oligo-symptomatic patients.\n\nIn the description of the case, please explain how the patient had the diagnosis of diabetes (glycosylated Hgb, fasting glucose etc).\n\nPlease provide a table or a figure with basal versus control (6 months) data, stressing parameters that were improved (BMI, eGFR etc).\n\nDiscussion: at least 24 genes have been described; mortality of BBS is quite unknown, it has been recently summarized, together with less common clinical manifestations, by Melluso et al. (2023)1.\nPlease point out the importance of this work: this is one of the first reports showing improvement of kidney dysfunction. The reduction of body weight, physical activities, blood pressure control were paralleled by reduced eGFR. These data suggest that metabolic abnormalities are quite important in the pathogenesis of kidney disease progression, and the recent Metabolomics studies (Marchese et al. (2022)2; Marchese et al. (2022)3) corroborated the presence of systemic and renal metabolic abnormalities in BBS. Please indicate the importance of getting genetics: it is of help in understanding genotype to phenotype correlation.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\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? Yes",
"responses": []
},
{
"id": "183959",
"date": "13 Jul 2023",
"name": "Jean Muller",
"expertise": [
"Reviewer Expertise Ciliopathies",
"Bardet-Biedl syndrome",
"Molecular genetics",
"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\nThe manuscript from Sandip Ghimire et al entitled “Case Report: Managing Bardet-Biedl syndrome at a tertiary care centre” is interesting to highlight how to handle BBS patients that are discovered lately in their life. The manuscript is giving a very detailed clinical description that is rarely observed in studies involving BBS patients. Two interesting points can be highlighted in this manuscript. The first one is the fact that the patient was lately examined showing how patient care is variable depending on the health system in different countries or on due to geographical constraints. The second one is related on how careful clinicians are in trying to diagnose such patients even with typical (BBS) clinical presentation and how patient handling and diagnosis can improve their lifestyle. Indeed, being an adult all the clinical manifestations event the later one such as blindness (progressive vision loss over the first decade), renal dysfunction, even diabetes should be present and facilitate the differential diagnosis by limiting the options for the clinicians.\nBeing a molecular geneticist, I will provide several suggestions in my area of expertise for this manuscript:\n1. Introduction:\nI would suggest presenting the clinical signs in order of penetrance, by starting with retinitis pigmentosa (rod-cone dystrophy) etc…\n\nThe number of BBS genes is now 24 for sure complemented with a few candidates (n=2) and contributing alleles (TTC21B, NPHP1). A recent reference is nicely summarizing the gene list in their Table S2, see PMID: 372939561. Please update and cite this one.\n\nAuthors are also mentioning the absence of proper treatments and at least symptomatic treatments, however the recent availability of the Setmelanotide is very interesting. A few studies have been published in 2023 that can be referenced here (ex PMID: 366470772).\n2. Case description:\nInterestingly, only a few BBS cases have been described with children. In this case report, the BBS patient has 2 children demonstrating again that infertility is not to be considered in BBS. Two recent studies from our lab are highlighting this point (PMID: 328353783 and 351787614).\n\nDespite the fact that the phenotype is almost covering all main aspects of the BBS, I am missing the molecular diagnostic encompassing the gene and pathogenic variant(s) involved in this case. This could have a dramatic impact for the genetic counselling in this family.\n\nIn the paragraph describing the BBS diagnosis (starting with “Diagnosis of BBS is done…”, the last sentence is describing early signs that can be observed at birth and not much related to the antenatal part. Those signs are almost similar and covering polydactyly (as mentioned by the authors) renal dysfunction as observed by ultrasound (hyperechogenic/enlarged kidney). I would add a sentence describing quickly this. A few references also exists for this (PMID: 229983905, 306145266)\n\nI would suggest, in line with the HGVS basic recommendations (http://varnomen.hgvs.org/bg-material/basics/), to use the term variant/variation (aka pathogenic variant) in replacement of “mutation”.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\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? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-86
|
https://f1000research.com/articles/12-85/v1
|
23 Jan 23
|
{
"type": "Brief Report",
"title": "Online algorithm for assignment of specimens to pooled or individual testing using risk models provides a practical way to increase testing capacity",
"authors": [
"Alexander V. Alekseyenko"
],
"abstract": "Background: To improve throughput in diagnostic and screening testing for infectious diseases, I developed a straight-forward algorithm that uses individual risk to optimize the decision about pooled or individual testing.\nMethods: The online greedy algorithm provides an recommendation for filling pooled testing queue for optimal testing in pools of variable size. Observational data from Medical University of South Carolina COVID-19 diagnostic testing was used to estimate capacity gains under this algorithm versus optimal fixed pooling based on population prevalence.\nResults: The online pooling recommendations based on this algorithm resulted in statistically better capacity gains than optimal pools of fixed size (P-value 0.003 and 0.002, for pools of 5 or 6, respectively). This is especially significant since the underlying individual-level risk prediction model attained only a moderate predictive accuracy.\nConclusions: This result suggests that when combined with a better risk prediction and integrated in an appropriate informatics ecosystem this approach cab offers an opportunity for resilient pooled testing strategies for pathogens while incorporating relevant operational constraints of pathology laboratories.",
"keywords": [
"pooled testing",
"individual-level risk",
"machine learning",
"COVID19"
],
"content": "Introduction\n\nThe coronavirus disease 2019 (COVID-19) pandemic has placed a demand for massive, rapid, and accurate diagnostic testing. A number of reports recommend pooled testing to help increase testing capacity. For example, a recent report provides specific estimates of cost savings in a pooled testing setting.1 Biochemically, multiple reports demonstrate that RT-qPCR (reverse transcription quantitative real-time polymerase chain reaction) tests are amenable to pooled testing strategies.2–4\n\nPooled testing has a long legacy of quantitative methodologies and some practical implementation successes. A review of pooled testing can be found at Wiley StatsRef: Statistics Reference Online.5 Within pooled testing methodologies, hierarchical two-step approach is the oldest and the simplest. The approach involves splitting subjects to be tested in equal size groups (pools) and testing each pool first. If a group test result is negative, so is the entire group. If the group is positive, each individual in the group is tested individually. Many variations of this approach have been proposed over the years. The most relevant set of techniques uses individual-level risks in conjunction with pooled testing to determine appropriate pool sizes for more efficient testing. These methods are typically concerned with optimization for given a collection of specimens (e.g. Ref. 6). Unfortunately, such algorithms do not always fit the workflow of pathology and laboratory medicine. It is desirable to be able to make online (at the time of encounter) decisions to assign a specimen to a pool at a point the specimen is first received in the laboratory. Many labs have limited ability to manipulate and rearrange the specimens multiple times to establish optimal pools. Therefore, an online algorithm that provides an immediate recommendation about better pooling strategies for the specimens is of practical importance for successful implementation of pooled testing strategies. For this reason, fixed size pooling, which cannot account for individual-level risk even when available, is by far the most popular approach in practice.\n\nInformatics and artificial intelligence tools have been mobilized to help with the pandemic by allowing for infection risk prediction at the individual level. These risk predictions can be leveraged workflows to prioritize valuable clinical resources.7 In this report I demonstrate that a greedy online algorithm for specimen assignment based on individual risk predictions can increase COVID-19 testing capacity in a way suitable for providing pooling recommendations for specimens as they come in for testing. Figure 1 presents and overview of this approach.\n\nA. The algorithm relies on predictive model informed risk that a given specimen to be tested is positive, pi. Population prevalence rates and arbitrary predictive models can be used based on the available predictors, such as basic demographics, risk factors, symptoms, natural language processing derived features from clinical notes, etc. The probabilities are used to group a stream of specimens to be tested into pools that will be tested together. Should a pool test negative, all of the specimens in the pool are recorded as negative, resulting in increased capacity for testing. For a positive pool, additional ascertainment of each individual specimen will be required for a final result. B. online algorithm makes a decision for any new specimen to either add it to a pool that is being formed or to end forming that pool and start a new one with this specimen. The decision is made based on expected capacity gain by using pooled testing calculated from the pi of the specimen. EHR: Electronic health record.\n\n\nMethods\n\nSuppose the positivity rate is p among the k individuals to be tested. The probability that the pool of these individuals tests positive is Pk=1−1−pk, which is one minus the probability that all subjects are negative. Two-step pooled testing requires individual retesting of everyone in a positive pool (Figure 1A). Thus, the expected number of tests is Ek=1+kPk. The capacity gain is the ratio of the number of subjects tested to the number of physical units of test performed, Gk=k/Ek. Capacity gains with pooled testing are achieved when a pool of specimens tests negative (Figure 1A).\n\nSuppose individual (a priori) estimates of being positive are available for each individual. Given these estimates, p=pi1≤i≤k, the probability that a pool tests positive is Pkp=1−∏i=1k1−pi=Pk−1p1−pk+pk, and the expected capacity gain is Gkp=k1+nPkp. The key to deriving a greedy online algorithm is that both of these quantities, Pkp and Gkp, can be expressed as recurrence relationships, which depend on the quantities already computed for a pool of smaller size. This allows one to maintain an online estimate of the capacity gain of a collection of already processed specimens when making a decision about a new specimen.\n\nThe estimates of a priori individual risk have been obtained using logistic regression. The evaluation data has been collected incidental to a Medical University of South Carolina (MUSC) IRB (Pro00079660) approved study on the Living μBiome BankTM study8,9 of the microbiomes associated with infectious disease testing. The data consisted of COVID-19 test result (response) for the subjects with conclusive test result (“Positive” or “Negative”) for adult (age ≥18) subjects undergoing testing at MUSC Molecular Pathology Lab between March 12 and June 6, 2020 (32,851 cases in total). The design of this study was based on convenience sampling in a relatively short time interval. Cases obtained between May 21st and 6th, 2020 were not used for model fitting, and constituted the testing data. Predictors included subject age and indicator variables for whether the test is a (i) follow-up, (ii) immediately preceding test has been positive; (iii) the patient is hospitalized; (iv) hospital order location; and interaction term between age and (ii). Logistic regression model followed by stepwise backward feature elimination based on Akaike Information Criterion (AIC) was used for model selection in training data only. The performance of the model has been evaluated in both the training and the testing data separately. The analyses have been conducted using R statistical programming environment version 3.6.1.\n\nThe number of physical tests needed and capacity gains of the online algorithm has been compared with optimal uniform fixed pool sizes for based on population prevalence rates.1 For observations in each day in the testing data, averages of 1,000 permutations of the order of the specimens provided for order-independent estimates of the number of tests. One-sided Wilcoxon signed rank sum test was used to evaluate the hypothesis that online recommendations resulted in less tests.\n\n\nResults\n\nThe online pooling algorithm (Figure 1B) has been specifically designed to make pooling decisions about each specimen as it arrives for testing. The individual risk information and the estimates of the capacity gains from already processed specimens allows the algorithm to make a determination to add the specimen to the pool that is currently being filled or to close that pool and start a new one with the current specimen.\n\nThe logistic regression model was meant to provide simplistic estimates of individual risk to demonstrate the feasibility and utility of the approach. The variables included in the data showed statistically significant differences across the training and testing data (Table 1), indicating the potential for suboptimal predictive performance.11 The predictive model provides for a moderate predictive accuracy with 0.62 area under receiver operating characteristic curve estimate in testing data.\n\na The remaining tests have been ordered from ambulatory or community locations.\n\nb Dropped from the model based on Akaike Information Criteria (AIC) in backward elimination step.\n\nc Included as interaction term of age and indicator of a previous positive test.\n\nParameter estimates and other details of the model fit are shown in Figure 2. The model demonstrates that age, hospitalization status and whether the individual has been previously tested and/or tested positive are all good high level predictors of risk of positive test. The model is plagued by the imbalance of low and high risk patients, indicative of the relatively low population-level risk. Nonetheless, the predicted and empirical risk seem to correlate well, albeit with large variability in the high risk group.\n\nA. R generalized linear regression function call and output following backwards stepwise elimination is illustrated. The features included in the final model were an indicator of whether this was a follow up test (Follow_up), an indicator of whether the individual had tested positive at any point previously (Previous_positive), age group (18–40, 40–70, >70), and indicator of whether the individual is hospitalized. An interaction of age and previous positivity is likewise retained in the model. B. Model performance evaluation included comparison of the empirical and predicted probabilities for groups of individuals with matching predictor values (follow up testing indicator, previous positivity, age, and hospitalization status). The model shows good concordance between the empirical and predicted risk in the lower risk range (inset), and large variability within the higher risk groups.\n\nAs is already known from the recent literature, two-step pooling can provide capacity gains over testing everyone individually. This is also demonstrated in our testing data using fixed pools of 5 or 6 specimens (Table 2). These fixed pool sizes have been chosen for comparison because of their optimality given prevalence rates. The evaluation of the online algorithm shows that the implementation of this approach may result in doubling of the testing capacity over testing individually (Table 2). Moreover, on 12 out of 17 days in the testing data the online approach resulted in less tests than fixed pool sizes. These differences were statistically significant for both fixed pool sizes (P value 0.003 and 0.002, respectively).\n\na Each row represents an individual day in the training data.\n\nb Results based on 1,000 random permutations of the specimen input order.\n\nc Highest capacity increase strategy for each day is shown in bold.\n\n\nDiscussion\n\nThe online nature of the presented algorithm allows for its easy implementation in many existing laboratory medicine workflows. For example, it may be used to provide pooling recommendations as the specimens are scanned upon receipt in the lab for testing. This feature is unique and important for a feasible and practical solution that fits the existing laboratory medicine workflow. Alternative approaches that optimize the pools globally for a collection of specimens (e.g. Ref. 6) may offer better performance in terms of capacity gains, but require additional manipulation of the specimens to form the pools, which may be feasible in some, but not all workflows. Implementations of these global optimizing approaches may be feasible when pool assignments can happen off-line, for example during transport of a batch of specimens from a collection site to a testing facility. With that respect, the online approach offers simplicity and appeal for laboratory management that is traded for potential global suboptimality.\n\nThe exact implementation of online pooling approach may need to meet specific operational constraints to be practical. For example, some laboratories may only be capable of testing in pools of fixed maximum size. These constraints can be naturally incorporated into modified online pooling algorithms. More sophisticated versions of the algorithms are easy to imagine as well. For example, a parallel fulfilment of multiple pools simultaneously can be accommodated in a straightforward extension.\n\nInstitutional implementation of any pooled testing approach that utilizes individual-level risks requires solutions to many informatics ecosystem problems. First, the models providing individual-level risk predictions need to be updated frequently to account for changes in prevalence by risk factors, and other contributors to model drift. In practice, a nightly model fit update may be feasible and necessary. Second, the model predictions need to be triggered at an appropriate time between specimen collection and the time it arrives into a laboratory for testing. Third, pooling recommendations have to be either pre-computed or involve only lightweight computations. In either case these recommendations have to be easily available in the laboratory information system. Combined these challenges point to likely requirement of high intra-institutional cooperation between laboratory medicine, analytics, data science, and informatics operations.\n\nThe testing capacity increases by pooled testing rely on the quality of the predictive models. When predictors are not available population prevalence rates can be input into the online algorithm, and the resulting two-step groupings will be equivalent to optimal pooling into pools of fixed size. In this paper, the evaluation of the algorithm involved clearly suboptimal sets of predictors and risk prediction approach (multivariable logistic regression). Nonetheless, the online algorithm provides an improvement over simple two-step pooling. Better predictive models will result in even larger capacity gains. Improved model predictivity could result from employing the data that is readily available or computable at the time of diagnostic specimen collection. For example, many of the data elements from the Health and Human Services guidance on laboratory reporting10 could be included. Other structured data, such as questionnaires collecting evidence and degree of exposure, and telehealth-derived variables can prove useful as well. Likewise, unstructured text data processed by natural language processing techniques can be useful.7 Further, more sophisticated machine learning and artificial intelligence approaches may be used to combine all of the available data sources for superior risk estimates in online pooling recommendations.\n\n\nConclusions\n\nThe results reported herein are immediately translatable to laboratory medicine operations. Even without sophisticated predictive models, given the current state of the pandemic the online pooling algorithm can double the COVID-19 testing capacity. Better risk prediction models may result in even better capacity improvements. In the longer term, similar strategies can be used for implementation of massive scale testing for other diseases.",
"appendix": "Data availability\n\nAccess to the full dataset cannot be made available publicly since it contains elements of personal health information (PHI); however, access will be granted to readers and reviewers upon signing MUSC IRB-approved data use agreement. Please contact the author to initiate the process (alekseye@musc.edu).\n\nSummary data and software in support of this work is available at https://github.com/alekseyenko/AIIAT/ and https://doi.org/10.5281/zenodo.7541444. 11 The file predict_positive_r2.pdf contains summary data.\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 author would like to thank Katie Kirchoff, Bashir Hamidi, Jihad Obeid, Matthew Turner, Stephane Meystre, and Leslie A. Lenert for discussing the merits of the ideas presented in this brief report.\n\n\nReferences\n\nCherif A, Grobe N, Wang X, et al.: Simulation of Pool Testing to Identify Patients With Coronavirus Disease 2019 Under Conditions of Limited Test Availability. JAMA Netw. Open. 2020; 3(6): e2013075. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLohse S, Pfuhl T, Berko-Gottel B, et al.: Pooling of samples for testing for SARS-CoV-2 in asymptomatic people. Lancet Infect. Dis. 2020; 20: 1231–1232. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYelin I, Aharony N, Shaer Tamar E, et al.: Evaluation of COVID-19 RT-qPCR test in multi-sample pools. Clin. Infect. Dis. 2020; 71: 2073–2078. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbdalhamid B, Bilder CR, McCutchen EL, et al.: Assessment of Specimen Pooling to Conserve SARS CoV-2 Testing Resources. Am. J. Clin. Pathol. 2020; 153(6): 715–718. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBilder CR: Group Testing for Identification. Wiley StatsRef: Statistics Reference Online.2019; pp. 1–11.\n\nXiong W, Lu H, Ding J: Determination of Varying Group Sizes for Pooling Procedure. Comput. Math. Methods Med. 2019; 2019: 4381084.\n\nObeid JS, Davis M, Turner M, et al.: An AI approach to COVID-19 infection risk assessment in virtual visits: a case report. J. Am. Med. Inform. Assoc. 2020; 27: 1321–1325. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiving BioBank:2020.Reference Source\n\nAlekseyenko AV, Hamidi B, Faith TD, et al.: Each patient is a research biorepository: informatics-enabled research on surplus clinical specimens via the living BioBank. J. Am. Med. Inform. Assoc. 2021; 28(1): 138–143. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCOVID-19 Pandemic Response, Laboratory Data Reporting: CARES Act Section 18115: Department of Health and Human Services.2020.Reference Source\n\nAlekseyenko A:alekseyenko/AIIAT: For F1000 publication (v1.0). [Dataset]. Zenodo. 2023. Publisher Full Text"
}
|
[
{
"id": "206489",
"date": "01 Nov 2023",
"name": "Barathidasan R.",
"expertise": [
"Reviewer Expertise Diagnostic virology",
"toxicologic 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\nSummary: This article describes an online algorithm developed by the author for assigning samples to different pools based on the risk data available from patient health records. The algorithm is back-tested on patient samples collected for detecting COVID-19. Improvement in testing capacity has been reported in this article over conventional pooling strategies. The algorithm has been back-tested on samples received by a lab over a period of 17 days, during which the test positivity rate ranged from 0-7% (single outlier, 18% not included). Testing capacity enhancement for conventional pooling for the same data was 2.66 (5-sample pool) and 2.75 (6-sample pool); whereas, online algorithm-based pooling strategy had very marginally increased the testing capacity i.e. 2.82.\n\nMethods & Source data: The health record parameters (i.e. age, symptoms, exposure history, other patient demographics) based on which the sample is assigned to a pool could have been described in detail. Classifications of pools i.e. high-risk pool, medium-risk pool, low-risk pool, and the basis for classification could have been included.\nThough the capacity enhancement is very marginal for the given data set, the author's opinion can be agreed that improvement in the algorithm can improve the capacity enhancement.\n\nSuch algorithms implemented at the sample collection site can definitely reduce the workload on the laboratory in deciding the pool, assigning pool numbers to samples and testing.\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? 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? Yes",
"responses": [
{
"c_id": "12371",
"date": "06 Sep 2024",
"name": "Alexander Alekseyenko",
"role": "Author Response",
"response": "Thank you for taking the time to review the manuscript. I am encouraged to see that you recognize the potential of improving pooled testing via our method. As we state in our manuscript, we use an (almost) strawman predictive model individual risk to inform our pooling strategy. I have published with colleagues on better predictive models that can be incorporated into the same framework (doi: 10.1093/jamia/ocab186). Ultimately, I hope that this and other similar work will encourage the laboratory instrumentation manufacturers to improve automation to allow for implementation of variable pool size testing."
}
]
},
{
"id": "206487",
"date": "02 Nov 2023",
"name": "Md S. Warasi",
"expertise": [
"Reviewer Expertise Statistics",
"biostatistics"
],
"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 author introduces a pooled testing algorithm, referred to as the 'online algorithm,' with the goal of enhancing disease screening efficiency and increasing testing capacity. The specimen pooling strategy and determination of the optimal pool size are clearly described, and the results are concisely presented. The study focuses on screening individuals for SARS-CoV-2. While the methodological contribution may not be ground breaking, the approach's simplicity and flexibility make it appealing. Overall, this is an interesting, well-written article with the potential for practical applications. Here, I present some comments and concerns.\nMethods:\nThe article relies on the assumption of perfect test outcomes, which may limit its applicability to situations where highly sensitive and specific assays are available. However, it's crucial to acknowledge that pooled testing has been used in scenarios with less-than-perfect assay sensitivity and specificity. Therefore, addressing the handling of testing errors (false negatives and false positives) would broaden the article's scope and practicality.\n\nThe article should explicitly state the assumptions it makes, such as perfect sensitivity and specificity, to provide clarity to readers and highlight potential limitations.\n\nIt's essential to include information about the sensitivity and specificity of the assay used for SARS-CoV-2 testing. If these values are not perfect, as is often the case in practice, discussing how the algorithm accounts for this imperfection is important.\n\nThe article's flexibility in dynamically forming pools as specimens arrive is a significant strength. However, this flexibility relies on reliable estimates of disease probabilities using individual covariates and predictive models based on historical data. The author should emphasize the importance of accurate probability estimates to ensure the algorithm's effectiveness, possibly in the concluding sections.\n\nThe inclusion of a flowchart to summarize the pooling strategy is a positive aspect of the article, enhancing its clarity.\n\nA related method in McMahan, Tebbs, and Bilder (2012, Biometrics, 68(1): 287–2961) is not cited in the article. Including this citation would provide readers with a broader perspective on the topic.\nResults:\nThe presented results appear to be reasonable, and the use of logistic regression for building a predictive model is a sound approach.\n\nThe comparison of the expected number of expended tests with Dorfman's testing is noted. However, it might be more informative and appropriate to compare the method with a more closely related approach, such as the one proposed by McMahan, Tebbs, and Bilder (2012)1. This would provide a more relevant benchmark for readers to assess the method's performance.\nMinor Comments: There are several typographical errors or areas needing clarification. Here are some from the first page:\n\"an recommendation\" should be corrected to \"a recommendation.\"\n\nThe phrase \"this approach cab offers\" appears unclear. Please clarify its meaning or correct the typographical error.\n\nThe sentence mentioning \"resilient pooled testing\" requires clarification to ensure readers understand the concept.\nOther Comments:\n\nThe title of the article is a complete sentence, which is uncommon for a research article. Additionally, it is fairly long. The author may consider shortening and rephrasing the title.\n\nA well-documented, user-friendly R function should be provided with the article for clinicians.\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? No\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "176925",
"date": "11 Sep 2024",
"name": "F. M. Javed Mehedi Shamrat",
"expertise": [
"Reviewer Expertise Data Science",
"Machine Learning",
"Artificial Intelligence",
"Bioinformatics",
"Image Processing"
],
"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 effectively written and presents the novelty in a proficient manner.\nThe clarity of the methodological approach requires further elaboration.\n\nIt is suggested that the author incorporate more statistical analysis into the Results section to evaluate the findings.\n\nThe visual representations appear to be lacking in clarity, and it is recommended that the author provide high-resolution images.\n\nThe clarity of the work in the conclusion section could be enhanced.\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? 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? Yes",
"responses": [
{
"c_id": "12411",
"date": "12 Sep 2024",
"name": "Alexander Alekseyenko",
"role": "Author Response",
"response": "Thank you for taking the time to submit these points. I am happy to respond to any specific concerns. As they stand your comments are too general to be actionable. I kindly request that you either provide more detail about the changes you request, or change your evaluation to APPROVED."
}
]
}
] | 1
|
https://f1000research.com/articles/12-85
|
https://f1000research.com/articles/12-83/v1
|
23 Jan 23
|
{
"type": "Opinion Article",
"title": "Is rationality a cognitive faculty?",
"authors": [
"Elias L. Khalil"
],
"abstract": "Rationality cannot be a form of intelligence or any other cognitive faculty such as memory, language faculty, mathematical skill, and so on. To establish this thesis, this paper uses a distinction from set theory, namely, the distinction between “binary relators” and “binary operators”. Rationality acts as a binary relator in the sense that it is an optimization method, while cognitive ability acts as a binary operator in the sense that it is a transformational function. Rationality as an optimization method (binary relator) does not differ from the neo-Darwinian notion of natural selection: either method seeks to find the best choice or fit trait given the constraints. A cognitive faculty as a transformational function (binary operator) simply translates inputs into outputs. The distinction between rationality and cognitive functions has wide-ranging implications regarding the theory of evolution.",
"keywords": [
"Set Theory",
"Binary Relator",
"Binary Operator",
"Optimization Method",
"Natural Selection",
"Intelligence",
"Memory",
"Technology"
],
"content": "Introduction\n\nThe literature in the biological sciences generally shies away from the concept of rational choice. When the literature alludes to rational choice, it considers it as a cognitive faculty similar to memory, intelligence, linguistic ability, mathematical skill, and so on. As such, rationality is the subject of natural selection akin to these cognitive faculties. Even some economists, whose discipline canonizes rationality as the central pillar in explaining choice, concur and treat rationality as a cognitive faculty and, hence, the product of natural selection (e.g., Robson, 2001; Robson & Samuelson, 2010).\n\nThis paper questions this literature. Rationality cannot be another cognitive faculty. It is rather, similar to natural selection, an optimization method:\n\nCore Thesis: Rationality radically differs from cognitive abilities such as memory, intelligence, language faculty, mathematical skill, and so on. Rationality is rather an optimization method of determining the best choice or fit trait.\n\nThis core thesis stands irrespective of the many detractors and critics of rational choice theory in the social and behavioral sciences.1\n\nThis paper advances its thesis via a distinction borrowed from set theory (Rai et al., 2012). The distinction is between “binary relators” and “binary operators”. Rationality acts as a binary relator, i.e., as an optimization method. In contrast, any cognitive faculty acts as a binary operator, i.e., as a transformational function. Rationality as an optimization method (binary relator) does not differ from the neo-Darwinian notion of natural selection: either method defines the best choice or fit trait given the constraints. A cognitive faculty as a transformational function (binary operator) simply translates inputs into outputs.\n\nThe distinction between rationality and cognitive faculties has great ramifications regarding the theory of evolution. Primarily, the distinction entails that rationality cannot be the subject of evolutionary change. It is rather a constant feature of any organism, i.e., simply what makes an entity a living entity. This implication can be called the “Organismus economicus hypothesis”. It is in contradistinction of the view that organisms do not make decisions, but rather behave according to rules selected by natural selection. This view can be called the “Organismus automaton hypothesis”, which is at the core of neo-Darwinism (see Khalil & Marciano, 2010).\n\nThis paper commences with a sharp distinction between the two hypotheses via the distinction between the optimization method, which specifies the best outcome, and the transformation function, which translates inputs to outputs. Then it finds that the neo-Darwinian approach, as a result of treating rationality as a trait selected by the optimization method, commits a self-reference paradox, akin to the Russell paradox (Russell, 1956). This finding questions the core of the neo-Darwnian approach a questioning that is usually avoided out of the specter of metaphysics. This paper registers that there is no basis of such specter and, hence, we should welcome the Organismus economicus hypothesis.\n\n\nOptimization method contra transformation function\n\nThe Organismus automaton hypothesis entails the treatment of rationality as a trait, specifically as a cognitive faculty. It is based on the fundamental thesis that the organism operates according to rules, where such rules are the products, ultimately, of natural selection. Such rules are the operational function of faculties such as memory, intelligence, and supposedly rationality. In this picture, the organism follows rules in the final analysis as an automaton.\n\nThis paper ignores sophisticated versions of the The Organismus automaton hypothesis (e.g., Godfrey-Smith, 1996, 2009). This allows us to focus, see Figure 1, on the basic minimal schemata of the optimization structure of the Organismus automaton:\n\nwhere E = a set of fitness ends such as the flight speed of zebra (too much flight speed weakens other abilities and too little undermines the survival fitness of the organism); xitj = the particular trait (t) and the instinctual behavior requiring certain set of goods (x) (different organisms are characterized by different combinations of t and x); TFk = the transformational function of level or type k that transforms inputs onto outputs; and OM = the optimization method that ensures that the optimum E (Ei*) is selected or chosen.\n\nIt is crucial to distinguish among three entities in the above schemata: i) the trait-as-input that is an element of the input set on the left-hand side; ii) the trait-as-technology that acts as the binary operator of level k (TFk) between the input set and the output set; iii) the optimization method (OM) that acts as binary relator.\n\nTo use a distinction from set theory, OM is the “binary relator” while TFk is the “binary operator” (see Rai et al., 2012). The binary relator that acts as OM performs two roles. The first role works within each set, as it ranks the different outputs in a consistent fashion, that is, it specifies which output is better than the other while abstracting from the constraints. For example, it can rank different speeds of flight without considering the constraints. The OM also ranks correspondingly the different inputs. However, what is selected as the optimum cannot be determined without specifying the environmental constraints. This highlights the second role, once the constraints are specified, the OM relates the input with the output sets in a certain way that shows what is the appropriate input that produces the optimum output (Ei*).\n\nIn contrast, the binary operator (TFk) transforms inputs into output according to k-level trait-as-technology. As such, TFk is neither the optimization method (OM) nor the trait-as-input (xitj) that make up the left-hand input set. TFk is merely the technical listing of outcomes that the TFk can produce from the given set of inputs.\n\nThe structure of the Organismus automaton hypothesis is almost identical to the structure of Organismus oeconomicus hypothesis. The input in the former is the population of individuals where each individual is characterized by an input set, whereas each gives rise to a different end, called a phenotype. The input in the latter is the bundle of goods, whereas each gives origin to a different end, called utility.\n\nThe Organismus oeconomicus hypothesis, based on standard rational choice, also consists of the binary relator assuring us the production of the optimum, i.e., the employment of OM, and the binary operator that expresses the transformational function, say, at k-level, i.e., the employment of TFk. Again here, the binary relator (OM) has two roles. As for the first role, the theory of rationality assures us the ends, that is, the utility values, are consistent and, correspondingly, that the inputs are consistently ranked. Consistency depends on many axioms, the most important are two: transitivity and completeness (see Gilboa, 2012; Khalil, 2023). As for the second role, once constraints are determined, the binary relator identifies the optimum end, that is, the optimum utility, and its corresponding set of inputs.\n\nAs for the binary operator at k-level (TFk), there is a set of technologies, institutions, and beliefs transforming each set of inputs into output. As in the case of the Organismus automaton hypothesis, the binary operator merely lists the technical aspect of what is the outcome of each set of inputs if the given TFk is employed in their transformation. It neither assures any internal consistency nor determines the optimum outcome.\n\nOnce an optimum is selected by nature or by choice, the optimum is stable as long as shocks disturb neither the set of inputs nor the set of environmental constraints. The stable decision equilibrium, not to be confused with market equilibrium, can be upset if at least one of the following two conditions changes: (i) a mutation of traits-as-inputs (t) or goods (x) takes place; or (ii) a change in the set of environmental constraints.\n\nThe set of environmental constraints is implicit in the above schemata. Namely, the binary relator can only select the optimum end considering such set. Let us see the consequence of the change of such set of environmental constraints (C) from Ci to Cc. Nature should select or the individual should choose, as Figure 2 shows, a new set of inputs, xctd*, corresponding to the new optimum end, E*c:\n\nHowever, nature as well as the individual may face hurdles, mainly arising from transitional cost (Marciano & Khalil, 2012; Khalil, 2013), as it tries to adjust. Hence, there can be an adjustment period or, worse, a lock-in arrangement where the status quo dominates. Natural selection or rational choice may opt for the status quo—i.e., the old end, Ei. In this case, natural selection or rational choice (OM) would still select the old inputs, xitj. If nothing happens, Ei will continue forever as the “second best” actual outcome, where the OM is denoted as second-best (OMSB). In contrast, E*c continues to be the ideal or “first-best”, where the OM is denoted as first-best (OMFB). However, what matters, the first-best (E*c) is suboptimal while the second best (Ei) is optimal—given the transitional cost that secures the lock-in arrangement.\n\nThis gap between E*c (first-best) and Ei (second-best) may shed light on the controversy between the “hard” and “soft” neo-Darwinian approaches. For the “hard” approach (for example, Dawkins, 1989; Dennett, 1984), OM should surely generate the E*j. For the “soft” approach (for example, Gould & Lewontin, 1979), the binary relator is rather OMSB, generating the seemingly suboptimal outcome Ei. However, as Marciano and Khalil (2012) explain, Ei is actually optimal, if we (as we should) take into account the lock-in arrangements, such as the body-plan of the organism or the technological/institutional/legal make up of the community. E*c is optimal in the “ideal” sense, in a world that forcefully ignores transitional cost as if we live in arrangement-free world.\n\nIn the given optimization problem above, the binary operator at k-level (TF) cannot be the subject of the optimization method (OM). However, what guarantees that the binary operator is fit or efficient? In the above representation, there is no guarantee. It is taken as a given and, hence, cannot be assessed at this level of selection or choice. It can, however, be the subject of selection or choice when it is the object of rational choice or evolutionary selection. This could be the case, as Figure 3 demonstrates, if the binary operator is acting at a deeper level, say at k+1 level:\n\nThe binary operator, which consists of technology, rules/instructions, or body-plans, involves a hierarchy. It can be at k-level or deeper such as k+1 level. We do not find such a hierarchy with respect to the binary relator (OM) specifying the optimum.\n\nWhile the elements of the input set, and corollary the output set, are different, the binary relator (OM) does not change, performing the same function irrespective of the level of hierarchy of the binary operator, i.e., whether it is TFk or TFk+1. In the above schemata, OM selects or chooses xiTFk* as the optimum input that corresponds to the optimum end, E*k. While the binary operator (TFk) cannot play the role of natural selection (binary relator), it is the product of natural selection at a deeper level, at k+1 level. However, when the binary relator functions, i.e., as OM, it must take the binary operator, whether TFk or TFk+1, as given. Such a limited optimization function should not be taken, à la “soft” neo-Darwinians or à la critics of standard economists (see Khalil, 2013), as a shortcoming that undermines or repudiates the notion of optimization per se. To wit, the raison d'être of optimization is the existence of limits taken as given. So, the term “limited optimization” is pleonasm.\n\nThere are other nuances, which this paper ignores, of the common structure that underpins the Organismus automaton and Organismus oeconomicus hypothesis. What matters for this paper, the structure of either hypothesis is the same and can handle different kinds of complications and qualifications at secondary and tertiary approximations. What is most important in this proposed structure is that the trait-as-technology, i.e., the binary operator, functions as a transformation function that varies according to the level of the hierarchy. In contrast, the binary relator (OM) remains constant, i.e., irrespective of the level of hierarchy.\n\nThe conflation of the binary operator and the binary relator sheds another insight regarding the controversy between “soft” and “hard” neo-Darwinians--as well as between “soft” and “hard” neoclassical economists. This cannot be detailed here. What concerns this paper is the seperation of rationality or any OM from the object of optimization. As shown next, such separation has one important ramification, rationality cannot be a trait.\n\n\nCould rationality ever be a trait?\n\nThe proposed distinction between OM, which acts as binary relator, and transformational function (TFk), which functions as binary operator, entails the incoherence of what can be called “Rationality-qua-Trait Thesis”.\n\nIt should be immediately clear that OM (the binary relator) can be either the standard rational choice or, equivalently, the neo-Darwinian natural selection. In contrast, TFk (the binary operator) is the given technology or cognitive faculty, such as intelligence, memory, and other so on. OM cannot be TFk, as OM is not about transforming inputs to output in the technical sense.\n\nMore importantly, rational choice or OM cannot be trait-as-input, that is, an element of the left-hand inputs set. OM (binary relator) cannot be a member of the set—when its function is about making sure that the elements are consistently ranked. To treat OM as a member of itself leads to self-contradiction, i.e., incoherence.\n\nAs shown above, TFk—such as intelligence, memory, or other cognitive faculties—can be an element of the left-hand inputs set—but then the transformation is taking place at a deeper level. There is a hierarchy of technology or body-plan. The transformation function (TF) cannot apply to OM, as OM cannot become a member of the left-hand inputs set. There is no hierarchy of rationality as the case with TF. What applies to TF cannot apply to OM. And if we conceive OM as a member of the inputs set, this leads to incoherence à la Russell Paradox.\n\nThe Russell Paradox (Russell, 1956) emerges when one conceives a set as a member of itself. To treat rational choice as a member of the set that is the object of rational choice is an example of the Russell Paradox.\n\nOne helpful illustration of the Russell Paradox is the well-known Cretan liar paradox and, better, the Barber Paradox (Irvine & Deutsch, 2021). The only barber in a village has a sign posted in his shop that states, “I cut the hair of everyone in the village that does not cut his own hair.” But who cuts the hair of the barber? If he cuts his own hair, then the barber cannot cut it. And if he does not cut his own hair, then the barber cuts it. Such a self-contradiction arises from treating the set, which is the barber’s statement, as a member of itself. Such treatment entails that the barber is an element of the set of people who do not cut their own hair, on one hand, and the barber is the set itself as the one who cuts the hair of such people, on the other.\n\nThe Russell Paradox arises from what philosophers recognize as the problem of self-reference. In the case of the Rationality-qua-Trait Thesis, it treats rationality both as OM as well as an element of the set that is the subject of OM. This self-reference is best illustrated by some of the drawings of M.C. Escher (see Hofstadter, 1980). The first role of the binary relator (OM) is to make sure that the output is consistently ranked and, corollary, the corresponding inputs are also consistently ranked. Such an organization of inputs cannot also include OM: how could the OM calls for the substitution of one input in favor of another when the OM itself is one such input?\n\n\nWho’s afraid of the Organismus Oeconomicus hypothesis?\n\nThe implication of the above analysis is that rationality cannot be selected or chosen. Rationality cannot be a trait such as musical skill, intelligence, or any cognitive faculty. As an OM, it is analytically akin to natural selection.\n\nIt is obvious that some species, such as Homo sapiens, behave rationally. A difficulty arises when a researcher draws a line between such species and supposedly species deemed to be non-rational. Such a line, most obviously, leads to the creation of a fictitious dichotomy that juxtaposes “rational species” and “non-rational species.” This dichotomy is fictitious as it supposes a natural set that includes species such as bacteria and, say, lower primates as having a common trait that sets them apart from another set that includes only upper primates. To avoid such fictious sets, researchers need to examine whether rationality is a trait in the first place. The Organismus oeconomicus hypothesis certainly avoids such pittfalls, as it ascribes rationality to all living entities (Khalil, 2023).\n\nHowever, if we treat rationality as OM, and hence, cannot be seen as a trait, this gives rise to questions about the status of rationality with respect to living entities, if not to questions that conjure the specter of metaphysics—the specter of conceiving rationality as existing separately from living entities.\n\nBiologists need not fear the Organismus oeconomicus hypothesis for at least five reasons.\n\n1. The rationality concept, at least as used by economists (e.g., Becker, 1978; Gilboa, 2012; Khalil, 2023), amounts to a rule or a method that does not specify any particular content—not to mention free will, imagination, creative action, or ambition. Rational choice means organisms generally make the best decision possible given the environmental constraints and their technological capacities that include cognitive faculties, physiological traits, technologies, and institutions.\n\n2. Biologists and psychologists usually restrict rationality to mental or cognitive processes (e.g., Chater et al., 2018; Felin et al., 2017). They conclude that organisms with limited cognitive processes, and especially plants and other brainless organisms, cannot be rational. However, once one understands rationality properly, one cannot conflate it with cognitive faculties (see Khalil, 2010).\n\n3. Biologists (e.g., Gardner, 2009) are afraid of what philosophers call “reification”—that is, the thinking of an idea such as rationality and supposing it is true, i.e., choices made by organisms express rational choice. This raises the specter of metaphysics (see Winn, 1939)—the belief in an “uncaused cause” (Dennett, 1995). For instance, the supposed reification of rationality may conjure up uncaused cause and, hence, uphold creationism, that is, the idea there must be an external agent (e.g., a god) who created rationality. However, the specter of reification need not arise if one can trace rationality to a defining feature of being a living being. But this task is outside the scope of this paper.\n\n4. Biologists who use the foraging theory pioneered by Eric Charnov (e.g., 1976; see Stephens & Krebs, 1986) or who employ the tools of “bioeconomics” (e.g., Ghiselin, 1974; see also Tullock, 1971, 1994; Khalil & Marciano, 2010) already use cost-benefit calculations, that is, rational choice. A few biologists have recently taken the first step to recognizing openly the relevance of rationality to the understanding of behavior or organisms (e.g., Vermeij, 2004; Hurley & Nudds, 2006).\n\n5. Biologists implicitly employ the rational choice approach when they explain behavior as elastic, that is, as responsive to changes in environmental constraints. They call such elasticity “phenotypic plasticity” (Gould, 1997, 2002; Stanley, 1979; Matsuda, 1987; West-Eberhard, 1989; Raff, 1996; Müller & Newman, 2003; Hall et al., 2004; DeWitt & Scheiner, 2004). They are making great strides in showing how even invertebrate organisms make decisions in light of uncertainty (e.g., Oberhauser & Czaczkes, 2018). They are documenting how animals generally make decisions in reaction to the so-called “contrast effect” (e.g., McNamara et al., 2013).\n\nRegarding phenotypic plasticity, biologists need to recognize explicitly and openly the fact that it amounts to rational choice. As shown elsewhere (Khalil, 2009, 2010), rational choice theory is simply the proposition that the organism’s choice changes in light of changes in environmental constraints or, in short, incentives. With each choice, the organism maximizes the benefit (fitness) given the cost or, what is the same thing, minimizes the cost given the benefit.\n\n\nConclusions\n\n\n\n1. There is an incongruent gap in the natural sciences. On one hand, the sciences that focus on the study of non-human organisms do not largely give weight to rationality. On the other hand, the sciences, especially economics, that focus on the study of human organisms pay great attention to rationality.\n\n2. The sciences that focus on non-human organisms do not need to appeal to rationality, as they largely appeal to natural selection as the optimization method. Still, they have to explain rationality if they are natural sciences, i.e., sciences that cannot exclude humans from nature. Such sciences, if pushed, tend to explain rationality as a trait—i.e., similar to intelligence and other cognitive faculties. However, such explanation leads to the self-reference problem, a variety of incoherence à la Russell paradox: how could rationality that is an optimization method be a trait, i.e., the subject of natural selection that is an optimization method?\n\n3. We can easily avoid the Russell paradox regarding rational choice or any optimization method if we employ a distinction from set theory, namely, the difference between “binary relators” and “binary operators”.\n\n4. Rationality cannot be a trait given that it is a binary relator that allows us to identify the optimum. In contrast, cognitive faculties are traits, as they are binary operators that transform inputs into outputs.\n\n5. Once we distinguish between binary relators and binary operators, we can conceive rationality as an OM (binary relator) that cannot be a trait (binary operator). Hence, there would be no need to appeal to another OM to explain its origin.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgments\n\nOlder versions received comments from Steven Orzack, Ulrich Witt, Steve Abedon, Jack Vromen, Timothy Crippen, Elliott Sober, Casey Mulligan, Franjo Weissing, Yew-Kwang Ng, Martin Burd, Avi Waksberg, Deby Cassill, David Haig, and especially Davide Vecchi. It also received comments from participants of sessions at the Australian National University, Monash University, the Konrad Lorenz Institute of Evolution and Cognition Research, the European Association of Evolutionary Political Economy, and the International Society for the History, Philosophy and Social Studies of Biology. The paper benefited from the research assistance of Steven Gardner, Michael Dunstan, and Maks Sipowicz.\n\n\nReferences\n\nBecker GS: The Economic Approach to Human Behavior. new ed.Chicago:University of Chicago; 1978.\n\nCharnov EL: Optimal foraging, the marginal value theorem. Theor. Popul. Biol. 1976; 9: 129–136. Publisher Full Text\n\nChater N, Felin T, Funder DC, et al.: Mind, rationality, and cognition: An interdisciplinary debate. Psychon. Bull. Rev. 2018; 25: 793–826. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDawkins R: The Selfish Gene. revised ed.Oxford:Oxford University Press;1989.\n\nDennett DC: Elbow Room: The Varieties of Free Will Worth Wanting. Cambridge, MA:MIT Press;1984.\n\nDennett DC: Darwin's Dangerous Idea: Evolution and the Meanings of Life. New York:Simon & Schuster;1995.\n\nDeWitt TJ, Scheiner SM: Phenotypic Plasticity: Functional and Conceptual Approaches. Oxford:Oxford University Press;2004.\n\nFelin T, Koenderink J, Krueger JI: Rationality, perception, and the all-seeing eye. Psychon. Bull. Rev. 2017; 24(4): 1040–1059. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGardner A: Adaptation as organism design. Biol. Lett. 2009; 5: 861–864. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGhiselin MT: The Economy of Nature and the Evolution of Sex. Berkeley:University of California Press;1974.\n\nGilboa I: Rational Choice. Cambridge, MA:MIT Press;2012.\n\nGodfrey-Smith P: Complexity and the Function of Mind in Nature. Cambridge:Cambridge University Press;1996.\n\nGodfrey-Smith P: Darwinian Populations and Natural Selection. Oxford:Oxford University Press;2009.\n\nGould SJ: Ontogeny and Phylogeny. Cambridge, MA:Harvard University Press;1997.\n\nGould SJ: The Structure of Evolutionary Theory. Cambridge, MA:Harvard University Press;2002.\n\nGould SJ, Lewontin RC: The spandrels of San Marco and the Panglossian paradigm: A critique of the adaptationist programme. Proceedings of the National Academy of Science USA. 1979; 205: 581–598.\n\nHall BK, Pearson RD, Müller GG(eds.): Environment, Development, and Evolution: Towards a Synthesis. Cambridge, MA:MIT Press;2004.\n\nHofstadter DR: Gödel, Escher, Bach: An Eternal Golden Braid. New York:Vintage Books;1980.\n\nHurley S, Nudds M: Rational Animals? Oxford:Oxford University Press;2006.\n\nIrvine AD, Deutsch H: Russell's Paradox. Stanf. Encycl. Philos. 2021. (Spring 2021 Edition), E. N. Zalta (ed.).Reference Source\n\nKahneman D: Thinking, Fast and Slow. New York:Farrar, Straus and Giroux;2011.\n\nKhalil EL: Buridan's ass, uncertainty, risk, and self-competition: A theory of entrepreneurship. Kyklos. 1997; 50: 147–163. Publisher Full Text\n\nKhalil EL: Natural selection and rational decision: Two concepts of optimization. J. Evol. Econ. 2009; 19: 417–435. Publisher Full Text\n\nKhalil EL: Are plants Rational? Biol. Theory. 2010; 5: 53–66. Publisher Full Text\n\nKhalil EL: Lock-in institutions and efficiency. J. Econ. Behav. Organ. 2013; 88: 27–36. Publisher Full Text\n\nKhalil EL: The information inelasticity of habits: Kahneman’s bounded rationality or Simon’s procedural rationality? Synthese. 2022; 200. online publication. Publisher Full Text\n\nKhalil EL: A great blunder: Why cannot rationality be the outcome of evolution? Heliyon. 2023. revise-and-resubmit.\n\nKhalil EL, Marciano A: The equivalence of neo-Darwinism and Walrasian equilibrium: In defense of Organismus oeconomicus. Biol. Philos. 2010; 25: 229–248. Publisher Full Text\n\nKhalil EL, Amin A: The parallelism hypothesis of cognitive economy and physiological economy: A rationality-based dual process theory. Curr. Psychol. 2022. online publication. Publisher Full Text\n\nMarciano A, Khalil EL: Optimization, path dependence and the law: Can judges promote efficiency? Int. Rev. Law Econ. 2012; 32: 72–82. Publisher Full Text\n\nMatsuda R: Animal Evolution in Changing Environments with Special Reference to Abnormal Metamorphosis. New York:Wiley & Sons;1987.\n\nMüller GB, Newman SA: Origination of Organizational Form: Beyond the Gene in Developmental and Evolutionary Biology. Cambridge, MA:MIT Press;2003.\n\nMcNamara JM, Fawcett TW, Houston AI: An adaptive response to uncertainty generates positive and negative contrast effects. Science. 2013; 340: 1084–1086. PubMed Abstract | Publisher Full Text\n\nOberhauser FB, Czaczkes TJ: Tasting the unexpected: Disconfirmation of expectations leads to lower perceived food value in an invertebrate. Biol. Lett. 2018; 14: 20180440. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRaff RA: The Shape of Life: Genes, Development, and the Evolution of Animal Form. Chicago:University of Chicago Press;1996.\n\nRai BK, So CK, Nicholas A: A primer on mathematical modeling in economics. J. Econ. Surv. 2012; 26: 594–615. Publisher Full Text\n\nRobson AJ: The biological basis of economic behavior. J. Econ. Lit. 2001; 39: 11–33. Publisher Full Text\n\nRobson AJ, Samuelson L:The evolutionary foundations of preferences. Handbook of Social Economics. Benhabib J, Bisin A, Jackson MO, editors.Amsterdam:North-Holland;2010; Vol. 1A. : pp. 221–310.\n\nRussell B:Mathematical logic as based on the theory of types. Logic and Knowledge: Essays 1901-1950. Marsh RC, editor.London:George Allen and Unwin;1956; pp. 59–102. (Originally published in the American Journal of Mathematics, 1908.)\n\nStanley SM: Macroevolution: Pattern and Process. San Francisco:Freeman;1979.\n\nStephens DW, Krebs JR: Foraging Theory. Princeton, NJ:Princeton University Press;1986.\n\nThaler RH, Sunstein CR: Nudge: Improving Decisions About Health, Wealth, and Happiness. New York:Penguin;2009.\n\nTullock G: The coal tit as a careful shopper. Am. Nat. 1971; 105: 77–80. Publisher Full Text\n\nTullock G: The Economics of Non-Human Societies. Tucson, AZ:Pallas Press;1994.\n\nVermeij GJ: Nature: An Economic History. Princeton, NJ:Princeton University Press;2004.\n\nWest-Eberhard MJ: Phenotypic plasticity and the origins of diversity. Annu. Rev. Ecol. Syst. 1989; 20: 240–278.\n\nWinn RB: Is nature rational? Philos. Sci. 1939; 6: 285–300. Publisher Full Text\n\n\nFootnotes\n\n1 This core thesis—viz., rational choice is a method of selecting among options--is widely accepted (e.g., Becker, 1978; Gilboa, 2012; Khalil, 2023). However, this should not entail that rationality is an exhaustive description of all human behavior. Behavior may involve imagination, creativity, aspiration, or what economists recognize as “entrepreneurship” that goes beyond mechanical rules of optimization (see Khalil, 1997, 2010). Further, behavior involves biases that arise from failed heuristics (see Thaler & Sunstein, 2009; Kahneman, 2011; Khalil, 2022; Khalil & Amin, 2022). However, these issues need not undermine the rationality concept—but may in fact open opportunities to expand it."
}
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[
{
"id": "232942",
"date": "24 Jan 2024",
"name": "Piotr Kozak",
"expertise": [
"Reviewer Expertise Philosophy",
"Cognitive Psychology"
],
"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 paper focuses on the concept of rationality in economics and (probably) cognitive psychology. According to the main thesis, rationality is not a cognitive faculty. Instead, it is a method of optimization. The author argues that rationality (as a method of optimization) can be cashed out in terms of binary relators, i.e., binary relations partially ordering a set. In contrast, cognitive faculties should be understood as binary operators, i.e., transformation functions. According to the author, such a distinction gives a reason to believe that rationality (in terms of an optimization method) is “a constant feature of any organism, i.e., simply what makes an entity a living entity.” Although I deeply admire the wide scope and gravity of the author’s analyses, I have serious objections to the way the analyses are presented in the paper. First, it is challenging to assess the paper's scientific domain: economics, cognitive psychology, epistemology, theory of evolution, or all of them. It does not have to be a problem. One of the main advantages of the paper is that it attempts to cover (probably) all these areas. However, it is done without going into any serious debate with the positions discussed in these areas. For instance, there is no reference to the so-called Great Rationality Debate, the positions of Gigenrenzer and Stanovich are not even mentioned, etc. Thus, it is very difficult to say what kind of ideas the author debates with. Not to mention the fact that the author doesn’t give any hints or references regarding the positions he argues against. Second, the author opposes the idea that rationality is a cognitive faculty or a skill. It’s not clear what kind of a position he argues against. In philosophy and cognitive psychology, we commonly distinguish between the concept of rationalism in descriptive and normative understanding of the term. The descriptive understanding of rationality covers, e.g., the idea of tests on rationality one can be better or worse at. The normative understanding covers, e.g., the logical validity of an argument. Both understandings are not equal but are complementary. For instance, one can act irrationally, but a product of one’s actions, by chance, can be rational. It is unclear what kind of novel feature or description of rationality the distinction between binary relators and binary operators brings to the table. Third, the distinction between binary relators and binary operators is unclear. Although the idea that the concepts of binary relators and transformation functions are not the same is correct, it doesn’t follow that these concepts are opposite. Binary relators and binary operators are both some kind of a binary relation since every function is a relation. Thus, even if rationality is a binary relator, it does not follow that it cannot be a binary operator. Fourth, the argument from the Russell’s Paradox seems invalid. It would apply to the argument, if we assumed that rationality cannot be a cognitive skill. However, that is something that has to be proven by this very argument. Fifth, the conclusion that evolution is somehow rational in terms of being an optimized method of selection is far unsupported. The author does not engage in discussions with contemporary authors in evolution theory. At this point, it is rather an author’s statement, which we can take at its face value or not, but not a conclusion of an argument. To sum up, although the paper shows some promise, it does not seem likely to be presenting a sound and well-supported argument. I strongly recommend narrowing down the paper's goal and focusing on a certain part of a debate in economics and/or cognitive psychology. The author should supplement the paper with the context of the debate. He should at least mention the authors he is discussing with or against. It would make his arguments clearer and more understandable.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? No\n\nAre all factual statements correct and adequately supported by citations? No\n\nAre arguments sufficiently supported by evidence from the published literature? No\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? No",
"responses": []
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https://f1000research.com/articles/12-83
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https://f1000research.com/articles/11-1518/v1
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14 Dec 22
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{
"type": "Research Article",
"title": "Harassment of game makers: Prevalence and impact",
"authors": [
"Rachel Kowert",
"Eve Crevoshay",
"Eve Crevoshay"
],
"abstract": "Background: Online harassment is a relatively commonplace occurrence in the video gaming industry and player communities. A lack of diversity has unquestionably contributed to the high levels of such incidences. Methods: In this paper, we take an exploratory approach, via a cross-sectional observational study, to evaluate the harassment of game industry professionals on social media. In this new sphere of growing concern, there is evidence of significant harm for game makers and their radius of impact. We will discuss the prevalence rates, nature of harassment, and the ways in which a lack of diversity has contributed to this phenomenon. Results: In total, 282 video game industry professionals completed the survey in its entirety. More than half of all participants reported experiencing harassment on social media (59.6%) and nearly all reported witnessing harassment happening to other members of the videogames industry via social media (92.2%). This harassment can have a significant impact on well-being, including increased anxiety (62.1%), feelings of isolation (37.6%) and increased depression (36.2%). Almost one quarter (23.8%) reported symptoms related to post-traumatic stress disorder. One out of 10 participants reported suicidal thoughts because of online harassment. A significant number of respondents (37.3%) reported that had to take steps to reduce their physical safety due to online harassment. Over half of all respondents saying they were targets of hate because of some aspect of their identity. Conclusions: The results indicate high rates of online harassment, both direct and indirect, among members of the gaming industry at all levels. Responses also pointed to substantial mental health and behavioral impacts of both experiencing and witnessing online harassment. Without large-scale action, this problem will continue to reinforce the lack of diversity inside game studios, pushing out marginalized employees due to a hostile work environment.",
"keywords": [
"video games",
"game development",
"hate",
"harassment",
"mental health",
"diversity"
],
"content": "Introduction\n\nOnline harassment is a relatively commonplace occurrence in digital game and game adjacent spaces (Anti-Defamation League, 2022; Kowert & Cook, 2022). A 2022 report from the Anti-Defamation League (ADL) indicated that 83% of adults and 60% of teenagers experienced harassment in online multiplayer games in the last six months. Of these, 71% of adult online multiplayer gamers experienced severe abuse, including physical threats, stalking, and sustained harassment. This high rate of incidence is supported by other frequency reports (Bryter, 2020; Kowert & Cook, 2022), which have found the more extreme forms of hate and harassment to be more the exception than the norm. For example, Kowert and Cook (2022) reported that nearly half of all game players have directly experienced sexual harassment (45%) and violent threats (46.8%) in game, and more than half have experienced hate speech (64%). These experiences can have significant mental health impacts on the victim, including short-term distress to long-term post-traumatic stress symptomatology (ADL, 2021). This experience tends to be magnified for victims of marginalized genders and ethnic backgrounds (Bryter, 2020; Fagan, 2021). The sheer prevalence of hate and harassment in gaming communities suggests a level of normalization of these behaviors. This normalization is also sometimes referred to as “toxic gamer culture,” which is a phrase that has entered our common vernacular to reference to the set of culturally justified behaviors within gaming communities that are harmful to others within and outside of gaming spaces.\n\nIn the last few years, there has been a growing trend for hate and harassment in gaming cultures to expand beyond other players towards game makers. The aim of this study is to quantify these trends and explore the prevalence rates, nature of harassment, and the ways in which a lack of diversity has contributed to this phenomenon. As no known research has previously examined these outcomes among video game industry professionals, this work is exploratory.\n\n\nBackground\n\nIn the last few years, there have been several high-profile cases of the harassment of game makers. In this context, “game maker” refers to a professional in the video games industry that works in any aspect of video game production at any level.\n\nThe harassment of game makers first made its way into the spotlight when former Guild Wars 2 narrative designer Jessica Price’s was fired from ArenaNet after engaging in a Twitter exchange with a player. Because the Twitter exchange itself was relatively innocuous, her firing surprised and angered many. As Price noted:\n\n“[ArenaNet CEO Mike O’Brien] spent some time insisting that developers must be friends with the company’s customers, and that it was unacceptable to say that we aren’t, even when we’re not on the clock.” (Campbell, 2018).\n\nDiscussions about the harassment of game makers reemerged in 2021 after the release of Boyfriend Dungeon by Montreal studio Kitfox Games and subsequent harassment campaign of one of the game’s voice actors, Alexander Gross, who voiced the game’s main villain, Eric. Players developed a universal disdain for this character due to his use of emotional manipulation towards the character-controlled protagonist. This, combined with an insufficiently specific content warning, led to players being taken aback by Eric’s overtly manipulative behavior. A small but significant number turned to harassment of Gross in response (Gach, 2021).\n\nMultiple other cases of online harassment of game developers also came to light in the last few years. Several developers and voice actors of The Last of Us 2, received harassment and death threats following its release; largely centered around discontent about the main character being depicted as a strong woman with a muscular physique (Hernandez, 2019). Ron Gilbert, the creator of Return to Monkey Island, was relentlessly abused online by fans who did not like the art style that was shown in previews of his new release in the series (Troughton, 2022). In an in-depth interview (Mazanko, 2022), Joe Hobbs, lead prop artist at Ubisoft, and Chris Goodswen, an artist at Ubisoft, disclosed that they have received death threats in the past over the release of new titles. Estelle Tigani, the Cinematic Producer on God of War Ragnarok, was subject to online sexual harassment after an announcement of a production delay (Mansoor, 2022).\n\nWhy these incidents happen is a multifaceted question. We know from previous work from online harassment that there are many interpersonal and environmental reasons someone may be motivated to harass another person online – including lower levels of empathy, the online disinhibition effect, a lack of formal punishment, etc. (Cook, 2019; Cook et al., 2018, 2019; March, 2019). However, there are additional variables to be considered specifically within the context of the harassment of game makers, such as the lack of clear boundaries between professional and personal social media accounts belonging to game makers, toxic gaming cultures within the gaming industry, and a lack of diversity within gaming content and cultures.\n\nAs noted in the previously mentioned quote from Price, there are often blurred lines between player and creator; making it difficult to negotiate social boundaries. One aspect of this is a lack of formal delineation between the professional and personal social media accounts of game makers. This is, at least partially, because many studios do not have formal social media policies and, if they do, the policies are often unclear about the boundaries between one’s personal and professional online presence. Today, whilst there remain many different guides available online about the best way for game makers to engage with game players online, very few (if any) discuss the role of personal and professional boundaries. Organizational climate can also contribute to the harassment of game makers. Some scholars argue that game companies themselves are fundamentally toxic within their organizational structure (Bourdreau, 2022) and the games they create reinforce toxicity through in-game narratives and mechanics (Bergstrom, 2020; Tompkins & Martins, 2021). Some have argued that this is a result of a cycle that starts in early childhood. Referred to as the “Cycle model of exclusion in gaming content and cultures” (Kowert et al., 2017), it is agued that early socialization of games as a male activity leads to the exclusion of non-men in the industry, which creates a male dominated industry and gendered game content and a normalization of gendered views of the world, including sexist attitudes and beliefs within gaming communities and the industry itself. This cycle is self-perpetuating. The outcome of this cycle, “toxic cultures”, are particularly concerning as “toxic cultures” in game studios are often overlooked or denied. As discussed by Price in an interview, “Game companies are generally unwilling to be honest with themselves about how they’re complicit in creating and sustaining that [toxic] environment” (Farokhmanesh, 2018).\n\nThe “cycle model of exclusion” discussed above would also provide some context for understanding the lack of diversity in game content and game industry professionals. A lack of diversity among game industry professionals has unquestionably contributed to high levels of hate and harassment in gaming spaces and towards game makers specifically (Anti-Defamation League, 2022; Kowert & Cook, 2022). The global video game industry is overwhelmingly white and male (Game Developers Association, 2022; International Game Developers Association, 2021), with the self-reported number of women and people of ethnically and racially marginalized identities being significantly lower than that of the general US population (International Game Developers Association, 2021). Similar trends are found in the UK, with the most recent industry report (UKIE, 2022) confirming that most game makers are male (67%), white (66%) and heterosexual (76%).\n\nGame content itself is another element for consideration, as it can reinforce heterogeneity though the reinforcement of stereotypes (Burgess et al., 2008). For example, the systematic lack of female characters (Williams et al., 2009) and/or noticeably and disproportionately sexualized female characters (Dill & Thill, 2007). The nature of this content has been under scrutiny for many years, perhaps most notably by Anita Sarkeesian with her Tropes vs women in video games YouTube series (Sarkeesian, 2013). The popularity of this video series itself sparked a round of hate and harassment towards Anita and was a precursor to the 2014 Gamergate movement. Gamergate was arguably the first famous example of how public backlash by a small subset of people can directly impact the mental health of industry employees (Mortensen, 2018). It resulted in a psychologically damaging public attack on predominantly female members of the game industry by a subset of predominantly male fans and developers. This movement, which started in 2014 and remains problematic today, quickly devolved from baseless accusations to character assassinations, misogyny, hate speech, and death threats (Campbell, 2014), the repercussions of which were severe. Personal information, including home addresses of the targets and their families, social security numbers, and even nude photos were posted online, forcing people from their jobs and their homes (Robertson, 2014). It is worth noting that while game content has become notably more diverse in the last decade, gaps remain and award-winning and best-selling titles continue to underrepresent characters with marginalized gender, ethnic, and racial identities (Lopez et al., 2019).\n\nWhile it is possible to draw the connections between a lack of diversity in the industry to game content and then to online harassment, little remains known about the extent to which game creators and other online creators are experiencing this kind of abuse online, and how it impacts their lives, beyond anecdotal evidence (Francis, 2022; Grayson, 2019). Understanding the prevalence and impact of hate and harassment among industry professionals is the first step towards understanding how to address the problem.\n\nHate and harassment within gaming communities has received a large amount of attention, both publicly and within scholarly communities. However, less attention has been given to the rising incidences of the harassment of game creators even though there seem to be disproportionately high rates of hate and harassment in professional gaming spaces, both within studios and directed at gaming professionals online. To better understand the prevalence and nature of the harassment of game makers, we conducted a cross-sectional study of game makers via an online survey.\n\n\nMethods\n\nThe survey was advertised online across social media platforms (Twitter and Facebook) and email lists targeted at game professionals (e.g., gamesnetwork). The survey was also directly emailed to the authors’ points of contact at several game studios, from small independent studios to large AAA studios. Data was collected throughout the month of October 2021.\n\nThe only requirement for participation in this study to be a professional within the games industry at any level. After providing informed consent, participants were asked a series of questions about their direct and indirect (i.e., witnessed) experiences with online harassment via social media. All participants completed the questions in the same order. The survey consisted of six sections: workplace role and culture, direct experiences of harassment, witnessed experiences of harassment, general experience and impact of harassment, general thoughts about harassment via social media, and demographic questionnaire. Demographic questions were presented at the end of the survey for all participants to reduce any potential priming effects for gender or ethnicity.\n\nParticipants were asked to complete the Game Developers Social Media Experience Survey (Kowert R. & Crevoshay, E. 2021). This measure includes a series of questions about harassment via social media. First, they were asked about the kinds of actions they had experienced, the perceived motivations behind them, any changes in behavior due to the harassment, and their mental health impact. They were then asked the same series of questions in relation to their indirect (i.e., witnessed) experiences. Participants were also asked their general thoughts on actions that could mitigate these behaviors in the future. The full questionnaire can be found in the extended data.\n\n\nResults\n\nOur survey results, presented below, are openly available in full on the open science framework repository (Kowert & Crevoshay, 2021).\n\nIn total, 304 participants responded to the online call for participation and completed the survey. 7.2% (22 participants) were excluded from the final analysis as they indicated that they did not work in the games industry. Of the 282 participants who fully completed the survey, 46.1% worked for an AAA developer, 42.6% for an Indie developer and 11.3% did not work directly within a game studio. Most participants worked in core creation or development roles within their studio. 17% of participants held management positions and 11% were administrative or ancillary roles. The rest of the participants were primarily game publishers (3.5%), journalists or critics (1.8%) educators (1.1%) who work with the gaming industry, game artists (0.7%), or producers of game related events (0.7%). Most participants were White (72.3%), male (54.8%), aged 26-45 (78.7%), and resided in the United States (50.7%).\n\nMore than half of all participants reported experiencing harassment on social media (59.6%) and nearly all participants reported witnessing harassment happening to other members of the videogames industry via social media (92.2%). Most of the reported harassment had been directly experienced (82.1%) and witnessed (94.2%) on Twitter. However, as seen in Table 1, a significant amount of harassment was reported being experienced and witnessed across platforms. Several respondents specified “Other” platforms in their responses, including Tumblr, Snapchat, and personal email.\n\nParticipants were asked to identify which of a series of behaviors they had experienced and witnessed from a list of eight behaviors: trolling/griefing (deliberate attempts to upset or provoke someone), offensive name-calling, threats of physical violence (conveying threats of physical or mental injury), stalking (online monitoring and/or information gathering used to threaten or harass), sexual harassment, discrimination by a stranger due to age, gender, ethnicity, ability or sexual orientation, doxxing (having personally identifying information made public), swatting (having a stranger make a false report to emergency services to target someone), and sustained harassment (harassment that occurs over multiple instances or a longer period of time).\n\nMore than half of all participants reported experiencing harassment on social media (59.6%) and nearly all participants reported witnessing harassment happening to other members of the videogames industry via social media (92.2%). The type of harassment directly experienced and witnessed by members of the gaming industry ranged from offensive name-calling to sustained harassment, to one incidence of an entire website being created mimicking an alternate history to one’s life. Several participants reported “Other” forms of harassment as well, including threats to one's job, impersonation attempts through the creation of fake social media profiles, hacked social media accounts, and violent physical assault. The rates of the most common forms of harassment, both directly experienced and witnessed, is presented in Table 2.\n\nTrolling/griefing (broadly defined as deliberate attempts to provoke someone) were the most common form of harassment reported, followed by offensive name calling. Identity based harassment was experienced by 42.9% of participants.\n\nNearly one in two participants reported experiencing threats of physical violence, with three out of four participants having witnessed threats of physical violence directed at another member of the industry. Stalking was also experienced (38.7%) and witnessed (56.9%) by a large percentage of participants. Sustained harassment, defined as harassment that occurs over multiple instances or over time, was experienced (39.9%) and witnessed (63.1%) by almost half of everyone surveyed. Doxxing, which refers to one's personal information being shared online and is considered one of the most severe forms of online harassment, was experienced by a quarter of all participants (25.6%) and witnessed by more than half (53.5%). Swatting, which is when a stranger makes a prank call to emergency services to have them dispatched to you and was the most severe form of online harassment on the list of selections, had been witnessed by more than one in five individuals (21.9%).\n\nWhen asked what they thought the motivating factors behind the harassment were, a variety of responses were selected. The most popular included: being a public figure in the games community (47.9%); identity-based harassment (46.1%); the norms of the games industry generally independent of the game studio one works for (38.3%); displeasure towards a recent game release (37.1%) and the general reputation of working for a particular studio (35.9%). A similar proportion of responses were found when asked about what they believed motivated their witnessed experiences of harassment. These findings are presented in Table 3.\n\nAs a direct target, participants reported varying degrees of response to online harassment. Blocking and reporting (85.1%) and ignoring the comment or behavior (83.3%) were the most common responses. Many also reported that they confronted or challenged the harasser (33.3%) and shared information about the experience with others (26.2%). Almost one-third (29.2%) of participants noted that they contacted their workplace for information on how to respond and/or to seek support. 43.3% of all participants reported that they have attempted to hide an aspect of their identity (e.g., age, gender, ethnicity, ability) because of being targeted by hate.\n\nAs a witness to online harassment, participants most often blocked or reported the person (84%), followed by ignoring the comment (49.4%). As was found when being the direct target, just about one-third of participants reported that they directly confronted or challenged the offender (30.4%) and shared information about the experience with others (34.6%). Only 17.5% of participants reported that they sought information from their workplace about how to respond and/or seek support when witnessing online harassment of others in the gaming industry.\n\nParticipants reported that being a direct target and/or directly witnessing online harassment has had a significant impact on their mental health and offline behavior. In terms of mental health, most participants reported feeling uncomfortable or upset (77.7%). Most participants reported increased anxiety (62.1%) and being less social (51.1%). Around a third of participants reported feeling more isolated or alone (37.6%) and increased depression (36.2%). Almost one quarter (23.8%) reported symptoms related to post-traumatic stress disorder. One out of 10 participants reported suicidal thoughts because of online harassment.\n\nIn terms of offline behavior, many participants reported it had negatively impacted their work performance (41.1%), they had sought professional psychological help (27.3%), and had personal relationships disrupted (22%). Just about a third reported they had to take steps to reduce risk to their physical safety (37.2%). One out of 10 participants had contacted the police because of online harassment. These results are summarized in Table 4.\n\nAround half of all participants reported that their studio had a policy about online harassment already in place (47.5%); however, most did not have support structures in place around online harassment specifically (58.5%).\n\nMost respondents believe that gaming companies should have stronger policies in place around hate and harassment (87.2%). Most respondents believe that the games industry contributes to the ease with which people engage in online hate and harassment (62.4%) and should be doing more to support employees being targeted by online hate and harassment (92.2%). The way that social media works is also believed to contribute to the ease with which people engage in online hate and harassment (96.5%) and respondents think social media companies should be doing more to support people being targeted online (93.7%). Most respondents (80.1%) believe laws need to be created to enact consequences around online harassment. These numbers are significantly higher than those reported by the ADL from a survey of the overall game playing population in 2021, who found only 68% of respondents believe games companies should be doing more to support people being targeted by online hate, with 59% endorsing the need to create new laws being developed to address hate and harassment online.\n\n\nDiscussion\n\nThe harassment of game makers through social media is a growing concern. This study looked at the prevalence and nature of online harassment among game makers to better understand the scope of this problem. Results indicated high rates of online harassment, both direct and indirect, among members of the gaming industry at all levels. Responses also pointed to substantial mental health and behavioral impacts of both experiencing and witnessing online harassment. Notably, the harassment of game makers seems directly tied to a lack of diversity within the industry, as evidenced by the ubiquity of identity-based harassment.\n\nThe impact of hate and harassment of game makers appears to be more severe than found among a general game playing population. As reported by the ADL in 2019, less than one-third of their respondents reported feeling uncomfortable or upset (31%), felt isolated or alone (14%), took steps to reduce risk to physical safety (12%). depressive or suicidal thoughts (11%), or had their occupational performance negatively impacted (13%). Comparable outcomes between game makers and the general game playing population (as reported by the ADL) are presented in Table 5. This may be, at least partially, due to the high rates of the more severe forms of harassment, doxxing and swatting, being reported by game makers.\n\n* Information is drawn from ADL (2019) but percentages are attributed to a 2020 data collection.\n\nThe prevalence of the more severe forms of harassment are noteworthy when compared to the frequency at which these behaviors occur within the general gaming community, specifically doxxing and swatting. As reported by Kowert and Cook (2022), of the general game playing population, 11.1% had experienced doxxing directly, and 24.1% had witnessed it happen to someone else. In this analysis, we found 25.6% of game makers report a direct experience and 53.5% reporting directly witnessing, respectively. For swatting, similar numbers of direct experience are found among the general game playing population (3%) and members of the gaming industry (3%), however far more industry members have witnessed swatting (21.9%) than among the general population (1.5%). We postulate that one of the causes of these higher rates among industry members is because awareness of this phenomenon is higher among this population. Notably, threats of physical violence are similar between industry members (48.2%) and the general game playing population (46.8%), suggesting that these behaviors may be more endemic to gaming cultures rather than something specific to members of the gaming industry.\n\nWhile the results of this work are noteworthy, there are limitations to consider. First, the sample was recruited primarily via social media. It is possible that this led to an oversampling of those most active on social media and, as such, these findings may be over-representative of the proportion of game industry professionals who have experienced or witnessed harassment through these platforms. Future work should aim to recruit samples through studios directly to obtain a more representative sample. Secondly, most participants within the sample worked in core creation or development roles within the studio. However, we know harassment towards industry professionals can happen to those in any role and at any level. Future work should aim to sample more professionals in different areas of the gaming industry to better evaluate the frequency and impact of these behaviors across job functions. Lastly, this work was developed to be exploratory, with the aim of providing a broad overview of what harassment via social media looks like for game industry professionals. Future work should build upon these findings to evaluate any potential points of intersectionality between harassment experiences, mental health impact, role within the industry, and demographic factors.\n\n\nConclusions\n\nHarassment of game industry professionals is a large problem with most people in the game industry having directly experienced some form being directed at them specifically. This harassment can be (and often is) magnified if the person is a marginalized voice, with over half of all respondents saying they were targets of hate because of some aspect of their identity. The harassment has a negative impact on industry members’ feelings of comfort, isolation, wellbeing, and job performance. Many game makers also recognize the need for more policy change to better address this growing issue. Games leadership need to create stronger policies around hate and harassment of their employees, delineate clearer social boundaries between game maker and game player, and provide greater mental health support should their employees become targets of online harassment. Without large-scale action to address the norms of interaction between developers and fans, this problem will continue to drive people out of the industry and reinforce the lack of diversity inside game studios, pushing out marginalized employees due to a hostile work environment.\n\nHowever, we are hopeful that these first steps are being taken as, in 2022, Bungie, a major game studio based in Washington State, filed a lawsuit against a Destiny 2 player and streamer who had harassed and threatened staff members (Good, 2022). Many game studios have also started to speak publicly about zero tolerance for the harassment of their employees, including, most recently, Respawn. Respawn saw a marked increase in harassment after dealing with a crashing issue in their game Apex Legends, as well as an AMA (Ask Me Anything chat on Reddit) about the game (Respawn (@Respawn), 2022). It will take more than Twitter statements for these norms to change, but the public pushback from game studios is a relatively recent development, a marked shift from the perspective of ArenaNet CEO Mike O’Brien in 2018 that developers “must be friends” with players. The authors hope that this shift marks the beginning of an era of more comprehensive response and proactive support of people who make games by their employers.\n\nHowever, while change can, and should include, greater institutional support, this isn’t the starting point for sustainable change. In efforts across the industry, we are starting to see game studios make the connection between the people in the room, making decisions about game content, mechanics, and marketing and the resulting harassment. With this shift to more diversity, and with the newfound sense of responsibility that game makers have towards their employees, we can begin to see the seeds of a sustainable and substantive change in both the expectations and incidence of harassment of people who makes games and of other players. We firmly believe a more diverse group of people making games that work well for a more diverse player base is the first step towards a more inclusive and less hateful environment.\n\n\nConsent\n\nTo retain data integrity and anonymity, the survey data was collected and retained on private servers hosted by Take This. Participant responses were anonymized and no identifying information was collected.",
"appendix": "Data availability\n\nOSF: ‘Game Developers Social Media Experience Survey’. DOI: https://osf.io/5bd4g/ (Kowert & Crevoshay, 2021)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nThe project contains the following underlying data:\n\n- Data collection 2021, Game Developers Social Media Experience Survey (internet recruitment).csv (raw data)\n\nThis project contains the following extended data:\n\n- Game Developers Social Media Experience Survey, (Game Developers Social Media Experience Survey.pdf )\n\n\nReferences\n\nAnti-Defamation League: Hate is No Game: Harassment and Positive Social Experiences in Online Games 2021. 2022.Reference Source\n\nBeres NA, Frommel J, Reid E, et al.: Don’t you know that you’re toxic: Normalization of toxicity in online gaming. Proceedings of the 2021 CHI Conference on Human Factors in Computing Systems (CHI '21). Association for Computing Machinery, New York, NY, USA,. 2021; 1–15. Article 438. Publisher Full Text\n\nBergstrom K: Destruction as deviant leisure in EVE online. J. Virtual Worlds Res. 2020; 13(1). Publisher Full Text\n\nBourdreau K: Beyond deviance: toxic gaming culture and the potential for positive change. Crit. Stud. Media Commun. 2022; 39(3): 181–190. Publisher Full Text\n\nBryter:2020. Female Gamer Survey 2020. Bryter - Female Gamers Survey 2020.pdf Bryter - Female Gamers Survey 2020.pdf (bryter-research.co.uk).\n\nBurgess MCR, Dill KE, Stermer P, et al.: Playing with prejudice: The prevalence and consequences of racial stereotypes in video games. Media Psychol. 2008; 3: 289–311.\n\nCampbell C: Sarkeesian driven out of home by online abuse and death threats. Polygon. 2014.Reference Source\n\nCampbell C: ArenaNet ‘folded like a cheap card table,’ says fired Guild Wars 2 writer. Polygon. 2018.Reference Source\n\nCook C: Between a troll and a hard place: the demand framework’s answer to one of gaming’s biggest problems. Media Commun. 2019; 7(4): 176–185. Publisher Full Text\n\nCook C, Conijn R, Antheunis M, et al.: For whom the gamer trolls: A study of trolling interactions in the online gaming context. J. Comput.-Mediat. Commun. 2019; 24: 293–318. Publisher Full Text\n\nCook C, Schaafsma J, Antheunis M: Under the bridge: an in-depth examination of online trolling in the gaming context. New Media Soc. 2018; 20(9): 3323–3340. PubMed Abstract | Publisher Full Text\n\nDill K, Thill KP: Video Game Characters and the Socilization of Gender Roles: Young People’s Perceptions Mirror Sexist Media Depictions. Sex Roles. 2007; 57: 851–864. Publisher Full Text\n\nFagan K: I felt helpless - the IRL impact of harassment in gaming. YR Media. 2021; Reference Source\n\nFarokhmanesh M: Guild Wars studio fires two employees after clash with streamer. The Verge. 2018.Reference Source\n\nFrancis B: More developers are pushing back against player toxicity. Game Developer. 2022. Reference Source\n\nGach E: Boyfriend Dungeon voice actor responds to harassment over playing a villan. Kotaku. 2021.Reference Source\n\nGame Developers Association: 2022 State of the Game Industry. 2022.\n\nGood OS: Bungie sues Destiny 2 streamer alleged to cheat, harass employees. Polygon. 2022, July 18.Reference Source\n\nGrayson N: For streamers dealing with stalkers, Twitch’s solutions fall short. Kotaku. 2019.Reference Source\n\nHernandez P: Overwatch artist says Sigma’s bare feet meant to ‘sell the asylum look’. 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Exputer. 2022.\n\nMarch E: Psychopathy, sadism, empathy, and the motivation to cause harm: New evidence confirms malevolent nature of the internet troll. Personality and Indivdiual Differences. 2019; 141: 133–137. Publisher Full Text\n\nMazanko V: Ubisoft artist says entitled gamers make game launches “a horrid experience”. The Gamer. 2022.Reference Source.\n\nMortensen TE: Anger, fear, and games: The long event of #GamerGate. Games Cult. 2018; 13(8): 787–806. Publisher Full Text\n\nRespawn (@Respawn): Recently we have seen increased harassment towards members of our development team. 2022.\n\nRobertson A: What’s happening in GamerGate? The Verge. 2014, October.Reference Source\n\nSarkeesian A: Damsel in Distress: Part 1 (A. Sarkeesian (ed.)). Feminist Frequency. 2013.Reference Source\n\nTompkins JE, Martins N: Masculine pleasures as normalized practices: Character design in the video game industry. Games Cult. 2021; 17(3).\n\nTroughton J: Ron Gilbert “Won’t be posting anymore” about Return to Monkey Island following abuse. The Gamer. 2022, June.Reference Source\n\nUKIE: UK Games Industry Census. 2022.Reference Source\n\nWilliams D, Martins N, Consalvo M, et al.: The virtual census: Representations of gender, race and age in video games. New Media Soc. 2009; 11(5): 815–834. Publisher Full Text"
}
|
[
{
"id": "158166",
"date": "04 Jan 2023",
"name": "Amanda C. Cote",
"expertise": [
"Reviewer Expertise Games",
"gender",
"identity",
"audience studies",
"media industry studies"
],
"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 an online survey of 282 gamesworkers to assess their direct and witnessed experiences with harassment. It breaks down the types and prevalence of harassment they have experienced or witnessed, the perceived motivations of harassers, and the impacts harassment has had on themselves and others in terms of mental and physical health. Overall, this study is clearly conducted and written, with good attention to limitations. It also addresses a newer and significant aspect of harassment and toxicity in gaming communities and cultures. There is little to no academic work currently addressing the harassment of game makers, although a lot of anecdotal evidence shows that it occurs frequently and significantly.\nThere are only a few small things I would like to see the researchers consider moving forward.\nFirst, the literature review could benefit from slightly clearer organization and attention to the broader history of harassment directed at gamesworkers. The piece opens with recent examples of harassment (pg. 1-2), stating, “The harassment of game makers first made its way into the spotlight when former Guild Wars 2 narrative designer Jessica Price’s was fired from ArenaNet after engaging in a Twitter exchange with a player.” This event, however, did not occur until 2018; the harassment of game makers, especially female ones, and public recognition of these issues predate this event by several years, at minimum - e.g., Jennifer Hepler’s harassment at Bioware in 2012-2013, GamerGate, etc. Some of these events come up later in the article, but it would be useful to note and trace some of this broader trajectory (and the role of identity) from the start. Harassment in the games industry is not a new issue! This only makes it more in need of studies like this. Similarly, it’s worth briefly noting the intellectual development of concepts such as the cycle of exclusion in gaming. These also date back until at least the early 2000s (e.g., Fron et al. (2007)1), and that labor should be recognized. Other work on the industry, such as Robin Johnson’s studies of masculinity in studio culture, would also be useful here (see suggested citations at end2,3).\nSecond, the content analysis section (pg. 4, lack of representation in games) could benefit from some more updated stats, such as those by Lynch et al. (2016).4\nFinally, the analysis and discussion could benefit from more connections back to existing work on industry, as well as on players’ experience with harassment and their means for coping with this. The ADL data is useful, but there are also many critical analyses of these issues that fit the survey data well and could be tied in. The results of this study are important and meaningful; be sure to situate them within the field effectively to demonstrate this to the fullest extent.\nSuggested Citations:\nFron, J., Fullerton, T., Morie, J. F., & Pearce, C. (2007). 'The Hegemony of Play'. Situated Play, Proceedings of DiGRA 2007 Conference1\n\nJohnson, R. S. (2013). 'Toward Greater Production Diversity: Examining Social Boundaries at a Video Game Studio'. Games and Culture2\n\nJohnson, R. (2014). 'Hiding in Plain Sight: Reproducing Masculine Culture at a Video Game Studio'. Communication, Culture & Critique3\n\nLynch, T., Tompkins, J. E., van Driel, I. I., & Fritz, N. (2016). 'Sexy, Strong, and Secondary: A Content Analysis of Female Characters in Video Games across 31 Years'. Journal of Communication4\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": "9207",
"date": "20 Jan 2023",
"name": "Rachel Kowert",
"role": "Author Response",
"response": "Reviewer's comment: First, the literature review could benefit from slightly clearer organization and attention to the broader history of harassment directed at gamesworkers. The piece opens with recent examples of harassment (pg. 1-2), stating, “The harassment of game makers first made its way into the spotlight when former Guild Wars 2 narrative designer Jessica Price’s was fired from ArenaNet after engaging in a Twitter exchange with a player.” This event, however, did not occur until 2018; the harassment of game makers, especially female ones, and public recognition of these issues predate this event by several years, at minimum - e.g., Jennifer Hepler’s harassment at Bioware in 2012-2013, GamerGate, etc. Some of these events come up later in the article, but it would be useful to note and trace some of this broader trajectory (and the role of identity) from the start. Harassment in the games industry is not a new issue! Author's response: The reviewer is correct in that this is not a new issue. Highlighting the event with Jessica Price was meant more to illustrate this is when the discussion of the harassment of game makers moved out of more niche communities and whisper networks and towards a more broad acknowledgement of its existence within this industry specifically. The wording has been changed slightly in the introduction to reflect this. Specifically, the following text has been added: While the harassment of game makers (especially female ones) has been a very real issue for many years, in 2018 we started to see discussions of these behaviors within a broader public spotlight when former Guild Wars 2 narrative designer Jessica Price was fired from ArenaNet after engaging in a Twitter exchange with a player. Reviewer's comment: Similarly, it’s worth briefly noting the intellectual development of concepts such as the cycle of exclusion in gaming. These also date back until at least the early 2000s (e.g., Fron et al. (2007)1), and that labor should be recognized. Other work on the industry, such as Robin Johnson’s studies of masculinity in studio culture, would also be useful here (see suggested citations at end2,3). Author’s response: The aim of this paper is not to explore why these events happen but rather shed light on their frequency and mental health impact. That said, the text has been amended to recognize that there has been work in this space examining the potential underpinning motivations/causes for this behavior. Specifically, the following text has been added: There has also been research exploring a potential cycle of exclusion in gaming cultures (Fron et al., 2007; Kowert et al, 2017) and the role masculinity in studio culture may specifically play in creating a culture of harassment (Johnson, 2013; 2014). The cycle of exclusion in gaming culture is also more formally described later in the paper. Specifically with the following passage: Some have argued that this is a result of a cycle that starts in early childhood. Referred to as the “Cycle Model of Exclusion in Gaming Content and Cultures,” (Kowert et al., 2017), it is believed that early socialization of games as a male activity leads to the exclusion of non-men in the industry, which creates a male dominated industry and gendered game content and a normalization of gendered views of the world including sexist attitudes and beliefs within gaming communities and the industry itself. This cycle is self-perpetuating. Reviewer's comment: Second, the content analysis section (pg. 4, lack of representation in games) could benefit from some more updated stats, such as those by Lynch et al. (2016).4 Author's response: Thank you for this suggestion! Lynch et al. (2016) has been added as a reference in that section. Reviewer's comment: the analysis and discussion could benefit from more connections back to existing work on industry, as well as on players’ experience with harassment and their means for coping with this. The ADL data is useful, but there are also many critical analyses of these issues that fit the survey data well and could be tied in. The results of this study are important and meaningful; be sure to situate them within the field effectively to demonstrate this to the fullest extent. Author’s response: We agree that situating this work within the context of the ongoing work within this field is important. We lean heavily on the ADL work here as it is publicly available data looking at a broad range of experiences and impact. While it can be useful to draw on work looking at player harassment, the harassment of game makers is something that needs to be examined through a more nuanced lens because of the additional contextual factors that are specific to this experience among game developers (studio culture, lack of personal/professional boundaries, personal and professional consequences to action and inaction). That said, additional text has been added to better contextualize this work and lend more insight into potential solutions and strategies. Specifically, the following text has been added: There is also a growing number of researchers in this space actively seeking strategies for victims of online harassment to better mitigate the negative mental health impacts and avenues for support (Cote, 2016; Tang et al., 2019). Drawing from this research and work from other disciplines, such as the online harassment of female journalists (Ferrier & Garud-Paktar, 2019), we can begin to develop effective reporting strategies, support structures for the victims, and tools to dismantle the systems for harassment."
}
]
}
] | 1
|
https://f1000research.com/articles/11-1518
|
https://f1000research.com/articles/12-81/v1
|
20 Jan 23
|
{
"type": "Research Article",
"title": "Pragmatics in the context of English for occupational purposes: Speech acts produced by Japanese workers",
"authors": [
"Yuko Hijikata",
"Rachael D. Roberts",
"Masakazu Ueno",
"Rachael D. Roberts",
"Masakazu Ueno"
],
"abstract": "Background: Second-language (L2) pragmatics is one of the important fields of second-language acquisition research, where the native speakers’ norm is the standard. However, in another subfield of applied linguistics, English for occupational purposes (EOP), the importance of speakers’ expertise is instead emphasized. Although pragmatics plays an important role in workplace communication, few empirical studies examined Japanese workers’ English usage. This study clarifies how appropriately the participants can produce speech acts of request, apology, refusal, and advice-giving, and what factors affect their performances. Furthermore, we investigate the relationship between pragmatics scores and the strategies used by participants.\n\nMethods: We recruited 100 Japanese workers who speak English through a crowdsourcing platform. Complete responses from 92 participants were included in data analysis; eight people input the completion code but failed to save data on the survey response form, thus were excluded from the study. The participants answered demographic questions and then answered a written discourse completion task. We posed 12 situations, representing four speech acts: request, apology, refusal, and advice-giving. Considering the situation, the participants typed the English expression they would offer in response. Their responses were graded with a six-point rating rubric and coded using the strategy framework. Results: Multiple strategies influenced the pragmatics scores, regardless of the type of speech act. Those who obtained higher scores tended to use multiple strategies, and not only main strategies but also modifications. The L2 proficiency was a significant factor affecting how participants offer an apology, while participants’ experiences of working abroad affected how they expressed refusal. Participants who obtained higher scores tended to use indirect pragmatics strategies, accompanied by modifications. Conclusion: The application of multiple pragmatics strategies is essential, regardless of the speech act type. To extend the findings, further EOP research is required with a variety of transferred employees in inner/outer/expanding circles.",
"keywords": [
"English for Occupational Purposes",
"pragmatics",
"speech acts",
"discourse completion task"
],
"content": "Introduction\n\nSecond language (L2) pragmatics is a discipline composed of L2 acquisition and pragmatics (Culpeper et al., 2017) and one of the major fields in the second language research domain (e.g., Bardovi-Harlig, 2013; Taguchi & Roever, 2017). In Bardovi-Harlig’s (2013) definition, L2 pragmatics is a study that reveals learners’ development of how to say what to whom, when, and in what context (pp. 68–69). Acquiring L2 pragmatics requires learners to understand not only linguistic rules but also communication functions and the context in use (Taguchi, 2022).\n\nMany previous studies investigating L2 pragmatic development had younger participants ranging from children to university students (e.g., Achiba, 2003; Bella, 2012; Haselow, 2021; Taguchi & Kim, 2016). However, L2 pragmatics is especially difficult for adult learners because they (a) lack grammatical knowledge and vocabulary and/or (b) are not aware of which form is pragmatically appropriate and when it can be used (Yates & Springall, 2010). In this study, we focus on a less-researched population, namely Japanese adult workers who speak English at their workplace.\n\nIn pragmatics research, the term speech acts refers to “functions performed through language” or “doing things with words” (Ishihara & Cohen, 2022, p. 11) and is among the most well-researched topics in pragmatics (Taguchi & Roever, 2017; Taguchi et al., 2016; Tatsuki & Houck, 2010). There are many kinds of speech acts, such as greeting, inviting, requesting, refusing, apologizing, complaining, complimenting, and thanking (Ishihara & Cohen, 2022, p. 11). While requests are the most studied speech act, some types (e.g., teasing and criticizing) have not been examined sufficiently (Cohen, 2020). It is also known that certain speech acts are strongly influenced by the speaker’s native language (e.g., Cohen, 2020; Yates & Springall, 2010). For example, Japanese speakers tend to show disfluency when producing apologies and refusals as a means of politeness toward interlocutors (Cohen, 2020).\n\nSeveral assessments have been used to examine the production of speech acts. The most traditional and frequently used task is a discourse completion task (Taguchi & Roever, 2017). In a DCT, a certain context is given to participants, who are then asked what they would say in that situation. A DCT can involve a free response or a cued response multiple-choice (Hudson et al., 1995). While several researchers have criticized written DCTs because they lack authenticity and it is not clear if the participant would really speak in a particular way in the real situation (e.g., Taguchi & Roever, 2017), some researchers use them in addition to other assessments (e.g., Gilmore, 2011). DCTs have strengths in terms of their practicality and ease of use in data collection (Cohen, 2020). Recent data collection methods include oral DCTs, role play, naturalistic data gathering such as through recordings (Cohen, 2020), and the use of virtual reality (Taguchi, 2022).\n\nThe significance of L2 pragmatics has been recognized in the era of globalization. Specifically, the number of L2 pragmatics studies in the context of English as a lingua Franca (ELF) has been increasing, and this new type of work has transformed and expanded the traditional L2 pragmatics research in several ways, such as emphasizing the role of L2 speakers in negotiations of meaning when they face communication difficulties (Culpeper et al., 2017). However, compared with cross-cultural pragmatic studies, there has been scarce research that has examined the connection between L2 pragmatic and intercultural competence (e.g., Taguchi et al., 2016). Intercultural competence is important in contexts in which cultural differences are found and is attributed by individual factors including “personal qualities, attitudes, knowledge, and skills” (Taguchi et al., 2016). Recent empirical studies have verified the positive effect of studying abroad on L2 pragmatic learning (e.g., Alcón-Soler, 2015; Cohen & Shively, 2007; Taguchi et al., 2016), which indicates that being exposed to a culture plays an important role in developing L2 pragmatic skills. In fact, choosing the appropriate phrases to use in a particular social situation requires a great deal of cultural understanding, which reveals the speaker’s understanding of their membership within their respective speech communities. Bardovi-Harlig (2012) revealed that while these phrases are not always formulaic, researching the use of formulaic language helps to emphasize the importance of context related to the pragmatic nature of such formulaic social interactions.\n\nTaguchi (2022) argued that due to English’s status as a dominant language utilized in intercultural contexts by nonnative speakers, native-speaker norms cannot function as the only reference for denoting the sufficiency of nonnative speakers’ English. Specifically in the context of English for Occupational Purposes (EOP), the native speaker’s norm is not as crucial as that of an expert (Tarone, 2008).\n\nRecent EOP studies have investigated pragmatics in the following disciplines: medical (e.g., Dahm et al., 2022), business (e.g., Kaur & Birlik, 2021; Park et al., 2021), aviation (e.g., Ishihara & Prado, 2021), and the professional kitchen (Pang, 2019). Kaur and Birlik (2021) investigated the pragmatic strategies that are used in business meetings at a multicultural corporation. The strategy scrutinized in this study was explaining that either followed an implicit request or was done without such a request. Data were collected from six business meetings; although the personal profile of each participant was not clear, the participants’ native languages were Malay, a Chinese dialect, Tamil, and German. The major finding of this study was that the participants tended to add some background information so that the attendees of the meeting would establish shared knowledge. Park et al. (2021) explored how requests are made in a business context, and compared 50 Korean and 50 American office professionals’ email writing. Data was collected through a written DCT, and the collected emails were analyzed focusing on moves as well as lexical and syntactic complexity. They revealed some cultural differences between the Korean and American professional groups. First, members of the Korean group provided more self-introduction than those of the American group. Second, the American group used specific strategies, such as complimenting and offering compensation, more often than the Korean group. Third, the subject lines were longer and more detailed in the Korean group than in the American group. Park et al. explained that these differences reflect sociocultural differences between Korea and America.\n\nThe production of requests and directives was examined in a professional kitchen in Pang (2019). The study focused on interactions, and the data was collected using field notes and participant observation, and the participants’ workplace communication was also recorded. The participants comprised eight trainees and 55 kitchen workers. Pang (2019) revealed that the strict hierarchy in the kitchen created an environment in which a clear distinction in power status allowed directives to be issued by workers with higher authority.\n\nIshihara and Prado (2021) scrutinized the pragmatics in radiotelephony communications between pilots and air controllers. Their focus was on negotiation of meaning, and data were extracted from the Radiotelephony Plain English Corpus (RTPEC) (Prado & Tosqui-Lucks, 2019). The authors claimed that aviation English and particularly radiotelephony communications have some similarities and differences with general ELF.\n\nWhile the number of L2 pragmatic studies in the context of EOP has been increasing, so too has the importance of investigating a wide variety of populations (Pang, 2019; Park et al., 2021) and using multiple types of strategy (Kaur & Birlik, 2021).\n\nAlthough the pragmatic differences between Japanese and English have been mentioned in previous studies (e.g., Cohen, 2020; Yates & Springall, 2010), compared with cross-cultural pragmatic studies that have compared English and Japanese languages (e.g., Fukushima, 1996) and L2 pragmatic development by Japanese EFL university students (e.g., Matsumura, 2003; Takahashi, 2005, 2015; Takahashi & Beebe, 1987), few empirical studies have examined Japanese workers who have worked overseas while focusing on L2 speech act production.\n\nKubota and Takeda (2021) conducted political discourse analysis on governmental documents and interviews with corporate workers. From their interviews with Japanese transnational workers in Asia, it was found that Japanese corporate workers did not believe the connection between English test scores and job satisfaction (Kubota & Takeda, 2021). It is important to recognize that obtaining good scores from the Test of English for International Communication (TOEIC) does not guarantee the test taker’s success in his/her business, although not achieving native command tends to be regarded as not sufficiently proficient in Japan (e.g., D’Angelo, 2018).\n\nAccording to the statistics reported by the Ministry of Foreign Affairs of Japan as of October 1, 2021, there are as many as 807,238 Japanese citizens abroad. These individuals were reported as staying in a foreign country for longer than three months but planning to return to Japan in the future (Ministry of Foreign Affairs of Japan, 2022a). Also, the Ministry of Foreign Affairs of Japan (2022b) revealed that 77,551 companies operate overseas and that the number of business operations in Asia (n=53,431) is much higher than that in North America (n=9,827) and that in Europe (n=8,300). However, how Japanese workers use language pragmatically in an intercultural workplace has been under researched.\n\nConsidering the background discussed so far, the purpose of the current study is to clarify (a) challenging aspects in L2 pragmatics for Japanese workers and (b) individual difference factors (e.g., self-reported English proficiency, overseas work experiences) that influence speech act production. We have established the following research questions:\n\nRQ1: What influences the pragmatic score more: frequency of strategy use or individual difference factors?\n\nRQ2: What types of pragmatic strategy lead to higher pragmatic scores?\n\nRQ3: What perceptions do Japanese workers who have been employed in foreign countries have toward the intercultural workplace communication?\n\n\nMethods\n\nThis study received ethics approval from the University of Tsukuba Faculty of Humanities and Social Sciences Ethics Committee on January 14, 2021, with the approval number 2020-10. Potential participants read the explanations about this study and the participation instructions on a Japanese crowdsourcing service called CrowdWorks. It was impossible to obtain written consent from the participants because participants do not disclose their names when they accept tasks on CrowdWorks. Therefore, we clearly outlined that participating in this study would indicate that the participants had read the explanation, which stated that the data would be analyzed anonymously and used for academic publications, and had agreed to join on their own accord. The study explanation also clearly stated that the purpose of this study was to investigate workplace communication produced by Japanese workers and that the task would require potential participants to write down English expressions. When collecting data from an online survey, it was necessary to consider the type of question to include in order to avoid careless responses from the participants. According to Brühlmann et al. (2020), careless responses are a form of invalid responding, such as seeking social desirability and faking responses. It was also mentioned that careless responding is a phenomenon typically due to factors such as extrinsic motivation, length of survey, social contact, environmental distraction, as well as motivation and interest, which can negatively affect data collection in online survey responses. Furthermore, open-ended questions have been found to receive fewer careless responses (Brühlmann et al., 2020). Only those who agreed to take part in this study including such open-ended questions clicked on the button to join this study; thus, it was considered that having anonymized responses did not distort the scientific data. The University of Tsukuba Faculty of Humanities and Social Sciences Ethics Committee approved this form of implied consent acquisition.\n\nWe recruited 100 native Japanese speakers through CrowdWorks. The sample size was determined considering the two facts. The first one is that some pragmatic studies using written DCT had similar sample sizes (e.g., Jebahi, 2011; Park et al., 2021). The second one is that CrowdWorks can send our call to 100 potential participants who have specific qualifications as the optional service. We wished to reach out to those who have English skills, so having 100 participants seemed reasonable for our recruitment possibility. Due to problems with linking the crowdsourcing service and the questionnaire platform, Microsoft Forms, eight people were excluded from the data analysis. Therefore, 92 native Japanese speakers were included in the data analysis. Table 1 shows the demographic information of the participants.\n\nNearly one-third of the participants (n=34), including two participants who lived in English-speaking countries over 20 years, did not have any English test scores. Almost half (n=41) of the participants reported their TOEIC scores, and their mean score was 818.54 (SD=120.16), which falls in B2 of the Common European Framework of Reference for Languages (CEFR) proficiency levels (ETS Global, 2021). However, their scores ranged from 430 to 990, which were equivalent to CEFR A2 to C1. Also, nearly one-fourth (n=24) of the participants had Test in Practical English Proficiency (EIKEN) grades ranging from Grades one to four. The EIKEN grades, except Grade four, can be mapped with CEFR as follows (Eiken Foundation of Japan, 2022): Grade one is mapped to B2 and C1, Grade pre-one is mapped to B1 and B2, Grade two is mapped to A2 and B1, Grade pre-two is mapped to A1 and A2, and Grade three is mapped to A1. It should be noted that three participants have lived in America or the UK for more than 20 years, and they declared that they had native-command English proficiency. Based on these test scores/grades and their self-reported English proficiency bands, the proficiency levels of the participants were estimated from A1 to C1.\n\nThe materials included a demographic questionnaire, survey questions, and a written DCT, which can be found in Open Science Framework (Hijikata et al., 2022). The demographic questionnaire and survey questions were included in Part one, followed by Part two, a written DCT. The contents of the questionnaire included items on the participants’ age, gender, working status, languages used at work, and overseas work history. The survey questions featured items about participants’ experiences and challenges in working with colleagues with different linguistic and cultural backgrounds, what they do to overcome such challenges, and what they believe are essential to work abroad.\n\nWe developed and conducted a written DCT based on one of the authors’ own experiences working abroad. Twelve situations that could occur in workplaces were written in Japanese. Here is one example:\n\n[Situation 1] You are working as a customer service representative of a research company. You are calling your client for him/her to answer an online survey. This survey will help improve the sales representatives’ performance and will take five minutes of their time. What would you say to your client? [Request]\n\nThe DCT included speech acts of requesting, advice giving, apologizing, and refusals. Each speech act featured three situations, and the presentation order was randomized using Excel for Microsoft 365.\n\nAll data were collected through Microsoft Forms, which was linked to CrowdWorks. When recruiting participants, the advertisement called for participants who regularly used English at work or who had worked abroad. To reach people who use English at work, we added an option to CrowdWorks that allowed us to send our research advertisement to 100 people who had registered English as part of their skillset. The data collection started on January 11 and ended on January 12 in 2022.\n\nThis study consisted of two parts. The first was a survey with 19 questions to collect the participants’ demographic data and information about their beliefs as to what is important for Japanese workers working overseas and/or with colleagues from different countries/cultures. The second part was a DCT with 12 questions. The participants were asked to write “I don’t know” in Japanese when they were not sure how to respond. They were required to type what they would say in each situation in English and judge how often they encountered such a situation using a five-point scale (“Never,” “Once in 2–3 months,” “Once a month,” “Once in a couple of weeks,” and “More than 3 times a week”). The participants were instructed not to search for information on the Internet nor consult expressions with a dictionary while they engaged in the DCT. When they completed the study, they were given a completion code on Microsoft Forms. They were expected to input the completion code into CrowdWorks to receive their monetary reward. They received JPY 860 as compensation for their time.\n\nScores of speech acts\n\nThe speech acts produced were graded using rating scales contextualized by three perspectives: whether the expressions were appropriate in each context, if communication was clear, and whether each response was grammatically accurate as a whole (Taguchi et al., 2016). Possible scores were 1–6.\n\nOne-fourth of the data was graded by two authors, one native English speaker who has taught English in Japan for over six years, RDR, and one native Japanese speaker, who has taught English for more than 20 years, MU. The interrater reliability was checked for each question using R (version 4.2.1) with the vcd package. The initial reliability kappa (weighted) was 0.65. One question had lower interrater reliability, so the two raters discussed the disagreement; as a result, the interrater reliability improved to 0.74. Then, the remaining three quarters of the data were graded by the native English speaker, RDR only.\n\nStrategies\n\nWe adapted separate frameworks for each speech act with reference to the frameworks used in previous studies (Blum-Kulka et al., 1989; Ishihara & Cohen, 2022; Taguchi, 2022). Strategies in requests were further divided into main strategies that directly convey the act, and modifications that support the main strategies. Ten categories in the main strategies were adapted from Taguchi (2022), and we created one new category, “Japanese-like” because some responses were highly influenced by the Japanese language. We show the mapping between categories adapted from Taguchi (2022) and thus indicated in the quotation marks and sample responses in our study as follows. (1) “Imperative” includes imperative sentences with and without please (e.g., Please answer my questions/Please cooperate). (2) “Performative” includes statements which require a listener to act something or statements with the verb request (e.g., I’m requesting a questionnaire …). (3) “Obligation” indicates a duty to do something, so the use of structures and/or modal verbs such as should and must fall in this category (e.g., It is your duty to … /You should cooperate). (4) “Want statement” indicates speakers’ willingness to do something, so this category contains verbs such as want, wish, and need, and phrases such as would like to (e.g., I want to know … /I would like to ask you …). Different from (2) performatives, the want statement does not force the listener to do something. (5) “Direct question” asks a simple question which does not get permission to act something (e.g., Do you have time to answer … ?). (6) “Query preparatory” is in a question form to ask a hearer to ask a favor (e.g., Could you cooperate … ?/Can you give me 5 minutes?). (7) “Permissions” seeks permission to do something (e.g., May I ask you … ?/Can I … ?). (8) “Suggestions” shows giving a suggestion to a hearer (e.g., Why don’t you answer … ?). (9) “Mitigated expressions” represent embedded clauses (e.g., We appreciate if you can …). (10) “Hint” does not clearly ask a hearer to do something for the hearer but implies that such action is desirable (e.g., This survey is designed to improve … and takes about 5 minutes to complete). (11) Japanese-like is an expression influenced by Japanese and does not ask whether a hearer accepts the request or not (e.g., Thank you for your cooperation for 5 minutes). The categories (1)–(5) are direct expressions, while the categories (6)–(11) are indirect questions. Responses which did not apply to any of these were marked as (12) NA. Furthermore, these main strategies were supported by the following modifications, which were also adapted from Taguchi (2022): (a) “Hedging,” (b) “Reason,” (c) “Apology,” (d) “Preparator,” (e) “Confirmation,” (f) “Appreciation,” (g) “Minimizer,” (h) “External ‘please’,” (i) “Question,” (j) “Promise,” (k) “Positive Comment,” (l) “Alternative,” and (m) “Attention Getter.”\n\nNext, strategies in apology were coded based on the main strategies only. Five categories with the quotation marks were adapted from Ishihara and Cohen (2022), and we created one new category, Japanese-like. Thus, all main strategy categories related to apology are (1) “apology,” (e.g., We apologize/Sorry), (2) “responsibility,” (e.g., It is our fault), (3) “explanation,” which states why the trouble happened (e.g., We seem to have forgotten to check …), (4) “compensation,” which offers compensation (e.g., We will offer you complimentary drinks …), (5) “promise for the future,” (e.g., this won’t happen again), and (6) Japanese-like, with the discourse strongly affected by the Japanese style.\n\nRegarding refusals, the main strategies included 10 categories outlined by Taguchi (2022), and we created one new category, Japanese-like, because some responses were highly influenced by the Japanese language. Thus, all main strategy categories adapted from Taguchi (2022) as shown in the quotation marks and sample responses in our study are as follows: (1) “non-performative ‘no’,” (e.g., It is not refundable) (2) “negative willingness/ability” (e.g., We can’t …), (3) “mitigated refusal,” (e.g., I’m afraid we are unable to …) (4) “indefinite reply,” which is an evasive response, (5) “excuse,” which states the reason why the request is not acceptable (6) “wish,” (7) “apology,” which turns down the request with apology expressions, (8) “avoidance,” which avoids declining the request clearly, (9) “alternative,” which suggest something else instead of accepting the request, (10) “promise,” which implies that the request will be accepted in the future (e.g., We will have such instructors in the future), and (11) Japanese-like. Furthermore, these main strategies were supposed by the following modifications, which were also adapted from Taguchi (2022): (a) “positive comment,” (b) “well-wishing,” (c) “appreciation,” (d) “apology,” (e) “reason,” (f) “hedging,” (g) “confirmation,” (h) “external ‘please’”, and (i) “attention getter.”\n\nFinally, advice-giving was analyzed from the main strategies framework only. These main strategies included three categories by Ishihara and Cohen (2022): (1) “direct,” (2) “softened,” and (3) “indirect.” Their labeling and examples in our study are shown as follows. (1) “Direct” is straightforward, and the person who gives advice use imperatives or uses modals such as should and had better (e.g., Please consult). (3) “Indirect” leaves some room for not accepting the advice by using mild expressions (e.g., You might want to listen to others’ opinion). (2) “Softened” is even less direct (e.g., We are the team, and we are here to help you).\n\nThe strategies were coded by classifying speech act types by the authors: One coder, YH, had a doctoral degree in applied linguistics and had taught general and academic English at tertiary level for over 12 years and occupational English in the US for four years. She coded all of the main strategies, while RDR and MU coded half of the responses, respectively. The modification was coded by YH. The overall agreement rate between YH and RDR/MU was 77%. The disagreement was solved through discussion.\n\nTo calculate the overall scores and frequency of each strategy, we ran separate models. Generalized linear mixed-effects (GLMM) models using R (version 4.2.1; R Core Team, 2022) and R Studio (version 2022.07.1) with the lme4 package were used to examine RQ1. Our focus was the relationship between the pragmatics scores and the types of strategy, so we counted the number of frequencies and performed Fisher’s exact tests in a statistical analysis program called js-STAR (Tanaka & Nakano, 2022) and R studio to answer RQ2. RQ3 was mainly analyzed qualitatively, but Fisher’s exact test was also used. We included data even if no English expression was written for each question because we also counted the frequency of “non-applicable” (NA) in the data analysis. However, three out of 12 questions from one participant, who had lived and worked abroad for over a year, were excluded from the data analysis because he had to complete the experiment in 60 minutes to get compensation from CrowdWorks. In his case, coding his blank cell as NA could distort the relationship between scores and strategies.\n\nThe participants’ individual factors were also sum-coded as follows: English use at work (Yes: 0.5, No: −0.5), work experiences in an English-speaking country (Yes: 0.5, No: −0.5), self-reported English proficiency (Native: 1, Advanced: 2, Upper intermediate: 3, Intermediate: 4, Beginner or lower intermediate: 5, Limited: 6).\n\n\nResults\n\nIn this section, we report on our analysis of which factors influenced the pragmatic scores. As Table 2 and Figure 1 indicate, the mean scores were consistent for the speech act types, although refusals was the lowest and request was the highest.\n\nFollowing Taguchi’s (2022) analytical framework, we counted the number of strategies for each speech act. There were generally three requesting strategies, and the generalized linear mixed model (GLMM) using the Poisson distribution was fit by maximum likelihood (Laplace approximation). The best-fitting model included the following fixed effects: the number of main strategies, the number of modifications, self-reported English proficiency, and experience working overseas. Random effects included both participants and items, and a random slope of English use at work was applied to the participant data. The best-fitting model was\n\nIt was shown that the number of main strategies (β=0.22, SE=0.07, z=3.33, p<0.001) and that of modifications (β=0.11, SE=0.03, z=3.87, p<0.001) significantly improved the pragmatic score. However, neither the experience of working overseas nor the self-reported English proficiency significantly affected the score.\n\nApology was assessed using three questions, and the pragmatic score was modeled using the GLMM. Since this speech act did not have a framework of modifications, the fixed effects in the best-fitting model contained the number of main strategies, self-reported English proficiency, and experience working overseas. Random effects included both participants and items, and a random slope of English use at work was applied to the participant data. The best-fitting model was\n\nIt was shown that an increase in the number of main strategies significantly increased the pragmatic score (β=0.25, SE=0.05, z=5.44, p<0.001). Experience working overseas did not significantly affect the score. The advanced and beginner/lower intermediate groups showed a significant difference in English proficiency.\n\nRefusals included frameworks of main strategies and modifications, so the frequencies of these strategies were counted and included in the GLMM. The best-fitting model was quite similar to that of the model for requests:\n\nAn increase in the number of main strategies led to higher pragmatic scores (β=0.53, SE=0.10, z=5.36, p<0.001), and this was also the case for the number of modifications (β=0.11, SE=0.04, z=3.00, p=0.003). In this model, those who had experience working in a foreign country had significantly higher scores than those without such experiences (β=0.16, SE=0.08, z= 2.03, p=0.004); however, English proficiency was not a significant fixed effect.\n\nFinally, advice giving strategies were analyzed using the framework of the main strategies only. The best-fitting model was quite similar to that for apology:\n\nThe number of main strategies was the only significant factor that improved the pragmatic scores (β=0.83, SE=0.12, z=6.67, p<0.001), while other fixed effects were not significant.\n\nIn sum, the more main strategies speakers use, the more appropriately the speech acts sound in English. This tendency was confirmed regardless of the speech act. Only refusals showed a significant fixed effect of overseas work experience. This means that Japanese speakers learn how to appropriately refuse someone’s request in English by living and working abroad.\n\nIn this section, we scrutinize the relationship between the pragmatic scores and the strategies used in each question. Since the number of categories differs depending on the speech act, we analyzed the data for each speech act.\n\nRequests\n\nRequesting strategies outlined in Q1, Q2, and Q6 were coded from the main strategies and modifications. Table 3 and Figure 2 show the relationship between pragmatic scores and the main strategies used in requests. Furthermore, Table 4 and Figure 3 represent the relationship between pragmatic scores and modifications in requests made.\n\nThe Fisher’s exact test results were significant (p=0.0005 [main strategies]/p=0.0005 [modifications]), indicating that each score group used different strategies. The post hoc analysis with Bonferroni’s adjustment showed that, as the main strategies, those who scored 6 used Strategy 9 (mitigated expressions) more frequently more than the expected value (z=4.58, adjusted p=0). Those who scored 3 tended to use Strategy 1 (imperative) more than the expected value (z=3.61, adjusted p=0.018). Those who scored 1 did not use any strategies and were categorized as NA, more than the expected value (z=14.89, adjusted p=0), while their use of Strategy 6 (query preparatory) was significantly fewer than the expected value (z=-3.95, adjusted p=0.004). Those with a score of 6, 4, and 3 had fewer NAs than the expected values (z=-3.73, adjusted p=0.011 [Score 6]; z=-3.41, adjusted p=0.038 [Score 4]; z=-3.73, adjusted p=0.011 [Score 3]).\n\nThere was some variation in the use of common strategies depending on the question, but in general, participants with higher scores tended to use more modifications in addition to the main strategy. For Question 1, Strategy 6 (query preparatory) was the most commonly used main strategy overall. This was often combined with Strategy 4 (want statement) for participants scoring 6, Strategy 2 (performative) for participants scoring 3, and Strategy 1 (imperative) for participants scoring 2. Furthermore, the combination of modifications, Strategy 10 (promise) and Strategy 2 (reason), was common for participants with a score of 3 or higher. For Question 2, Strategy 6 (query preparatory) was the most popular among participants with a score of 5 or 6, while participants with a score of 6 combined this strategy with Strategy 5 (direct question) or Strategy 9 (mitigated expression). Participants with a score of 3 tended to use Strategy 1 (hedging), while participants with a score of 2 tended to use Strategy 5 (direct question). Higher-scoring individuals tended to combine a variety of modifications in addition to main strategies. Participants with a score of 5 used Strategy 2 (reason), Strategy 3 (apology), and Strategy 4 (preparator), while participants with a score of 6 combined the above strategies with Strategy 7 (minimizer) and Strategy 13 (attention getter). Participants with scores under 4 tended to use fewer modification strategies; however, participants with a score of 3 were found to prefer Strategy 13 (attention getter), while participants with a score of 2 were more likely to either use Strategy 4 (preparator) or no modification strategy at all. Finally, for Question 6, participants scoring 3 and 4 used both Strategy 4 (want statement) and Strategy 6 (query preparatory) for their main strategies. Participants who scored 5 varied too greatly for the measurement of any trends but participants who scored 6 used Strategy 6 (query preparatory). Participants scoring 3 or more used Strategy 2 (reason). Participants scoring 3 and 5 also used Strategy 3 (apology) as modifications, while participants scoring 6 used Strategy 4 (preparator) and Strategy 9 (question). Participants scoring 3 or 4 used Strategy 8 (external “please”), while participants scoring 3 had the tendency to not use any modifications as well. Individuals with lower scores tended to use fewer strategies. For Questions 1 and 2, participants with scores of 1 unanimously used no strategies at all, while participants who scored 2 or lower tended not to use any main strategies or modifications for Question 6.\n\nApology\n\nApology in Q5, Q7, and Q10 were coded from the main strategies only. Table 5 and Figure 4 show the relationship between pragmatic scores and the main strategies used in apology.\n\nFigure 4 indicates that Strategy 1 (apology) and Strategy 3 (explanation) were extensively used, especially by those who scored 4. Although Fisher’s exact test scores confirmed that the score groups and strategies used were significantly different (p=0), the post hoc analysis with Bonferroni’s adjustment showed that those who scored 5 used Strategy 4 (compensation) more than the expected value (z=3.59, adjusted p=0.013). Although no other score groups revealed statistically more frequent use from the overall analysis, those who scored 6 used Strategy 4 (compensation) significantly more than the expected value (z=3.57, adjusted p=0.001) in Q7 and Strategy 5 (promise for the future) (z=3.31, adjusted p=0.033) in Q10. As with other speech acts, the number of NA was significantly higher for those who scored 1.\n\nRefusals\n\nRefusal strategies in Q3, Q8, and Q9 were coded from the main strategies and modifications. Table 6 and Figure 5 show the relationship between pragmatic scores and main strategies, and Table 7 and Figure 6 show the relationship between pragmatic scores and modifications used in refusals.\n\nFisher’s exact test results showed that the score groups and main strategies had a significant difference in refusals (p=0.0005). As with other speech acts, the main strategies implemented varied according to the questions. The post hoc test with Bonferroni’s adjustment showed that those who scored 3 showed significantly greater usage of Strategy 4 (indefinite reply) than the expected value (z=4.25, adjusted p=0.001) in Q3. In Q8, those who scored 6 frequently used Strategy 9 (Alternative), (z=4.31, adjusted p=0). For all questions, those who scored 1 had an NA significantly greater than the expected value. Although Figure 3 indicates that Q3 saw Strategy 5 (excuse) used the most for respondents that scored 3 or higher, this was not supported by the post hoc analysis with Bonferroni’s adjustment. Likewise, Question 8 saw Strategy 2 (negative willingness/ability) as the most commonly used main strategy for responses that scored 2–5 while Strategy 1 (non-performative “no”) was used for respondents that scored 3, 4, and 6. Q9 saw Strategy 8 (avoidance) used most for scores of 3 and higher, while responses that scored 5 and 6 also used Strategy 9 (Alternative). However, these differences were not statistically significant.\n\nRegarding modifications, the overall analysis showed that the score group and strategy used were significantly different (p=0.0005). When we conducted the Fisher’s exact test for each question, those who scored 3 showed significantly greater use of Strategy 4 (apology) than the expected value (z=4.25, adjusted p=0.001) in Q3.\n\nThe common modifications to Q8 were Modification 4 (indefinite reply) and Modification 5 (reason) for scores of 3, 4, and 6. The most commonly used modification for Q9 was Modification 5 (reason) for responses that scored 3 or higher, while responses that scored 6 also used Modification 1 (positive comment). As with other speech acts, responses that scored 1 or 2 tended not to use any main strategies or modifications, which was supported statistically.\n\nAdvice giving\n\nAdvice giving in Q4, Q11, and Q12 was coded from the main strategies only. Table 8 and Figure 7 show the relationship between the pragmatic scores and strategies used in advice giving.\n\nFisher’s exact test confirmed that the score groups significantly differed in strategy use in advice giving (p=0). The post hoc test with Bonferroni’s adjustment showed that those who scored 6 used Strategy 3 (indirect) (z=3.30, adjusted p=0), those who scored 5 had Strategy 2 (softened) (z=3.67, adjusted p=0.005), and those who scored 3 used Strategy 1 (direct) (z=4.56, adjusted p=0) significantly more than the expected value, respectively. The frequent use of Strategy 1 by those who scored 3 was statistically significant only for Q11 (z=3.15, adjusted p=0.039). As with other speech acts, those who scored 1 showed significantly more NAs, regardless of questions.\n\nIn this section, we focus on 30 participants who had worked overseas and analyze their survey responses by classifying the countries in which they worked into the Three Circle Model of World Englishes by Kachru (2019): (a) Inner Circle, such as America and the UK, (b) Outer Circle, such as Philippines and Singapore, and (c) Expanding Circle, such as China and (South) Korea.\n\nThe first survey question asked if they had ever faced difficulties communicating with colleagues who had cultural and linguistic differences. Of the 30 participants with experience working overseas, 21 (70%) responded “Yes,” while 9 (30%) responded “No.” They also gave examples of such challenges, and their open-ended responses were categorized as (a) word choice, (b) direct/indirect expressions, (c) understanding jokes and implicatures, (d) accent or intonation, and (e) others. (a) Lack of word knowledge was reported by both those who worked in Inner Circle countries and those who worked in Outer/Expanding Circle countries. Specifically, the participants felt difficulty if Japanese expressions did not have equivalent ones in English. Subtle differences in nuance were also highlighted by both participants who had worked in Inner Circle countries and those who had worked in Outer/Expanding Circle countries. Next, (b) direct/indirect expressions were mentioned by three participants who had worked in Inner Circle countries. Two participants experienced language breakdowns, which were caused by their periphrastic utterances. They represented politeness in Japanese but were not understood by their colleagues. Another participant unnecessarily downgraded himself when he asked his colleague to do something so that he would not make his colleague uncomfortable. As a result, his colleague wondered if the participant was bullied in the workplace. Two participants who worked in Outer/Expanding Circle countries also mentioned (b) direct/indirect expressions. One intentionally used direct expressions to avoid a misunderstanding, but she felt that she was being impolite in that moment. Another participant was puzzled when workers estimated their own skills/knowledge. She stated as follows:\n\nJapanese people tend to underestimate their own skills, so they are often unassertive, even when we are confident with a certain task. In contrast, some people tend to overestimate their skills and say, ‘I can do it!’ with confidence. Such cultural and linguistic differences can cause difficulty in estimating who can do a certain task and to what extent.\n\n(c) Understanding jokes and implicatures was also highlighted by two participants who had worked in both Inner and Outer/Expanding Circle countries. Although this is not the focus of this study, four of 21 participants who experienced difficulties listed (d) accentedness. (e) Others highlighted the timing of turn-taking and perceptions toward Japan and the Japanese people.\n\nThe second question asked what types of strategies the participants used to avoid miscommunications with colleagues from different backgrounds. This question had the following answer options, and the participants were able to choose all the options that applied to them. The results are shown in Table 9 and Figure 8.\n\nThe Fisher’s exact test results showed that there was no significant difference in frequency (p=0.662). There is a possibility that increasing the number of participants who have worked overseas will reveal differences in intentional strategy use.\n\nThe final survey question asked what participants believed was necessary to work abroad. The responses did not differ regardless of whether they had worked in Inner Circle or Outer/Expanding Circle countries. Communicating with local associates, which does not necessarily mean language proficiency, was evaluated by ten participants, and understanding of religions and cultures was also mentioned by eight participants. People might assume that English proficiency is the key to success when working overseas, but less than half of the participants who had worked overseas (eight out of 30) mentioned English proficiency regardless of where they worked. Four participants claimed that fluent English is not required to work abroad. Eight participants believed that being flexible and tough is crucial, and two insisted that having special knowledge is more important than language skills because such specializations can mitigate language deficiencies.\n\n\nDiscussion\n\nThe purpose of this study was to examine the pragmatic strategies produced by Japanese employees who use English at work. We focused on four speech acts: requests, apologies, refusals, and advice giving. The relationship between pragmatic scores and strategies was scrutinized quantitatively and qualitatively. Here, we summarize our findings with reference to the RQs.\n\nRegarding RQ1 (What influences the pragmatic score more: frequency of strategy use or individual difference factors?), we found that those who obtained higher pragmatic scores tended to use more than one main strategy and multiple modifications regardless of the speech act type. In other words, speakers attempt to explain, make positive comments, use mild expressions, and produce a certain speech act clearly. The impact of the experience of working overseas was not as large as expected, but it affected the pragmatic scores of refusals. English proficiency partially affected the production of apologies. How often the participants encountered each situation was not a significant factor.\n\nAs for RQ2 (What types of pragmatic strategies lead to higher pragmatic scores?), the use of indirect strategies was key. In requests, many participants asked, “Could you … ?” (Query Preparatory). Whether they obtained a high score of 5 or 6 depended on whether they also had sufficient context for the request act, such as explaining the reason the speaker would like the addressee to do something and promising that it would lead to a positive result. Only those who marked the full score tended to use mitigated expressions (e.g., “I'm wondering if …”). Direct strategies, such as the use of imperatives (e.g., “Please answer …”), did not lead to higher scores, and many who used this strategy obtained a score of 3. In an apology, the use of an apology and reason was popular across the score groups. However, those who obtained a score of 5 or 6 tended to use remuneration in addition to apology-related expressions. Refusals were the most difficult speech act for the individuals in this study, and those who scored a score of 3 tended to use an apology (e.g., “Sorry”) without clearly refusing. In contrast, those who obtained a higher score used an alternative, such as offering another day. Advice giving showed a clear distinction among the score groups. Those who garnered a score of 6 frequently used the Indirect strategy, those who scored 5 used the softened strategy, and those who scored 3 extensively used direct expressions.\n\nConcerning RQ3 (What perceptions do Japanese workers who have been employed in foreign countries have toward the intercultural workplace communication?), we targeted 30 people with experience working overseas. There was no statistical disparity depending on where they worked, but qualitative analyses indicate that there were some distinctions regarding directness that were noticed between Japanese participants who worked abroad in Western contexts where English was likelier to be the sole language, unlike participants who worked in Asian contexts where multiple languages were likely to be utilized. Japanese participants who worked in Western contexts tended to use indirect strategies with longer responses and multiple strategies and modifications. Conversely, Japanese participants who worked in Asian contexts tended to utilize shorter responses with more direct approaches and fewer strategies.\n\nNewton and Kusmierczyk (2011) mentioned, “Choosing an appropriate level of directness in status-differentiated interactions involving requests and refusals or participating in small talk requires sensitivity to cross-cultural differences in the way talk functions in different work settings” (p. 81). Building on this and other previous research, it could be argued that the level of directness used is a sociopragmatic skill that might have varying approaches depending on the cultural context in which English is employed. Thus, when considering these disparities, we can only consider that overly direct short responses with fewer strategies employed might not be sufficient in a native-speaker context.\n\nAlthough we have discussed general tendencies, there were some variations within the speech acts. For example, in requests, Strategy 6 (query preparatory) was the most frequently used main strategy for subjects, with a score of 5 or 6 in Q1 and Q2. Nevertheless, this strategy was not used in Q6 compared to Q1 and Q2. In addition, Strategy 9 (mitigated expressions) was frequently used for those who scored 6. Participants used this main strategy in Q2, but this strategy was not so common in Q1 and Q6.\n\nSubsequently, we considered the possible reasons why individual difference factors did not affect pragmatic scores compared with the frequency of strategy use. Regarding English proficiency, self-reported proficiency was not as reliable. It was impossible to include a proficiency test in addition to the 12-item DCT within the time limit, which we could post as a task on CrowdWorks. However, it would have been better if we could have included a single proficiency index that accurately measures participants' English proficiency. Regarding the experience of working overseas, the average score of those who had worked overseas was higher than that of those who had never worked overseas. Nonetheless, their work experiences might have correlated with their English proficiency in this study. Even if some companies do not regard workers’ English proficiency as the most significant factor when choosing who should be transferred abroad, it can be one of the indicators of a good candidate. Some participants might have studied English extensively when they were students so they could work overseas in the future. By including two groups with the same English proficiency test scores—one with experience working overseas and the other without such experience—it will be possible to determine if overseas work experience affects the production of speech acts.\n\nAs discussed in the methods section, interrater reliability could be achieved between the two raters. For most participants’ responses, the two raters agreed on the scores to be coded in terms of grammar and social nuance. However, a few differences were observed in scoring methods. The Japanese rater tended to rate some responses slightly more generously by understanding the cultural norms of Japanese workplaces. This is mainly because they could imagine a phrase as a direct translation from Japanese and regarded it as a common expression in Japanese offices, particularly among higher-ranking individuals. The American rater, though, felt that these expressions would not be as widely accepted beyond the scope of Japan, requiring too much understanding of Japanese culture to fit intercultural contexts abroad. Consequently, through discussion and comparisons of these responses, the two raters could agree on appropriate scores that reflected how expressions would be accepted in a wider intercultural context, with consideration to how expressions would be interpreted by a wide range of speakers with different backgrounds, including native English speakers.\n\nThe study had several limitations. First, we collected data through a written DCT, in which subjects wrote down the expressions in a specific task. We selected this method to reach out to many Japanese employees who have worked overseas or those who are currently working abroad. An online survey was necessary to reach out to working adults for a quantitative study. However, as many researchers have claimed (e.g., Ishihara & Cohen, 2022; Taguchi, 2022), data from written DCTs do not necessarily reflect the actual language that participants use. Although spoken DCTs are more challenging for crowdsourcing studies, collecting spoken data is required for future studies. Second, individual difference factors must be controlled for more thoroughly. Some crowdsourcing services abroad specified for research participation (e.g., Prolific, see Palan & Schitter, 2018) have many prescreening options, such as industry, position, and customer service experience. However, we could not filter potential participants from several perspectives in our study. In our research advertisement, we emphasized that we were recruiting people who used English at work and/or people who had experience working overseas. Furthermore, we added an option so 100 potential participants who had English skills would see our research advertisement. Nonetheless, those who were not confident in their English skills also joined our study, and only one-third of the participants had experience working overseas. To confirm the difference between those who have worked in inner circles and those who have worked in outer/expanding circles, more research is necessary to determine whether such responses would be acceptable in Asian contexts. Third, pragmatic factors, such as “power relationship (P),” “social distance (D),” and “degree of imposition (I)” (e.g., Taguchi, 2022), were not thoroughly controlled in this study. It has been illustrated that PDI influences speech act strategies. However, due to the number of factors in this study, we could not include these factors in the research design. It would be desirable to control these levels and examine the relationship between PDI and industry.\n\nDespite the limitations above, we revealed that pragmatic strategies lead to more acceptable speech. We propose the following pedagogical implications based on our findings. First, English teachers in Japan should explicitly explain to students that using direct speech is not always the best choice. Meaning should be conveyed clearly, but there are several ways to show politeness. For example, teachers can notify students that speech acts can be produced appropriately if each main strategy is accompanied by modifications. Successful communication should be addressed as a whole, not just as a sentence. Second, showing sample expressions that can be used in refusing someone’s offer in several contexts would help learners. This is because the comparison between speech act types depicted that requests were the easiest, while refusals were the most difficult. Third, in the EOP context, it would be important to teach not only English expressions but also cultural disparities. For example, if the learner were to work in a country where offering compensation in an apology is regarded as inappropriate, he/she should follow the custom. Additionally, one expression can be offensive if a subordinate produces it to a boss, even if the opposite is acceptable. Such knowledge is useful for Japanese employees who work abroad and for multicultural corporations.\n\nWe scrutinized the pragmatic strategies produced by Japanese employees. Some people in Japan might believe we must be direct when we communicate with people in other countries in English, but direct strategies were mostly found in those who scored 3 and 4, not those who scored 5 and 6. In other words, to mark the full score, speakers use indirect strategies, softened strategies, and a softening context. We hope that this study sheds light on EOP research for Japanese workers who conduct business in English.",
"appendix": "Data availability\n\nOpen Science Framework: Pragmatics in the Context of English for Occupational Purposes: Speech Acts Produced by Japanese Workers. https://doi.org/10.17605/OSF.IO/TU7CQ (Hijikata, et al., 2022).\n\nThe project contains the following underlying data:\n\n- EOPJscore.csv (Dataset including all raw data).\n\nOpen Science Framework: Pragmatics in the Context of English for Occupational Purposes: Speech Acts Produced by Japanese Workers. https://doi.org/10.17605/OSF.IO/TU7CQ (Hijikata, et al., 2022).\n\nThe project contains the following extended data:\n\n- Tables and graphs showing the relationship between scores and strategies.xlsx\n\n- Demographic questionnaire & survey questions.docx\n\n- DCT materials.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\nAchiba M: Learning to request in a second language: A study of child interlanguage pragmatics. 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Retrieved December 10, 2022.Reference Source\n\nFukushima S: Request strategies in British English and Japanese. Lang. Sci. 1996; 18(3/4): 671–688. Publisher Full Text\n\nGilmore A: “I prefer not text”: Developing Japanese learners’ communicative competence with authentic materials. Lang. Learn. 2011; 61(3): 786–819. Publisher Full Text\n\nHaselow A: The acquisition of pragmatic markers in the foreign language classroom: An experimental study on the effects of implicit and explicit learning. J. Pragmat. 2021; 186: 73–86. Publisher Full Text\n\nHijikata Y, Roberts RD, Ueno M:Pragmatics in the context of English for occupational purposes: Speech acts produced by Japanese workers. [Dataset]. Open Science Framework. 2022, October 31. Publisher Full Text\n\nHudson T, Detmer E, Brown JD: Developing prototypic measures of cross-cultural pragmatics. University of Hawai‘i Press;1995.\n\nIshihara N, Cohen A: Teaching and learning pragmatics: Where language and culture meet. 2nd ed.Routledge;2022.\n\nIshihara N, Prado MCDA: The negotiation of meaning in aviation English as a lingua franca: A corpus-informed discursive approach. Mod. Lang. J. 2021; 105(3): 639–654. Publisher Full Text\n\nJebahi K: Tunisian university students’ choice of apology strategies in a discourse completion task. J. Pragmat. 2011; 43: 648–662. Publisher Full Text\n\nKachru BB: World Englishes and culture wars. Cambridge University Press;2019.\n\nKaur J, Birlik S: Communicative effectiveness in BELF (English as a business lingua franca) meetings: ‘Explaining’ as a pragmatic strategy. Mod. Lang. J. 2021; 105(3): 623–638. Publisher Full Text\n\nKubota R, Takeda Y: Language-in-education policies in Japan versus transnational workers’ voices: Two faces of neoliberal communication competence. TESOL Q. 2021; 55: 458–485. Publisher Full Text\n\nMatsumura S: Modelling the relationships among interlanguage pragmatic development, L2 proficiency, and exposure to L2. Appl. Linguis. 2003; 24(4): 465–491. Publisher Full Text\n\nMinistry of Foreign Affairs of Japan: Kaigai zairyu hojinsu chosa tokei [statistics on the number of Japanese citizens who stay abroad].2022a.Reference Source\n\nMinistry of Foreign Affairs of Japan: Kaigai shinsyutsu Nikkei kigyo kyotensu chosa [Investigation on the number of Japanese companies which operate overseas].2022b.Reference Source\n\nNewton J, Kusmierczyk E: Teaching second languages for the workplace. Annu. Rev. Appl. Linguist. 2011; 31: 74–92. Publisher Full Text\n\nPalan S, Schitter C: Prolific.ac. – A subject pool for online experiments. J. Behav. Exp. Financ. 2018; 17: 22–27. Publisher Full Text\n\nPang P: Directives in professional kitchens and potential learning opportunities. Appl. Linguis. 2019; 40(5): 754–772. Publisher Full Text\n\nPark S, Jeon J, Shim E: Exploring request emails in English for business purposes: A move analysis. Engl. Specif. Purp. 2021; 63: 137–150. Publisher Full Text\n\nPrado MCA, Tosqui-Lucks P: Designing the Radiotelephony Plain English Corpus (RTPEC): A specialized spoken English language corpus towards a description of aeronautical communications in non-routine situations. Research in Corpus. Linguistics. 2019; 7: 113–128. Publisher Full Text\n\nTaguchi N: Immersive virtual reality for pragmatics task development. TESOL Q. 2022; 56(1): 308–335. Publisher Full Text\n\nTaguchi N, Kim Y: Collaborative dialogue in learning pragmatics: Pragmatic-related episodes as an opportunity for learning request-making. Appl. Linguis. 2016; 37(3): 416–437. Publisher Full Text\n\nTaguchi N, Roever C: Second language pragmatics. Oxford University Press;2017.\n\nTaguchi N, Xiao F, Li S: Effects of intercultural competence and social contact on speech act production in a Chinese study abroad context. Mod. Lang. J. 2016; 100(4): 775–796. Publisher Full Text\n\nTakahashi S: The effects of learner profiles on pragmalinguistic awareness and learning. System. 2015; 48: 48–61. Publisher Full Text\n\nTakahashi S: Noticing in task performance and learning outcomes: A qualitative analysis of instructional effects in interlanguage pragmatics. System. 2005; 33(3): 437–461. Publisher Full Text\n\nTakahashi T, Beebe LM: The development of pragmatic competence by Japanese learners of English. JALT Journal. 1987; 8(2): 131–155.\n\nTanaka S, Nakano H: Js-STAR XR+ release 1.3.0j.2022.Reference Source\n\nTarone E:English for specific purposes and interlanguage pragmatics.Bardovi-Harlig K, Hartford BS, editors. Interlanguage pragmatics. Routledge;2008; (pp. 157–173).\n\nTatsuki DH, Houck NR:Pragmatics from research to practice: Teaching speech acts.Tatsuki DH, Houck NR, editors. Pragmatics: Teaching speech acts. TESOL Press;2010; (pp. 1–6).\n\nYates L, Springall J:Soften up! Successful requests in the workplace.Tatsuki DH, Houck NR, editors. Pragmatics: Teaching speech acts. Teachers of English to Speakers of Other Language;2010; (pp. 67–86)."
}
|
[
{
"id": "161133",
"date": "07 Mar 2023",
"name": "Yasuo Nakatani",
"expertise": [
"Reviewer Expertise Applied linguistics and business communication strategies"
],
"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 paper has reviewed very carefully about second-language (L2) pragmatics for second-language acquisition. To date, there is little research which examined how native speakers’ (NS) norm applied into English for occupational purposes (EOP) for Non-native speakers (NNS). This paper explored how pragmatics plays an important role in workplace communication between Japanese workers and NSs. In particular, authors revealed how appropriately the participants can produce speech acts of request, apology, refusal, and advice-giving, and what factors affect their performances. They used relevant pragmatics scores to investigate how the participants use the strategies.\n\nThere were 92 Japanese workers who provided the projects. They answered demographic questions and reported a written discourse completion task. The participants experienced the twelve tasks including four speech acts: request, apology, refusal, and advice-giving. During the tasks, they wrote down the English expression they would offer in response. These replies were graded with a six-point rating rubric and coded using the strategy framework.\nThe results indicated that the participants’ multiple strategy usages influenced the pragmatics scores in any case of the type of speech act. Higher score participants tended to use multiple strategies, and not only main strategies but also modifications. Their English proficiency level had significant effects on how they offer an apology, while participants’ experiences of working abroad affected how they expressed refusal. Japanese workers who obtained higher scores tended to use indirect pragmatics strategies and also modified their strategy use.\nIts research design is very good. Data collection and analyzing methods are relevant. It has enough discussion for its findings.\n\nThis paper surely contributes to this research field.\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": "9479",
"date": "23 Mar 2023",
"name": "Yuko Hijikata",
"role": "Author Response",
"response": "Dear Prof. Nakatani, Thank you so much for your comment. We are glad to receive encouraging feedback from you. We are going to revise our paper to present more details and hope you have another chance to read our study. Once again, thank you very much for your time and kindness."
}
]
},
{
"id": "161131",
"date": "14 Mar 2023",
"name": "Jihyeon Jeon",
"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 how appropriately Japanese workers can produce speech acts of request, apology, refusal, and advice-giving, and what factors affect their performances.\nIt was very interesting to see how the author combined the quantitative and qualitative method in this research to address an important topic, including the relationship between the pragmatic score and various factors (individual factor, strategies, frequency of strategy). If modified appropriately, the study will be beneficial to the readers interested in English of Occupational Purposes research.\nPlease see below for my suggestions to improve the article. Page numbers refer to the pdf version of the article.\n\nIntroduction:\nThe second paragraph on p3:\nYou need a stronger support for the need for this study. You may show the small number of studies on adult learners relatively less studied by adding a sentence that between the sentence ‘Many previous studies investigating L2 pragmatic development had younger participants ranging from children to university students (e.g., Achiba, 2003; Bella, 2012; Haselow, 2021; …’ and the sentence ‘However, L2 pragmatics is especially difficult for adult learners because they (a) lack grammatical knowledge and vocabulary and/or (b) are not aware of which form is pragmatically appropriate and when it can be used (Yates & Springall, 2010).’\n\nPlease see below for some articles on adult learners:\nHo, V. (2018). Using metadiscourse in making persuasive attempts through workplace request emails. Journal of Pragmatics, 134, 70-81.1\nLi, D. (2000). The pragmatics of making requests in the L2 workplace: A case study of Language socialization. Canadian Modern Language Review, 57(1), 58-87.2\nSpencer-Oatey, H. (2010). Intercultural competence and pragmatics research: Examining the interface through studies of intercultural business discourse. Pragmatics across language3\nThe third & fourth paragraph on p3 (L2 pragmatics and speech acts):\nThe author used the expression ‘the most’ three times here. A careful look at the reference is needed. Cohen (2020) expressed “ While numerous studies have been conducted on requesting behavior, as well as a fair number on apologizing, complaining, complimenting, thanking, and greeting, there is still much of speech act performance that has not been adequately researched (p.185).”\n\nThe author cited Cohen (2020) 5 times here. Please consider looking at other references on DCT like below.\nKasper, G. (2000). Data collection in pragmatics research. In H. Spencer-Oatey (Ed.), Culturally Speaking: Managing rapport through talk across cultures (pp. 316-369). London: Continuum.4\nEconomidou-Kogetsidis, M. (2013). Strategies, modification and perspective in native speakers’ requests: A comparison of WDCT and naturally occurring requests. Journal of Pragmatics, 53, 21-38.5\n\nPlease make the logical connection tighter for the following sentences.\n\"While several researchers have criticized written DCTs because they lack authenticity and it is not clear if the participant would really speak in a particular way in the real situation (e.g., Taguchi & Roever, 2017), some researchers use them in addition to other assessments (e.g., Gilmore, 2011). However, DCTs have strengths in terms of their practicality and ease of use in data collection (Cohen, 2020).\"\nIn the fifth paragraph on p3 (L2 pragmatics and cross-cultural differences):\n\"Specifically, the number of L2 pragmatics studies in the context of English as a lingua Franca (ELF) has been increasing\"\nYou need a citation for this statement. You might consider looking at the following references.\nAllami, H., & Naeimi, A. (2011). A cross-linguistic study of refusals: An analysis of pragmatic competence development in Iranian EFL learners. Journal of pragmatics, 43(1), 385-406.6\nChang, Y. F. (2009). How to say no: An analysis of cross-cultural difference and pragmatic transfer. Language Sciences, 31(4), 477-493.7\nMcConachy, T. (2019). L2 pragmatics as ‘intercultural pragmatics’: Probing sociopragmatic aspects of pragmatic awareness. Journal of Pragmatics, 151, 167-176.8\n\n\"Recent empirical studies have verified the positive effect of studying abroad on L2 pragmatic learning (e.g., Alcón-Soler, 2015; Cohen & Shively, 2007; Taguchi et al., 2016)\"\nYou may delete the reference Cohen & Shively, 2007 or add the following reference.\nVidal, C. P., & Shively, R. L. (2019). L2 pragmatic development in study abroad settings. In The Routledge handbook of second language acquisition and pragmatics (pp. 355-371). Routledge.[ref-9}\nIn last two paragraphs on p3:\nThe author wrote about Pragmatics in English for occupational purposes. The difference between EOP and EBP needs to be further elaborated. You may add a critical review on the studies on EOP rather than simply listing them.\np4:\nResearch on Japanese transnational workers’ communicative competence and belief was well presented.\nMethods\nThe ethics statement on p5:\nThe writing is detailed enough to allow other researchers to replicate the study.\nThe participants on p5:\n\"The second one is that CrowdWorks can send our call to 100 potential participants who have specific qualifications as the optional service.\"\nYou may delete this sentence because the support was already done by the previous studies.\n\n\"The EIKEN grades, except Grade four, can be mapped with CEFR as follows (Eiken Foundation of Japan, 2022): Grade one is mapped to B2 and C1, Grade pre-one is mapped to B1 and B2, Grade two is mapped to A2 and B1, Grade pre-two is mapped to A1 and A2, and Grade three is mapped to A1.\"\nThe participants’ English ability can be presented in a table for easier reading.\np5:\n\"We developed and conducted a written DCT based on one of the authors’ own experiences working abroad. Twelve situations that could occur in workplaces were written in Japanese. Here is one example:\"\nCan there be other supports other than the author’s own experiences?\n\n\"The DCT included speech acts of requesting, advice giving, apologizing, and refusals. Each speech act featured three situations, and the presentation order was randomized using Excel for Microsoft 365\"\nYou may elaborate further on the reasons for choosing the particular speech acts (requesting, advice giving, apologizing, and refusals) for this study.\n\np6: Grading and coding:\nThe speech acts produced were graded using rating scales contextualized by three perspectives: whether the expressions were appropriate in each context, if communication was clear, and whether each response was grammatically accurate as a whole (Taguchi et al., 2016). Possible scores were 1–6.\nIt would be interesting to see a discussion here on the differences in the ratings on the appropriateness, clarity, and grammatical accuracy. The ratings can be affected by the cultural background. See the references below for the perceptual difference. Discussion on intercultural aspects would be very interesting rather than focusing on the pragmatic norms set up from the native speakers’ view.\nEconomidou-Kogetsidis, M. (2016). Variation in evaluations of the (im)politeness of emails from L2 learners and perceptions of the personality of their senders. Journal of Pragmatics, 106, 1-19.10\nIde, S., Hill, B., Carnes, Y. M., Ogino, T., & Kawasaki, A. (2019). 11. The concept of politeness: An empirical study of American English and Japanese. In Politeness in language (pp. 281-298). De Gruyter Mouton.11\nLi, W. J., & Chen, Y. S. (2016). Politeness and effectiveness of English email requests: Taiwanese professors’ perspectives. Email discourse among Chinese using English as a lingua franca, 91-111.12\nSavić, M. (2018). Lecturer perceptions of im/politeness and in/appropriateness in student e-mail requests: A Norwegian perspective. Journal of Pragmatics, 124, 52-72.13\nIn the Strategies section on p 7:\nparagraph 2: \"(6) Japanese-like, with the discourse strongly affected by the Japanese style.\"\nparagraph 3: \"(11) Japanese-like\"\nPlease consider adding examples for these.\nResults:\np8-9:\nIt would be interesting to see the relationship between the details of the pragmatic scores (Appropriateness, Clarity, and Grammatical accuracy separately) and the strategies.\nTable 3-7 on p10-17:\nTable 3 to 7 seem too basic!\nTo reduce the space and to present meaningful results, you may consider categorizing the participants by their pragmatic scores (High/Low or High/Mid/Low) and see the group difference of the strategy use. It would be interesting to see what participant group uses more strategies. Just by glancing the raw tables in the current manuscript, there could be a tendency that mid group uses more strategies than the Low or the High group.\nDiscussion:\np19:\nSummary of finding paragraph 5: \"Building on this and other previous research...\"\nIt seems necessary to discuss the results of this study in connection with previous studies. Citations are needed for the yellow highlight.\n\nYou might need to see the following articles on Japanese workers:\nCrawford Camiciottoli, B. (2020). Using English as a lingua franca to engage with investors: An analysis of Italian and Japanese companies’ investor relations communication policies. English for Specific Purposes, 58, 90-101.14\nChen, H. J., Cramer, P. K., & Kojima, T. (1996). Japanese and American Cross-Cultural Business Pragmatics: A Study.15\nLee, H. E., Park, H. S., Imai, T., & Dolan, D. (2012). Cultural differences between Japan and the United States in uses of “apology” and “thank you” in favor asking messages. Journal of Language and Social Psychology, 31(3), 263-289.16\nOhashi, J. (2003). Japanese culture specific face and politeness orientation: A pragmatic investigation of yoroshiku onegaishimasu. Multilingua, 22(3), 257-274.17\np20:\nOn Rating perspective between Japanese and American teachers of English\nSpencer-Oatey, H., & Xing, J. (2019). Interdisciplinary perspectives on interpersonal relations and the evaluation process: Culture, norms, and the moral order. Journal of Pragmatics, 151, 141-154.18\nWinans, M. (2020). Email requests: Politeness evaluations by instructors from diverse language backgrounds. Language Learning & Technology, 24(2), 104-118.\np20: Limitations and directions for future studies\nThird, pragmatic factors, such as “power relationship (P),” “social distance (D),” and “degree of imposition (I)” (e.g., Taguchi, 2022),\nYou might consider citing Brown & Levinson (1987)\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": "9480",
"date": "23 Mar 2023",
"name": "Yuko Hijikata",
"role": "Author Response",
"response": "Dear Prof. Jeon & Ms. Park, Thank you so much for your useful and detailed comments. We found all of your comments very helpful in revising our paper. According to your suggestions, we are going to take a close look at our data and would greatly appreciate it if you would kindly read our paper again in the near future. Once again, thank you very much for your time and insightful comments."
}
]
}
] | 1
|
https://f1000research.com/articles/12-81
|
https://f1000research.com/articles/11-1203/v1
|
21 Oct 22
|
{
"type": "Study Protocol",
"title": "Epidemiology of pediatric schistosomiasis in hard-to-reach areas and populations: A scoping review protocol",
"authors": [
"Phyllis Munyiva Isaiah",
"Marta Sólveig Palmeirim",
"Peter Steinmann",
"Marta Sólveig Palmeirim",
"Peter Steinmann"
],
"abstract": "Background: Schistosomiasis is a neglected tropical disease (NTD) that affects millions of people. Children are the most vulnerable group to developing overt disease. An estimated 779 million people are at risk of schistosomiasis and 50 million preschool-age children (PSAC) need treatment. PSAC are not currently targeted by national chemotherapy campaigns due to a lack of suitable pediatric formulations of praziquantel. The Pediatric Praziquantel Consortium has developed an orally dispersible praziquantel formulation (arpraziquantel) and is facilitating its adoption for schistosomiasis control by endemic countries through the ADOPT program – an implementation research program that paves the way for the large-scale delivery of the child-friendly formulation to treat schistosomiasis in preschool-aged children in endemic countries. A key challenge for comprehensive NTD control including schistosomiasis is reaching all at-risk populations, including those hard to reach. Main access barriers include geographic, social and economic conditions. Objective: This scoping literature review aims to document the epidemiology of schistosomiasis in children under 6 years of age living in hard-to-reach areas and populations. Methods: This review will adopt the five-stage scoping review process of identifying the research question, identifying relevant studies, study selection, charting data and collating, summarizing and reporting results. Electronic databases including Medline, Web of Science, Embase (Ovid), LILACS and African Journals OnLine (AJOL) will be searched for relevant articles. Two independent reviewers will screen identified articles using a two-stage approach of reviewing the title/abstract and then the full text of provisionally retained articles. Relevant literatures will be downloaded into EndNote X9 to maintain and manage citation and facilitate the overall review process. A meta-analysis will be conducted if indicated. Relevance: The results will provide insights into the burden of schistosomiasis among marginalized PSAC, aiming to produce evidence on the need for inclusion of this population when designing the expansion of preventive chemotherapy programs.",
"keywords": [
"Schistosomiasis",
"Prevalence",
"Epidemiology",
"Pre-School Aged Children",
"Pediatric",
"Hard-to-reach",
"Praziquantel"
],
"content": "Abbreviations and acronyms\n\nDALYs: Disability-Adjusted Life Years\n\nNTD: Neglected Tropical Disease\n\nPSAC: Preschool-aged Children\n\nS. haematobium: Schistosoma haematobium\n\nS. mansoni: Schistosoma mansoni\n\nSAC: School-aged children\n\nSDG: Sustainable Development Goal\n\n\nIntroduction\n\nSchistosomiasis is a neglected tropical disease (NTD) that affects millions of people worldwide. It is estimated that 779 million people are at risk of developing this disease.1,2 Children are the most vulnerable group to developing overt disease with 50 million preschool-age (PSAC) children in need of treatment.3 Adults are most affected by the consequences of chronic infection.4 Schistosomiasis is cause by an infection with a Schistosoma species parasite.5 There are several species, the most common being S. mansoni and S. haematobium. In a human host, the adult parasites release eggs into the environment through faeces (S. mansoni) and urine (S. haematobium). An intermediate host snail living in stagnant water is involved in the transmission cycle. Human infections take place through skin penetration when in contact with stagnant water where Schistosoma spp. larvae are present. The disease mainly affects the poorest communities without access to safe water and improved sanitation, or exposed to water during occupational and domestic activities.6,7 Symptoms of chronic schistosomiasis include anaemia, cognitive impairment, deficits in linear growth leading to chronic under-nutrition (stunting) as well as acute under-nutrition (wasting),5 genital lesions,8 and irreversible organ damage as a result of fibrosis.9 The morbidity caused by schistosomes is commonly associated with moderate-to-heavy intensities of infection as measured by the density of excreted eggs, and is progressive.10 In addition to these health consequences, schistosomiasis is associated with negative economic and social impacts.11 Estimates indicate that schistosomiasis causes an annual loss of 4.5 million disability-adjusted life years (DALYs).12\n\nAlthough NTD control programs have been established in many endemic countries, the rolling out of schistosomiasis control and elimination components is still limited.13 Periodic deworming with praziquantel, the strategy recommended by WHO for the control of schistosomiasis, is available primarily to school-aged children (SAC; 5-15 years old) who can be reached efficiently through school-based programs.10 In addition to previous studies,14 the 2022 WHO guideline on control and elimination of human schistosomiasis15 has identified important treatment gaps in this strategy, including that infected PSAC are largely left untreated.\n\nThis could be because for a long time the PSAC group has been categorized as a low risk group for schistosomiasis infection16 and its impact on the health of this age group, although unknown, is often considered negligible.17 In addition, logistical and operational difficulties in collecting samples from PSAC for diagnosis, especially in hard-to-reach areas, lack of sensitive diagnostics for light schistosomiasis infections and a paucity of data on risk factors in PSAC have further biased schistosomiasis research to focus on SAC and adults over the years.16 Lastly, current donations of the main drug to treat schistosomiasis – praziquantel – are restricted to SAC.\n\nTreatment equity is not currently achieved for schistosomiasis control as hundreds of millions of the worlds’ most vulnerable, most disadvantaged people, including PSAC, are still left behind. This is true especially for people whose incomes are below the federal poverty threshold, who live in vulnerable social and economic situation such as undocumented persons, socially excluded groups due to language, religious and other societal barriers18 and in the remotest, hardest to reach parts of endemic countries. These hard-to-reach populations are often ethnic minorities, island and fishing communities and migrant populations and other minority or marginalized populations, hindering the attainment of the Sustainable Development Goal (SDG) 3 and the commitment of global leaders to ensure that “no one is left behind” from development progress.7,19\n\nThis scoping literature review aims to document the epidemiology of pediatric schistosomiasis (children under 6 years of age) living in hard-to-reach areas and populations. In this review, hard-to-reach populations are defined following Shaghaghi et al., as: i) migrants/island and fishing communities/nomads, ii) those living in remote physical and geographical location, and iii) those living in vulnerable social and economic situation such as minority groups, undocumented persons, socially excluded groups due to language and religious barriers.18\n\nThe aim is to produce evidence on the need for inclusion of this population when designing the expansion of preventive chemotherapy to also cover those living in hard-to–reach areas. This is in accordance with the WHO guideline of 2022 on control and elimination of human schistosomiasis15 recommendation on expansion of preventive chemotherapy to cover all in need.\n\nThe condition, context, and population (CoCoPop) framework to inform the review objective is shown in Table 1.\n\n\nMethods\n\nThis review will adopt the five-stage scoping review process guideline recommended by Arksey et. al.,20 taking into consideration the modifications recommended by Peters et al.21\n\nEvidence searches\n\nElectronic literature databases including Medline, Web of Science, Embase (Ovid), LILACS and African Journals OnLine (AJOL) will be searched for published scientific studies on pediatric schistosomiasis in hard-to reach areas, using a pre-determined search strategy (Table 2). With the guidance of a librarian (University Medical Library- University of Basel), we first developed and optimized a search strategy for PubMed. This search was then translated using the SR-accelerator tool22 developed by BOND university to generate the equivalent search terms for Embase (Ovid) and Web of Science.\n\nPublished grey literature, WHO literature databases and reports, and documentation obtained from schistosomiasis experts working in relevant organizations such as Kenya Medical Research Institute (KEMRI), Schistosomiasis Control Initiative Foundation (SCIF), Schistosomiasis Consortium for Operational Research and Evaluation (SCORE), the Foundation for Innovative New Diagnostics (FIND), Sight Savers, Hellen Keller and Merck KGaA will also be included in this review. Experts will be actively contacted with an invitation to share relevant documents and references.\n\nAll identified references will be screened independently by two reviewers (Phyllis Munyiva Isaiah and Marta Palmeirim) using a two-stage approach.\n\nFirst, a manual search will be conducted on the initial hit list by reviewing the title and abstracts to identify schistosomiasis studies conducted among PSAC. Second, we will review the full texts of the shortlisted articles to identify studies conducted in hard-to-reach areas and populations.\n\nAdditional references will then be retrieved by manually searching the bibliographies of identified articles. All relevant literatures will be downloaded into EndNote X9 to maintain and manage citation and facilitate the overall review process.\n\nInclusion/exclusion criteria\n\nWe will include cross-sectional, cohort and case control studies on schistosomiasis in children under 6 years old and living in hard-to-reach areas or belonging to hard-to-reach populations. Similar studies done on women of reproductive age and adults; or studies that did not apply cross-sectional or cohort or case control design (e.g. case reports) will be excluded from the review.\n\nReviewers will assess all included studies independently for possible bias by using the Joanna Briggs Institute (JBI) Prevalence Critical Appraisal Tool.23 All selected studies will be assessed using the 10 quality control items suggested by the tool. A score of 1 will be awarded for each item fulfilled while a 0 score will be awarded for each unfilled control item. Score aggregates will then be generated and converted into a low, moderate and high quality classification.24 Poor quality studies will be excluded, clearly documenting the reason for exclusion.\n\nData will be extracted from included documents and exported to a predefined summary template in Microsoft excel 2016. Extracted data will include:\n\ni. Bibliographic information (first author, journal/document, year of publication)\n\nii. Year and country of study\n\niii. Sample size\n\niv. Study population age and sex\n\nv. Prevalence and/or incidence of schistosomiasis\n\nvi. Mean eggs per gram of feces or infection intensity classification (if available)\n\nvii. Specific schistosome species observed\n\nviii. Diagnostic method\n\nix. Type of hard-to-reach population/area\n\nExtracted data will be analyzed using IBM SPSS statistics V.24. Descriptive statistics will be performed to allow for narrative synthesis. Weighted population mean outcomes will then be calculated for prevalence among PSAC.25 To calculate pooled prevalence estimates (PPE), the inverse variance heterogeneity (IVhet) model26 in MetaXL will be used for the selected studies, to ensure that statistical error is not underestimated.24 The level of heterogeneity on selected studies will be evaluated using Cochran’s Q and I2 statistics. This will be done by stratifying our data according to schistosomiasis prevalence and the region where the studies were conducted to determine heterogeneity between subgroups and within-groups.24 Forest plots will be used to show the estimated prevalence (95% confidence interval).\n\nAll findings will be published in a scientific article in a peer reviewed journal. The findings of this review will be reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses–Extension for Scoping Reviews (PRISMA –ScR) guidelines.\n\nElectronic databases have been searched using the above-mentioned search strategy for articles. The reviewers are currently screening the articles for duplicates.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "Acknowledgments\n\nWe acknowledge Dr. Thomas Fürst (University Medical Library- University of Basel) for his input and guidance in developing and optimizing search strategies used in this review.\n\n\nReferences\n\nSteinmann P, et al.: Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect. Dis. 2006; 6(7): 411–425. PubMed Abstract | Publisher Full Text\n\nUtzinger J, et al.: Schistosomiasis and neglected tropical diseases: towards integrated and sustainable control and a word of caution. Parasitology. 2009; 136(13): 1859–1874. PubMed Abstract | Publisher Full Text\n\nOrganization WH: Report of a meeting to review the results of studies on the treatment of schistosomiasis in preschool-age children.2011.\n\nAdenowo AF, et al.: Impact of human schistosomiasis in sub-Saharan Africa. Braz. J. Infect. Dis. 2015; 19: 196–205. PubMed Abstract | Publisher Full Text\n\nGryseels B, et al.: Human schistosomiasis. Lancet. 2006; 368(9541): 1106–1118. Publisher Full Text\n\nHotez PJ, et al.: Control of neglected tropical diseases. N. Engl. J. Med. 2007; 357(10): 1018–1027. Publisher Full Text\n\nTchuem Tchuenté L-A, et al.: Moving from control to elimination of schistosomiasis in sub-Saharan Africa: time to change and adapt strategies. Infect. Dis. Poverty. 2017; 6(1): 1–14. Publisher Full Text\n\nParkin DM: The global burden of urinary bladder cancer. Scand. J. Urol. Nephrol. 2008; 42(sup218): 12–20. Publisher Full Text\n\nKing CH: Toward the elimination of schistosomiasis. N. Engl. J. Med. 2009; 360(2): 106–109. Publisher Full Text\n\nStothard JR, et al.: Schistosomiasis in African infants and preschool children: let them now be treated!. Trends Parasitol. 2013; 29(4): 197–205. PubMed Abstract | Publisher Full Text\n\nHotez PJ, et al.: Rescuing the bottom billion through control of neglected tropical diseases. Lancet. 2009; 373(9674): 1570–1575. PubMed Abstract | Publisher Full Text\n\nMnkugwe RH, et al.: Prevalence and correlates of intestinal schistosomiasis infection among school-aged children in North-Western Tanzania. PLoS One. 2020; 15(2): e0228770. PubMed Abstract | Publisher Full Text\n\nColley DG, et al.: Contributions of the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) to schistosomiasis control and elimination: key findings and messages for future goals, thresholds, and operational research. Am. J. Trop. Med. Hyg. 2020; 103(1 Suppl): 125–134. PubMed Abstract | Publisher Full Text\n\nBustinduy AL, et al.: Expanding praziquantel (PZQ) access beyond mass drug administration programs: paving a way forward for a pediatric PZQ formulation for schistosomiasis. PLoS Negl. Trop. Dis. 2016; 10(9): e0004946. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOrganization WH: WHO guideline on control and elimination of human schistosomiasis.s 2022. Reference Source\n\nOsakunor DN, Woolhouse ME, Mutapi F: Paediatric schistosomiasis: What we know and what we need to know. PLoS Negl. Trop. Dis. 2018; 12(2): e0006144. PubMed Abstract | Publisher Full Text\n\nJordan P, Webbe G: Human schistosomiasis. Human schistosomiasis.1969.\n\nShaghaghi A, Bhopal RS, Sheikh A: Approaches to recruiting ‘hard-to-reach’populations into research: a review of the literature. Health Promot. Perspect. 2011; 1(2): 86.\n\nOrganization WH: Ending the neglect to attain the sustainable development goals: a road map for neglected tropical diseases 2021–2030.2020.\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\nPeters MD, et al.: Scoping reviews. Joanna Briggs Institute Reviewer’s Manual. 2017; 2015: 1–24.\n\nClark JM, et al.: Improving the translation of search strategies using the Polyglot Search Translator: a randomized controlled trial. Journal of the Medical Library Association: JMLA. 2020; 108(2): 195–207. PubMed Abstract | Publisher Full Text\n\nMunn Z, et al.: The development of a critical appraisal tool for use in systematic reviews addressing questions of prevalence. Int. J. Health Policy Manag. 2014; 3(3): 123–128. PubMed Abstract | Publisher Full Text\n\nKalinda C, Mindu T, Chimbari MJ: A systematic review and meta-analysis quantifying schistosomiasis infection burden in pre-school aged children (PreSAC) in sub-Saharan Africa for the period 2000–2020. PLoS One. 2020; 15(12): e0244695. PubMed Abstract | Publisher Full Text\n\nSpeiser S, et al.: Update on Noma: systematic review on classification, outcomes and follow-up of patients undergoing reconstructive surgery after Noma disease. BMJ Open. 2021; 11(8): e046303. PubMed Abstract | Publisher Full Text\n\nDoi SA, et al.: Advances in the meta-analysis of heterogeneous clinical trials I: the inverse variance heterogeneity model. Contemp. Clin. Trials. 2015; 45: 130–138. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "156449",
"date": "15 Dec 2022",
"name": "Dirk Engels",
"expertise": [
"Reviewer Expertise Tropical Diseases"
],
"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 is relevant as it is clearly important, especially in view of the ADOPT programme for pediatric praziquantel, to have best estimates of the global number of pre-school age children to be reached. My main remark would be: with such a substantial scoping review, why limiting the study to hard-to-reach populations only? I suggest to expand to all eligible studies reporting on schistosomiasis in PSAC and treat hard-to-reach populations as a sub-analysis. In this way as-broad-as-possible information is captured in one scoping review, leaving all options open for an access plan\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": "9213",
"date": "20 Jan 2023",
"name": "Phyllis Isaiah",
"role": "Author Response",
"response": "Question 1: The study is relevant as it is clearly important, especially in view of the ADOPT programme for pediatric praziquantel, to have best estimates of the global number of pre-school age children to be reached. My main remark would be: with such a substantial scoping review, why limiting the study to hard-to-reach populations only? I suggest to expand to all eligible studies reporting on schistosomiasis in PSAC and treat hard-to-reach populations as a sub-analysis. In this way as-broad-as-possible information is captured in one scoping review, leaving all options open for an access plan Response: Thank you for the feedback. A recent study by Kalinda et al., 2020 conducted a systematic review of schistosomiasis infection burden among PSAC. We also anticipate that in view of the availability of pediatric praziquantel, intervention need will shift to ensure the very marginalized PSAC are covered, hence the focus on hard-to-reach areas and population. We have however compared the results of the systematic review by Kalinda and colleagues with our results in the actual scoping review manuscript."
}
]
},
{
"id": "156448",
"date": "10 Jan 2023",
"name": "Zhou Xiao-Nong",
"expertise": [
"Reviewer Expertise Epidemiolgoy of schistosomiasis"
],
"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 are trying to review epidemiology of pediatric schistosomiasis in hard-to-reach areas and populations, the results will provide evidences to designing the extension of preventive chemotherapy (PC) programs in the global schistosomiasis control program, by using the five-stage scoping review process. It is worthwhile for publication of the protocol due to big gaps are existed in the previous global NTDs program that focus only on the population over 6 years old. But there are several limitations to design the protocol based on the objectives of the study, which can overcome by revision of the study protocol.\nThe scope of the population to be studied: based on the objectives to provide evidence to designing the extension of PC program, it is essential to understand the current situation of all pre-school age children (PSAC) versus PSAC living in the hard-to-reach areas. Therefore, in the protocol, it is suggested to include the data from whole PSAC population, then to compare the epidemic features between PSAC living in the hard-to-reach areas and all of PSAC in endemic areas.\n\nThe definition of hard-to-reach areas and hard-to-reach population should be different, but the authors only provide the definition of hard-to-reach population, which covers three types of features. For my understanding, the PSAC population living in the hard-to reach areas is the part of hard-to-reach population. In addition, those living in rich areas but always in the migrate status, such as boat family, etc. So it is suggested to give definitions both of hard-to-reach areas as well as hard-to-reach populations.\n\nIn the objective part, it is suggested to firstly provide a general objective with two to three specific aims, to indicate detail objectives of the study designing. Then followed by the definitions and scope of the review, in order to clearly describe the final outcomes of the study.\n\nIn the Methods part, it is suggested to provide the detail information of the data analysis, due to there is vague information of the statistical analysis approach provided in the current version. It is also suggested to provide the data collection tables as attached file, which is very important for researchers to collect data and form the datasets as well as to perform the data handling by using unified SOPs in different countries where studying.\n\nUnder the Methods part, data extraction and synthesis, point vi. “Mean eggs per gram f feces or infection intensity classification (if available) “ is only suitable for S. mansoni infection, but not suitable for S. haematobium. So please revise this sentence by consideration of both species of schistosomes.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": [
{
"c_id": "9214",
"date": "20 Jan 2023",
"name": "Phyllis Isaiah",
"role": "Author Response",
"response": "Question 1: The scope of the population to be studied: based on the objectives to provide evidence to designing the extension of PC program, it is essential to understand the current situation of all pre-school age children (PSAC) versus PSAC living in the hard-to-reach areas. Therefore, in the protocol, it is suggested to include the data from whole PSAC population, then to compare the epidemic features between PSAC living in the hard-to-reach areas and all of PSAC in endemic areas. Response: Thank you for the feedback. A recent study by Kalinda et al., 2020 conducted a systematic review of schistosomiasis infection burden among PSAC. We also anticipate that in view of the availability of pediatric praziquantel, intervention need will shift to ensure the very marginalized PSAC are covered, hence the focus on hard-to-reach areas and population. We have however compared the results of the systematic review by Kalinda and colleagues with our results in the actual scoping review manuscript. Question 2: The definition of hard-to-reach areas and hard-to-reach population should be different, but the authors only provide the definition of hard-to-reach population, which covers three types of features. For my understanding, the PSAC population living in the hard-to reach areas is the part of hard-to-reach population. In addition, those living in rich areas but always in the migrate status, such as boat family, etc. So it is suggested to give definitions both of hard-to-reach areas as well as hard-to-reach populations. Response: Thank you for pointing this out. This has been amended in the protocol. Question 3: In the objective part, it is suggested to firstly provide a general objective with two to three specific aims, to indicate detail objectives of the study designing. Then followed by the definitions and scope of the review, in order to clearly describe the final outcomes of the study. Response: Thank you for pointing this out. This has been amended in the protocol. We had only one objective. Question 4: In the Methods part, it is suggested to provide the detail information of the data analysis, due to there is vague information of the statistical analysis approach provided in the current version. It is also suggested to provide the data collection tables as attached file, which is very important for researchers to collect data and form the datasets as well as to perform the data handling by using unified SOPs in different countries where studying. Response: Thank you for pointing this out. This has been amended in the protocol. An annex (a data collection table) has been attached. Question 5: Under the Methods part, data extraction and synthesis, point vi. “Mean eggs per gram f feces or infection intensity classification (if available) “ is only suitable for S. mansoni infection, but not suitable for S. haematobium. So please revise this sentence by consideration of both species of schistosomes. Response: Thank you for pointing this out. This has been amended in the protocol."
}
]
}
] | 1
|
https://f1000research.com/articles/11-1203
|
https://f1000research.com/articles/12-79/v1
|
19 Jan 23
|
{
"type": "Research Article",
"title": "Appreciating visual arts may not foster medical diagnosis skills",
"authors": [
"Koji Matsumoto"
],
"abstract": "Background: This article examined intervention studies that used appreciation of visual arts to foster observation skills and discussed their effectiveness in making accurate diagnoses in terms of expertization. Methods: In order to collect journal articles and academic books (written in English) on empirical intervention studies that examined the use of visual arts for cultivating observation skills in health professionals’ education and training, the author first targeted articles that had been included in previous systematic reviews. In addition, they conducted a manual search. From this body of literature, the author selected studies that objectively measured observation skills only through the appreciation of visual art. They collected and read around 300 articles and selected 12 studies after applying the inclusion and exclusion criteria. Results: This article revealed no concrete evidence on whether appreciating visual art contributes toward an accurate diagnosis. Extant studies determined that such appreciation facilitates the observation of more visual features and a detailed view over time. However, they did not confirm the positive effects of appreciating visual arts on an accurate diagnosis. This article also confirmed that such appreciation does not reduce misdiagnoses or develop tolerance toward ambiguity that prevents premature closure. Moreover, the transfer of observation skills from one context to another is unlikely to be as successful as the intervention studies had intended. Conclusions: For fostering diagnostic skills, providing students with many instances of medical cases and appropriate knowledge to evoke implicit learning for extracting subtle differences in the cases, should be prioritized over visual art appreciation. On the other hand, such appreciation may foster verbalization skills and understanding or extraction of the patient’s background and context. These competencies may cultivate teamwork and perspective-taking, indirectly leading to an accurate diagnosis.",
"keywords": [
"visual arts appreciation",
"diagnostic skills",
"observation skills",
"expertization",
"perceptual learning",
"mental images",
"pattern recognition",
"intuition"
],
"content": "Introduction\n\nObservation is crucial in various areas or specialties of medicine1–4 and it is necessary for medical advancement.5 Though medical education has not included the cultivation of observation skills until recently,2,6 intervention studies on such training have been growing rapidly, sometimes in collaboration with art museums.7 These intervention studies usually use visual arts, such as painting, based on the assumption that there are similarities between observing visual arts and making observations in medical examination or potential applications of appreciating visual arts in making medical observations.6,8–11 For example, Jacques et al.12, p.9 asserted that “the arts foster many of the same skills required of physicians, including risk-taking, problem-solving, careful and attentive looking, interpretation and analysis, developing empathy for others, and seeing an issue from multiple perspectives.”\n\nGelgoot et al.13 and Elhammoumi and Kellam14 reviewed several studies on developing observation skills in medical or nursing education; however, they only listed the main findings without discussing them. Additionally, Perry et al.,15 Mukunda et al.,16 and Alkhaifi et al.17 concluded that such studies offer reasonable evidence in favor of using visual arts to improve observation skills. Dalia et al.18 reviewed the incorporation of visual arts in medical school and residency and identified the following four elements that should be included in the curriculum: pattern recognition, deep seeing, facial expression, and pertinent negatives. Though Turton et al.19 reviewed the intervention studies that used various forms of art for training in palliative care, their conclusions cannot be validated because they did not report all the literature that was used. Ike and Howell’s20 review is the only known study on intervention studies that used visual arts to develop observation skills among medical professionals. However, they only discussed the validity of the psychometric scales or quantitative observation metrics used in these studies.\n\nThus, although one of the primary goals of developing observational skills through visual arts appreciation should be to develop diagnostic skills, it remains unclear whether appreciating visual arts is effective for improving the accuracy of diagnoses. The present article provides an overview of intervention studies that used the appreciation of visual arts for fostering observation skills and discusses their effectiveness in making accurate diagnoses in terms of the expertization of medical professions. Medical experts can diagnose more accurately through the expertization.21–23 Hence, an analysis of expertization studies should provide rich insights.\n\nThe following sections of my paper are structured as follows. The Methods section explains the process of selecting the target articles. The Results section provides an overview of the intervention studies that considered the appreciation of visual arts for fostering observation skills. The Discussions section presents the findings of the target articles in terms of the expertization of medical professions. Finally we present the study’s main conclusions, limitations, and implications for future research and practice.\n\n\nMethods\n\nThis study referred to the search results of the aforementioned review studies13–20 to search journal articles and academic books (written in English) on empirical intervention studies that used visual arts for cultivating observation skills in health professionals’ education and training. Manual searches for additional articles were also conducted because the search results were inconsistent; moreover, it was difficult to collect information from databases by using typical search words such as “visual arts,” “observation skills,” and “medical education.”\n\nDetailed inclusion and exclusion criteria to assess the results of the interventions in which only appreciating visual arts affected observation skills were set, comprising those that used only visual arts to foster observation skills. Therefore, studies that included other activities were excluded, except for pre- and post-tests, such as drawing or creating visual arts and observing medical images. Additionally, studies on “graphic medicine”24 were also excluded, because these studies used comics that included written dialogues.\n\nMoreover, studies that objectively measured observation skills were included, such as using psychometric scales, quantitative metrics, or grading participants’ statements by predetermined criteria. Thus, studies that subjectively measured observation skills, irrespective of the method used (e.g., participants’ subjective evaluation of their skills were excluded, their free comments on the interventions, and scales of their impressions of the interventions). For example, studies that extracted key concepts from the participants’ comments, such as thematic analysis25 were excluded because they are not suitable for determining the learning effects for the entire concerned population since the concepts are identified from the comments of only a few participants.\n\nThe full texts of the related articles identified by the search results of the aforementioned review studies13–20 were collected. Through manual search, the titles of articles that seemed to use visual arts appreciation in health professionals’ education were selected by checking reference lists and the articles listed in PubMed’s sidebar or Google’s search result of related articles. Then, their abstracts were reviewed via websites, such as PubMed and Google. If the abstract met the inclusion criteria, the full-text article was collected. Additionally, if the abstract could not be obtained or was insufficient to determine whether the article met the inclusion criteria, the full-text article was collected. Therefore, if it could be clearly determined from the abstracts that the inclusion criteria were not met, full-text articles were not collected. This process was repeated until no more related articles could be found. I conducted this search from January to June 2022.\n\nAfter a review of the full texts that were collected, studies that met the inclusion criteria were selected. An exhaustive summary of each study was collated. The summary described the features, research design, and key results of the study (see Table 1).\n\na This review only covers the intervention that took place between 1998 and 1999.\n\nOn the basis of the summary, the features and tendencies were synthesized into the interventions’ goals and methods, research design, and findings of the studies. Then, the features and tendencies were examined in relation to the findings of the studies on expertization of medical diagnostic skills and visual perception, according to review articles on related themes as well as the articles discussed in those reviews. Through the examination, the aforementioned review studies13–20 and relevant articles that were collected but excluded in this study were also referenced.\n\n\nResults\n\nA total of around 300 articles were reviewed in detail. After applying the aforementioned inclusion and exclusion criteria, the literature search yielded 12 studies,26–37 as listed in Table 1. Thereafter, 3 of these 12 studies28,31,37 were found by manual search and missed by search results of the aforementioned review studies.13–20 Five studies38–42 were excluded from the analysis because they included activities other than visual arts appreciation.\n\nThe intervention studies were conducted for under- or post-graduate students in various disciplines, such as radiology, dermatology, and nursing. They were implemented in a specific school, hospital, grade level, program, or class. Sample sizes in these studies were relatively small. The frequency of sessions in each study was diverse, ranging from a single session lasting only a few hours to multiple sessions over two months. The intervention studies were often implemented in art museums.\n\nMost studies used paintings as visual art and asked the participants to describe and discuss the paintings’ details and their interpretations in pairs or groups. Some of the interventions utilized Visual Thinking Strategies (VTS), embodying the following three core questions: “What’s going on in this picture?,” “What makes you say that?” and “What else can we find?” These questions help participants to observe the entire painting carefully and make inferences based on the visual evidence.43 Other interventions focused on separating the description of visual evidence from the interpretation or using the concepts of visual elements, such as color, light, and texture.\n\nMost studies used control experiments or pre- and post-tests to examine participants’ descriptions of visual features in paintings or medical images. They revealed that the intervention enabled participants to describe what they saw in more detail and use more words. Some studies, however, did not show this effect, possibly due to few participants, disagreement between scorers, or a ceiling effect on the measurements. Concerning the qualitative aspects of participants’ descriptions, Jasani and Saks34 observed an increase in descriptions through the use of visual analogies and scope of interpretations that involved the patient’s surroundings, perspective, or emotional state. They also observed an increase in the number of words used to express speculative thinking, which indicated the possibility of multiple interpretations. Furthermore, Agarwal et al.26 reported that the intervention group spent a statistically significant and greater amount of time observing and describing than the control group.\n\nOf these studies, only Goodman and Kelleher29 directly measured diagnostic accuracy. They used the identification of abnormalities in the radiographs and reported that their intervention was successful. However, the correct identification rate was less than half, even though the abnormalities were conspicuous and of a low level of difficulty.\n\n\nDiscussions\n\nMost interventions instructed participants to carefully observe the entire target. As stated by Agarwal et al.,26 taking time to observe is considered a sign of careful observation. However, observing for a longer period is not necessary for an accurate diagnosis. Experts take less time than novices to diagnose accurately. In contrast, they are more likely to misdiagnose if they take longer.44–46\n\nMoreover, systematic viewing intervention, such as detecting radiograph abnormalities by viewing the images in a given order, or full-coverage viewing intervention, such as mentally dividing each image into nine imaginary segments (3×3) and inspecting each segment separately, did not outperform non-systematic viewing intervention, wherein participants were urged to inspect whatever attracted their attention.47 Systematic and full-coverage viewing took a longer (but not significant) time than non-systematic viewing. Van Geel et al.48 also reported similar results.\n\nMany studies44,49–51 and reviews52–58 on medical image perception have shown that experts’ diagnosis is generally characterized by holistic and quick recognition. This is due to pattern recognition59–61 or intuition composed of scripts, schemas, or mental models/images/representations (hereinafter collectively referred to as mental images).62 Experts compare medical images or patients with mental images—which are associated with domain-specific knowledge—of normal and abnormal cases at a single glance.23,63–65 A study using fMRI66 revealed that when radiologists looked at radiographs, the brain regions related to visual attention and the encoding, storing, and retrieval of visual memory were activated.\n\nNot just medical images, humans generally recognize things by associating them with mental images formed through our daily visual experiences.67 For example, humans can recognize a scene’s gist and gaze into areas of interest through their knowledge of the world.68–70 This top-down control of gaze by using mental images is common for humans and is not limited to those who diagnose medical images.\n\nThe experts’ intuition is cultivated through the accumulation of domain-specific knowledge and experiences. The number of mammograms observed is proportional to the accuracy of the diagnosis.71 Thus, it is not conducive if the intervention studies do not consider the participants’ pre-existing knowledge in measuring observation skills.\n\nFor encouraging persistent and detailed observation, some interventions33,35,72 (included in this article and others) are intended to cultivate tolerance for ambiguity. An increase in speculative thinking—which was observed by Jasani and Saks34—implies such cultivation.\n\nHowever, the intervention studies35,72 showed that using visual arts contributes very little or does not contribute toward building tolerance for ambiguity.\n\nThe intervention studies enabled the participants to describe the visual features in the paintings and medical images in greater detail. However, the observation and description of more visual features or signs in medical images or patient photographs do not lead to accurate diagnoses for novices and experts. Novices, such as medical school students, generate hypotheses based on constant information input and are unable to select appropriate hypotheses.73 An experiment that presented electrocardiograms to non-medical laypersons revealed that participants usually misdiagnosed the problem because they were unable to overlook irrelevant features.74\n\nNot just in the context of medical images, experts generally diagnose and make decisions based on mental images.75 They can extract more useful information about the given situation, immediately generate appropriate hypotheses, eliminate irrelevant hypotheses, and test the hypotheses.62,63,76 Thus, expert general practitioners can make a correct diagnosis without discovering all the features of a disease.60\n\nGoodman and Kelleher29 asserted that reducing misdiagnoses is one of the benefits of visual training, such as appreciating visual arts. Though they did provide an explicit reason for why visual training would reduce misdiagnoses, it can be asserted that misdiagnoses arise from careless observation, and appreciating visual arts can teach one to look carefully.\n\nHowever, the causes are complex77 and may not always be due to mere carelessness. In general, medical errors can be classified into search errors caused by not looking at the abnormality, recognition errors caused by not identifying an abnormality, and decision errors that occur in the process of clinical reasoning.78\n\nIn the context of novices, Brunyé et al.’s78 review showed that search errors generally occur when novices overlook definitive features with subtle visual features and look repeatedly at areas that are not relevant for a diagnosis. Misdiagnoses is also called when signs of extremely low prevalence are overlooked by novices (and experts). Novices are also likely to make recognition errors due to insufficient mental images and knowledge.49,65 This implies that novices’ errors are caused by the lack of top-down control of gaze due to insufficient mental images.\n\nOn the other hand, experts can diagnose quickly and accurately by using mental images. Mental images are compromises between fitting the data and minimizing the complexity of the model,67 which leads experts’ perceptions toward certain classes of stimuli in the domain.23 Therefore, many expert radiologists overlook the gorilla inserted into chest CTs.79 This demonstrates that experts’ errors, such as premature closure, may be a byproduct of expertization.23,80\n\nFurthermore, human and environmental factors that induce decision errors cannot be ignored.81 Therefore, cultivation of novices’ mental images, organizational/systematic support or use of cognitive tools/strategies82 may be more effective than appreciating visual arts to reduce medical errors.\n\nThe intervention studies intended to transfer observation skills for the visual arts to apply to medical examination, based on the assumption that there are similarities between these fields. However, the transfer occurs only to a very limited extent. Experimental studies showed that in terms of radiology, expertise was positively transferred to the task of finding small low-contrast dots in phantom X-ray images83 but not to the task of finding hidden targets in pictorial scenes.84 The same can be said for visual recollection memory. Expert cytologists and radiologists were not better at recognizing scenes or isolated objects than non-medical participants.85\n\nThe limitations of the transfer depend on the domain-specificity of mental images. Whether looking at medical images, patients, landscapes, or paintings, each requires unique domain-specific knowledge and experiences to form mental images.\n\nI suspect that the effectiveness of Goodman and Kelleher’s29 intervention is unsatisfactory. Their task was too easy, as making a diagnosis is more difficult than identifying abnormalities.86 There may be more efficient or effective ways of fostering diagnosing skills than appreciating visual arts. For example, learning modules, based on theories of perceptual learning, such as Perceptual and Adaptive Learning Modules (PALM), have been developed to foster pattern recognition of medical images.61,87 All the relevant studies have reported excellent results of diagnostic accuracy for medical school students and/or residents22,88–94 and non-medical participants,95–98 however, it is possible such excellent results across the board could be due to publication bias (see also the review by Guégan et al.99). Although it is difficult to directly compare the studies due to different testing methods, these modules seem superior to Goodman and Kelleher’s intervention.29 It is also notable that the outcome measures used by these modules included fluency, or the speed of recognition. This is consistent with research findings on expertization.\n\nLikewise, teaching a specific eye movement search pattern that corresponds with the characteristics of the area shown in the radiographs100 or demonstrating an expert model that searches visually and interprets symptoms (eye-movement modeling examples)101 could also be effective.\n\nIt would be more accurate to say that the interventions that use the appreciation of visual arts foster verbalizing skills. It also may be useful to teach concepts of visual elements, such as color, light, and texture in order to foster such skills. Verbalizing accurately and lucidly is important for various reasons in medical practice.102\n\nGroup discussions can also act as an opportunity to practice and reflect on one’s verbalization skills. This can contribute toward the development of communication skills that are required for teamwork. Klugman et al.35 intended to develop communication skills and claimed that their intervention achieved the same objective. However, they did not present any empirical data to support their claim.\n\nThe use of visual arts may also be useful for group discussions across specialties. For example, Katz and Khoshbin103 reported that their curriculum included visual arts to facilitate multidisciplinary team building. One possible reason for this was that the visual arts free the participants from the hierarchy of medical personnel and ensure their equal participation in discussions. It has been reported that even children who do not perform well academically or usually speak, actively participated in the VTS sessions.43\n\nThus far, I have shown that appreciating visual arts may not have a direct effect on making an accurate diagnosis. Meanwhile, Jasani and Saks34 observed an increase in descriptions of the scope of interpretation. Understanding the patient’s background and context—which are invisible—may be necessary for patient interviews. This corresponds with Shapiro et al.’s supposition104 that teaching through cases would be effective in fostering pattern recognition, while teaching through paintings would promote interpretation skills based on a broader context, including a patient’s subjective perception and understanding of diseases.\n\nPerspective-taking as cognitive empathy, such as knowing and postulating how another is thinking and feeling,105 is also essential for patient interviews. Appreciating visual arts and group discussions about observations and interpretations of them may foster such perspective-taking. Although there are several reports on such practice,106–111 none presented empirical evidence. On the other hand, Gurwin et al.32 used the Reading the Mind in the Eyes Test,112 which assesses the ability to recognize emotions based upon photographs of actors’ eyes, and reported no significant difference, possibly due to the ceiling effect. It would be beneficial to consider using other measures, such as the Theory of Mind Test113 and Faces Test,114 as exemplified by Pino and Mazza.115\n\nUnderstanding patients’ facial expressions is also likely to enhance perspective-taking for medical professions.18 It may be worthwhile to train such understanding because of the functional specialization for face perception in the brain.116 While several studies have reported on such practices,117,118 they did not provide any supporting empirical evidence.\n\n\nConclusions\n\nThis article revealed that there is no concrete evidence on whether appreciating visual art contributes toward an accurate diagnosis. Although the appreciation of visual arts has helped facilitate the observation of more visual features and the ability to see more thoroughly by taking more time, findings of the expertization studies do not prove that these contribute toward the cultivation of skills required for making a diagnosis. Additionally, the claim that such appreciation can reduce misdiagnoses or cultivate tolerance for ambiguity that prevents premature closure has not been proven. Moreover, the transfer of observation skills to different objects is unlikely to be as successful as the intervention studies intend. Rather, it would be better to use learning modules based on perceptual learning using cases to foster pattern recognition. However, such appreciation (sometimes with group discussions) may foster verbalization skills and understanding of the patient’s background and context. This may indirectly contribute toward accurate diagnoses by facilitating teamwork or fostering perspective-taking. However, the effects of such appreciation remain ambiguous.\n\nAlkhaifi et al.17 asserted that visual arts can be means to address important competencies that are difficult to teach using traditional methods; however, it is important to state that visual arts are not a panacea. The reasons why visual arts appreciation is unlikely to foster diagnostic skills can be summarized as follows. First, discovering more signs of a disease does not equate to diagnosis. Diagnosing medical images and actual patients involves determining whether the patients or medical images fit into a particular classification of diseases or not. Experts can make a correct diagnosis without discovering all the features of a disease because they focus only on useful features for such distinctions. Gibson’s theory of perceptual learning119 precisely explains expertization in such distinctions. Therefore, intervention studies have assumed that medical experts’ approaches to observation are similar to those adopted by artists; however, these approaches differ because no such distinctions are necessary for artists.\n\nSecond, such distinctions are intuitive and involve implicit perpetual learning.120 It is possible even if the rationale is not verbalized, although more effective if it is verbalized.119 Experimental psychology has shown that simply looking at various paintings with the names of the artists at random can enable novices to differentiate between artists.121–123 Similar results were obtained in experiments that had novices diagnose psychopathological cases presented visually (through words) or aurally.124 Additionally, novices have been shown to be able to detect melanoma by being shown benign and malignant cases side by side, but without being given instructions, such as the ABCD rule.125 Further, instructing novices on such rules has little effect on diagnostic accuracy.125,126 Protocols in which participants contrast similar cases—that learning modules such as PALM also adopt—use implicit learning to extract subtle differences in the cases. Therefore, it seems difficult to enhance such implicit learning through a closer look at a piece of visual art.\n\nThird, mental images are domain-specific. Visual arts do not substitute domain-specific knowledge or one’ s experience with medical cases.\n\nThis article has several limitations. First, I excluded articles published in languages other than English and those that subjectively measured observation skills. These studies may have included information that could have contributed to this article.\n\nSecond, I found only one study that directly examined the impact of appreciating visual arts on diagnostic skills. The conclusions of this article are tentative, while the findings of the expertization studies are sufficiently reliable.\n\nThird, I was not able to fully interpret the results of Goodman and Kelleher,29 specifically, the small transfer of visual arts appreciation to the identification of abnormalities in the radiograph. Although it may be due to adapting to the test format, it is not clear by what process the transfer occurred, if at all.\n\nI offer the following suggestions for future research. First, while studies on expertization reveal qualitative differences between novices and experts, the process of expertization is not understood very well.74,127 It is likely, albeit to a lesser extent, that listing more visual features and hypotheses is unnecessary for the process of expertization. Hence, it may be promising to investigate whether listing such features and hypotheses by appreciating visual arts is effective in scaffolding diagnosis skills. For example, such appreciation might accelerate learning through the learning module based on perceptual learning. Thus, longitudinal studies may be required13 because the effects of such appreciation may be delayed.\n\nSecond, to measure the effectiveness of appreciating visual arts, it is recommended to use the same tests that have been used to measure the effectiveness of learning modules on perceptual learning. Diagnostic accuracy and fluency should also be examined, as asserted by Kellman et al.22 Additionally, the influence of pre-existing knowledge should be considered.\n\nThird, as mentioned by Perry et al.,15 the intervention methods must also be reported adequately. It is unlikely that merely looking at visual art develops the skills required for medical diagnoses. Rather, the design of the experience, such as selection of the paintings, instruction, and facilitation and activities within peers/groups is required because the outcome of the intervention should vary based on the type and number of paintings that have been viewed and on the activities or reflections mentioned as instructions.128 It is also necessary to mention the responses that were evoked by the subjects (or paintings), prompts, and questions to identify whether the outcomes were intended or derived. Moreover, I found the following deficiencies in the studies used in this article: the number of missing samples from the participants; what did the control group do; details of the content and format of the lectures that the control participants were subjected to; maximum possible values of the scales or items for considering the ceiling effect; details of the scoring criteria; how many schools/organizations did the participants belong to; how many images were used for the test; and timing of the pre- and post-test. Thus, items listed in Table 1 should be reported in future studies.\n\nFourth, it is necessary to investigate whether the skills and knowledge that would be fostered by appreciating visual arts enhance diagnosis skills. This article found that appreciating visual arts may enhance verbalizing skills, teamwork skills, interpretive skills, and perspective-taking. Mukunda et al.’s16 review also found a paucity of rigorous studies on training modules that use arts to promote empathy, team building, communication skills, wellness/resilience, or cultural sensitivity.\n\nFifth, research is needed that directly compares the skills fostered by visual arts appreciation with other methods that attempt to foster the same skills, such as learning modules applied by perpetual learning and using other forms of arts. For example, we can use only visual arts and also performing arts for teamwork and communication skill development among health professionals.129 Due to time constraints imposed by the many demands of medical education and training, it is necessary to identify a more efficient method among those available.\n\nFinally, as Osman et al.130 suggested, further research exploring the process of learning through visual arts appreciation is required, as extant literature only focuses on outcomes. Dominant research methods such as controlled studies and psychometric scales do not allow for such investigation128,131; thus, further research should include alternative methods and outcome measurements, such as qualitative methods.15,132\n\nI also offer the following suggestions to practice fostering diagnostic skills. Given the time constraints, adopting visual art appreciation is not encouraged. Taylor64 claimed that education in medical school should provide students with many instances of medical cases and appropriate knowledge to form adequate mental images. Such provision must be made in an appropriate manner, as in PALM, to evoke implicit learning in order to extract subtle differences in the cases. This should be prioritized over visual art appreciation.\n\nFurthermore, since expert perception is a combination of observation and interpretation through intuition, separating observation and interpretation, as instructed in several intervention studies, seems to be unnatural and could be avoided. Jaarsma et al.133 showed that in clinical reasoning, experts used less descriptive terms, like expressing colors and shapes, and used more comparative terms to interpret findings in terms of normal/abnormal or typical/atypical.",
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The Handbook of Medical Image Perception and Techniques. Cambridge (UK):Cambridge University Press; 2018; pp. 470–482.\n\nJarodzka H, Balslev T, Holmqvist K, et al.: Conveying clinical reasoning based on visual observation via eye-movement modelling examples. Instr. Sci. 2012; 40(5): 813–827. Publisher Full Text\n\nKulatunga-Moruzi C, Brooks LR, Norman GR: Using comprehensive feature lists to bias medical diagnosis. J. Exp. Psychol. Learn. Mem. Cogn. 2004; 30(3): 563–572. Publisher Full Text\n\nKatz JT, Khoshbin S: Can visual arts training improve physician performance? Trans. Am. Clin. Climatol. Assoc. 2014; 125: 331–341.\n\nShapiro J, Rucker L, Beck J: Training the clinical eye and mind: using the arts to develop medical students’ observational and pattern recognition skills. Med. Educ. 2006; 40(3): 263–268. PubMed Abstract | Publisher Full Text\n\nBatson CD: These things called empathy: eight related but distinct phenomena.Decety J, Ickes W, editors. The Social Neuroscience of Empathy. Cambridge (MA):MIT Press; 2009; pp. 3–15.\n\nBorromeo M, Chiavaroli N, Gaunt H: The arts and visual thinking in education at the Melbourne Dental School.McLean CL, editor. Creative Arts in Humane Medicine. Edmonton (Alberta, Canada):Brush Education; 2014; pp. 40–54.\n\nKarkabi K, Cohen CO: Deepening compassion through the mirror of painting. Med. Educ. 2006; 40(5): 462. PubMed Abstract | Publisher Full Text\n\nWald HS, Norman DR, Walker J: Reflection through the arts: focus on photography to foster reflection in a health care context. Living beyond―an interactive photographic exhibit. Reflective Pract. 2010; 11(4): 545–563. Publisher Full Text\n\nWikström BM: Nursing education at an art gallery. J. Nurs. Scholarsh. 2000; 32(2): 197–199. PubMed Abstract | Publisher Full Text\n\nWikström BM: Work of art dialogues: an educational technique by which students discover personal knowledge of empathy. Int. J. Nurs. Pract. 2001; 7(1): 24–29. Publisher Full Text\n\nWikström BM: Intuition and visual art: student nurses’ projection into experiences of elderly women. Aust. J. Holist. Nurs. 2002; 9(2): 24–31. PubMed Abstract\n\nBaron-Cohen S, Wheelwright S, Hill J, et al.: The “Reading the Mind in the Eyes” Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J. Child Psychol. Psychiatry. 2001; 42(2): 241–251. Publisher Full Text\n\nRowe AD, Bullock PR, Polkey CE, et al.: ‘Theory of mind’ impairments and their relationship to executive functioning following frontal lobe excisions. Brain. 2001; 124(3): 600–616. PubMed Abstract | Publisher Full Text\n\nBaron-Cohen S, Wheelwright S, Jolliffe T: Is there a “language of the eyes”? Evidence from normal adults, and adults with autism or Asperger syndrome. Vis. Cogn. 1997; 4(3): 311–331. Publisher Full Text\n\nPino MC, Mazza M: The use of “literary fiction” to promote mentalizing ability. PloS One. 2016; 11(8): e0160254. Published 2016 Aug 4. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZeki S: Inner Vision: An Exploration of Art and the Brain. Oxford (UK):Oxford University Press;1999.\n\nBardes CL, Gillers D, Herman AE: Learning to look: developing clinical observational skills at an art museum. Med. Educ. 2001; 35(12): 1157–1161. Publisher Full Text\n\nWikström BM, Svidén G: Facial expressions in paintings as perceived by the student nurse. Aust. J. Holist. Nurs. 2005; 12(2): 5–12. PubMed Abstract\n\nGibson EJ: Principles of Perceptual Learning and Development. Englewood Cliffs (NJ):Prentice-Hall;1969.\n\nFahle M: Introduction.In:Fahle M, Poggio TA, editors. Perceptual Learning. Cambridge (MA):MIT Press; 2002; pp. ix–xx.\n\nKornell N, Bjork RA: Learning concepts and categories: is spacing the “enemy of induction”? Psychol. Sci. 2008; 19(6): 585–592. Publisher Full Text\n\nKornell N, Castel AD, Eich TS, et al.: Spacing as the friend of both memory and induction in young and older adults. Psychol. Aging. 2010; 25(2): 498–503. PubMed Abstract | Publisher Full Text\n\nKang SHK, Pashler H: Learning painting styles: spacing is advantageous when it promotes discriminative contrast. Appl. Cogn. Psychol. 2012; 26(1): 97–103. Publisher Full Text\n\nZulkiply N, McLean J, Burt JS, et al.: Spacing and induction: application to exemplars presented as auditory and visual text. Learn. Instr. 2012; 22(3): 215–221. Publisher Full Text\n\nGirardi S, Gaudy C, Gouvernet J, et al.: Superiority of a cognitive education with photographs over ABCD criteria in the education of the general population to the early detection of melanoma: a randomized study. Int. J. Cancer. 2006; 118(9): 2276–2280. Publisher Full Text\n\nSpeelman C, Martin K, Flower S, et al.: Skill acquisition in skin cancer detection. Percept. Mot. Skills. 2010; 110(1): 277–297. PubMed Abstract | Publisher Full Text\n\nArk TK, Brooks LR, Eva KW: Giving learners the best of both worlds: do clinical teachers need to guard against teaching pattern recognition to novices? Acad. Med. 2006; 81(4): 405–409. PubMed Abstract | Publisher Full Text\n\nVoeller M: The art of attending: arts-based observation training for health professions students at the University of South Florida.Costache I, Kunny C, editors. Academics, Artists, Museums: 21st Century Partnerships. Oxon and New York (NY):Routledge; 2018; pp. 99–110.\n\nAcai A, McQueen SA, McKinnon V, et al.: Using art for the development of teamwork and communication skills among health professionals: a literature review. Arts Health. 2017; 9(1): 60–72. Publisher Full Text\n\nOsman M, Eacott B, Willson S: Arts-based interventions in healthcare education. Med. Humanit. 2018; 44(1): 28–33. Publisher Full Text\n\nLake J, Jackson L, Hardman C: A fresh perspective on medical education: the lens of the arts. Med. Educ. 2015; 49(8): 759–772. Publisher Full Text\n\nBelling C: Commentary: sharper instruments: on defending the humanities in undergraduate medical education. Acad. Med. 2010; 85(6): 938–940. PubMed Abstract | Publisher Full Text\n\nJaarsma T, Jarodzka H, Nap M, et al.: Expertise in clinical pathology: combining the visual and cognitive perspective. Adv. Health Sci. Educ. Theory Pract. 2015; 20(4): 1089–1106. Publisher Full Text"
}
|
[
{
"id": "239810",
"date": "16 Feb 2024",
"name": "Nicole J Fernandez",
"expertise": [
"Reviewer Expertise Tolerance of ambiguity",
"teaching observational skills",
"case-based learning",
"clinical 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\nThis paper is a welcome addition to the literature on the humanities in medical education and attempts the daunting task of determining if art observation has a positive impact on medical diagnosis in novice learners. The approach to this question is logical, although in some areas, the reader would benefit from more explanation and context. The conclusion that there is little evidence to support improved diagnosis as a result of art observation is well-supported, although the broad reasons for this could be further detailed, and the statement that another approach would be better is outside the scope of the article.\nThe article could be improved by considering these further comments to the author:\nTitle: Use of “appreciating” -consider re-wording. This implies a casual approach to looking at art, while slow looking is an iterative rigorous process. Perhaps “art observation” instead of “appreciating visual arts”. Also “medical diagnostic skills” instead of “medical diagnosis skills”. Suggest including ‘who’ as well- medical students? Novice learners? Possible revised title: Art observation may not improve medical diagnostic skills in novice learners\nThe writing style is inconsistent and unusual in some places. Usually in English scientific writing “I” or “the author” is not used- recommend rephrasing throughout. (For example: “The author collected information on…” becomes “Information was collected on…”.)\nAbstract: The Background section of an abstract usually provides context for the study rather than describing what the study did. Make sure that any changes to the body of the article are reflected in the abstract (eg changes to the conclusions).\nThere are opportunities throughout to provide more context and help the reader’s understanding of the subject- some of these are noted below. Being explicit is important- there may be assumptions that are not shared by all readers, especially regarding definitions and terms used. -Define what you mean by intervention/empirical intervention study. This is important in helping the reader to know which studies you considered. -Clarify what you mean by diagnosis- visual diagnosis only (eg radiology, gross pathology)? Clinical reasoning (which would be much broader)? -Specifically outline your inclusion and exclusion criteria -How did you decide about diagnostic evidence? Is improved diagnostic accuracy the only criterion? What about other elements of the diagnostic process or approach to complex cases in which the diagnosis is unclear? -The term ‘expertization’ may not be familiar to readers and should be explicitly defined, including what is meant by ‘expertization studies’. -In Methods, “features and tendencies” of the selected articles is mentioned- please explain what is meant by this.\nThe final paragraph of the introduction is not needed, as this is the standard format for a journal article.\nMethods- The first paragraph mentions “studies that used visual arts for cultivating observation skills” but was this the only goal of the included studies? This does not seem consistent with what is stated elsewhere in the article. 3rd paragraph, second sentence “were excluded” needs to be moved to outside the parentheses Suggest including a figure that shows how articles were selected, numbers of articles at each step of the process, that 12 articles were selected for full review. How many articles were found using the review articles vs by manual search? There are many examples of figures like this in the published literature.\nResults- Abbreviations need to be explained in the table (regardless of whether they are also explained in the text- the table should be able to stand alone). Results could be strengthened by using numbers instead of terms like “most”\nDiscussion- -Overall the discussion would benefit from a clearer focus on the original question- specifically diagnostic skills, not art observation studies in general. -Why might improvement in diagnostic skills be difficult to demonstrate in a study? Provide context, difficulty of assessing long term effects. How could future researchers attempt this? (currently in conclusions) -Consider that one might not see an improvement right after the intervention in 2nd year, but could it be helpful once students have more diagnostic experience, eg in 4th year? -Clearly and briefly list what reported benefits of art observation are- the information is there, but scattered. It could be condensed, as this is not the original focus of the paper. -If included studies were only those designed to improve observation skills, is it reasonable to assess them for improvement in diagnostic skills? How strong can any conclusions be? Only 1 study assessed diagnostic accuracy, and this was in a limited domain.\nThe relevance of expertization studies is unclear, since the art observation interventions were done with novice learners. Novices are not experts, one can’t teach them the same way. Just because experts are more likely to misdiagnose if they take longer, it doesn’t necessarily follow that the same is true for novices. If your position is that novices should be taught like experts, this needs to be explicitly stated and supported from the literature. Throughout the discussion it needs to be made clear when you are referring to studies in experts vs studies in novices. This is not clear for a reader who is not already familiar with this literature.\nThe Discussion covers much material that does not seem closely related to the original goal and could be condensed and refined to focus on diagnostic skills. It is important to emphasize that only 1 art observation study explicitly looked at diagnosis, and did this in a limited way. The conclusion appears to be that the impact of art observation on diagnostic skill has not been adequately investigated, rather than that it is ineffective. I don’t agree that it has been “shown that appreciating visual arts may not have a direct effect on making an accurate diagnosis”; the statement “there is no concrete evidence on whether appreciating visual art contributes toward an accurate diagnosis” is more accurate.\nConclusions should be a single paragraph stating your major findings- the section titled Conclusions is not really a conclusion. This material is more appropriate in the Discussion.\nThe claim that “it would be better to…” was not the focus of this article- a review of this literature would need to be included in order to support this. It could be suggested that if improving diagnostic accuracy is the single goal, there may be other methods that are more effective than art observation. But is this the only goal of art observation interventions? I don’t believe so. Observation is the first part of the diagnostic reasoning pathway, but not the only part, certainly not a panacea. It seems simplistic to expect a single intervention to have a great and immediate impact on diagnostic accuracy.\nLimitations: -No veterinary medicine literature included, although nursing literature was included. Is there a reason for this? There are several relevant articles in the vet med literature. -Studies that included other methods were excluded- can’t comment on what the effects of these studies are -In methods you mention the limitations of eg thematic analysis, but there is no mention of the limitations of using quantitative population statistics\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? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "292047",
"date": "21 Jun 2024",
"name": "Margaret S. Chisolm",
"expertise": [
"Reviewer Expertise museum-based health professions 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 lacking in conceptual clarity/relevance and presentation of replicable methods and clearly stated results. The aim of this article as stated is to review intervention studies that used \"appreciation\" of visual arts to foster observation skills AND discussed impact on diagnostic accuracy. This aim contains at least two concepts that are problematic for me: 1) the use of the word \"appreciation\" as most visual arts-based methods used in medical education are not concerned with art appreciation and 2) enhancement of observation skills is just one of many targeted skills and attributes that may improve patient outcomes, via diagnostic accuracy or other mechanisms, all of which are more \"downstream.\" Thus, I'm concerned with the basic premise as articulated of the manuscript. However, putting that aside for the moment, and turning to the methods sentence of the abstract. This is not a systematic review yet the abstract implies it is as it includes the term \"previous systematic reviews.\" Systematic reviews need to follow PRISMA guidelines, which this review does not. It has no clearly stated inclusion/exclusion criteria, database names, search terms, duplicate review system, no flow chart, no clear search start and end dates, no exact numbers of articles reviewed etc. this lack prevents replication and limits assessment of strength of evidence and conclusions that can be drawn. Again, the aim of affects of \"appreciating\" art on \"diagnosis\" accuracy are questionable aims to begin with and lack of rigor in review methods makes this manuscript's conclusions more problematic. Moving to the results section of the abstract, few results are presented and this is more of a discussion section making it challenging to assess whether conclusions are supported by evidence. The conclusions section of the abstract is not supported by results as presented in abstract. No presentation of evidence for medical cases/knowledge to impact learning as compared to visual art \"appreciation.\" No evidence presented in results section of abstract to support verbalization skills enhancement, etc. In conclusion, the abstract is lacking in coherence and clarity. Introduction The manuscript would be enhanced by a clear articulation of the problem(s) that visual arts-based teaching is trying to solve and what the current non-visual arts-based methods are to address this problem. It would also be important to mention the international consensus that the arts and humanities are fundamental to medical education (as stated by WHO, NASEM and AAMC FRAHME reports) and the Moniz et al scoping review [Ref 1] and two papers on the Prism model describing the functions that the arts and humanities have served in medical education to date. Although one of the primary goals of developing observations skills is to improve diagnostic accuracy, this is a very downstream outcome to which many other skills may contribute and also other downstream outcomes are clinically relevant as well (e.g., being able to observe nonverbals and so enhance communication skills to build rapport and enhance adherence with treatment recommendations, as one example). Also it appears that results are included in introduction prior to presenting methods and results later, and would avoid including results in the introduction and instead put this in context of literature more broadly. A research question needs to be articulated. Methods The previously mentioned review studies should be placed in the results, not in the Introduction or Methods sections. The Methods section should include the search terms, the databases searched, the exact search date, the number of abstracts/titles identified in search, exact inclusion/exclusion etc as presented in PRISMA guidelines. The reader should know how many non-duplicate abstracts/titles were identified, how many of those were included in full text review, etc. Results The word \"around\" should never be part of a systematic review, which this is not. More precision throughout is necessary. Not clear why the term \"visual arts appreciation\" is used as \"appreciation\" is not integral to teaching visual arts-based medical education. The author mistates two of the three core questions of VTS. These are precisely researched and worded questions so getting two of them incorrect here is very concerning. These questions have the primary aim of holding the group in inquiry as well the aim as stated by the author of having the participants ground their inferences in visual evidence. The penultimate paragraph of the Results section was the most informative of the manuscript, describing the study design and outcomes, which are suggestive of impact on observation skills. More precision in the text would be helpful here (i.e., % studies versus \"most\" AAMC or \"some\"). The last paragraph brings up diagnostic accuracy, which - again - the author declares as a primary aim of this work, but I'm not sure it is THE primary aim of any of the use of visual arts in medical education, and so it's not surprising that only one study measured this. Discussion Use of the word \"target\" in the first sentence to describe the work of art is an odd choice; perhaps just saying \"artwork\" would be clearer. The author raises some interesting ideas in this section. However the idea that observing for a longer period of time is not necessary for an accurate diagnosis among experts obscures the important role of taking time for beginners (presumably the target learners for most of these exercises) to avoid premature diagnostic closure via arriving at a diagnosis too quickly and not staying open to possibilities is important to good patient outcomes. Plus even among experts who can quickly diagnose most presentations accurately, instances exist where taking more time would have resulted in a more accurate diagnosis for an individual patient. Similarly the ability to look should precede the ability to know what to discard as relevant, so a beginner's inability to overlook irrelevant features seems a bit irrelevant to teaching beginners to look. At least one more recent study does support visual arts to make a statistically significant contribution to tolerance for ambiguity (Tackett et al, Med Ed Online).[Rev 2] Again, the use of \"appreciating\" visual arts misses the mark of what visual arts-based teaching aims to do. Art appreciation is beside the point. The author raises good questions about the limitations of transfer and the need for more research to study the transfer of skills from the museum or classroom to the clinic. They make a good point about the role of visual arts to foster communication skills (both listening and \"verbalizing,\" which perhaps \"speaking\" or \"articulately\" would be a less awkward word choice) and team-building/perspective taking. Conclusions Although the methods/results presentation make it difficult to be sure that the conclusions reached are accurate, I would not be surprised by a lack of evidence on whether visual arts-based teaching aids diagnostic accuracy for the reasons outlined above. This is an emerging field whose focus has been on exploring the role of the arts in developing many clinically relevant skills and attitudes, which - taken as a whole - may support patient outcomes (including diagnosis and treatment planning) downstream. The field is in an exploratory phase and its aims are to explore an array of attributes that may have an effect on these and other \"downstream\" outcomes. Limitations should include that this is not a systematic review in accordance with the PRISMA guidelines, and that relevant articles may have been missed by the search strategy etc Clearly more rigor is needed in the field of visual arts-based medical education research. The author does well to point this out and give some ideas for future directions. However, the findings of the study and these recommendations for improvement should be place in the context of the broader literature on these research gaps as outlined in the Howley et al AAMC FRAHME report and the Moniz et al scoping review, which also suggests more research rigor etc. I would disagree with several conclusions. The conclusion that \"adopting visual art appreciation is not encouraged\" seems to me an overstatement given the limitations of this review and the exploratory nature of the field. Clearly innovation is needed that goes beyond medical cases and knowledge transfer to teach students an array of otherwise difficult-to-teach clinically relevant attributes, which may improve patient outcomes, whether via diagnostic accuracy or other effects. I also see great value in increasing learners' awareness of what is an observation and what is an interpretation. The metacognitive skills of recognizing that an interpretation lacks visual evidence, raises awareness of possible biased thinking.\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? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-79
|
https://f1000research.com/articles/11-23/v1
|
11 Jan 22
|
{
"type": "Research Article",
"title": "Assessment of serum hormone levels in female patients with acne vulgaris",
"authors": [
"Phu Cuong Nguyen",
"Hoang Van Nguyen",
"Van Tien Vu",
"Van Tran Pham",
"Dang Quyet Tran",
"Thanh Tung Nguyen",
"Phu Cuong Nguyen",
"Hoang Van Nguyen",
"Van Tien Vu",
"Van Tran Pham",
"Dang Quyet Tran"
],
"abstract": "Introduction: Acne is a chronic inflammatory disorder of the pilosebaceous unit with differential pathogenesis. To elucidate the roles of hormones in acne pathogenesis, we conducted a study to evaluate the serum testosterone, estradiol, progesterone levels in women with acne vulgaris. Methods: We conducted a cross-sectional descriptive study, and 175 women with acne vulgaris were examined; their serum estradiol, progesterone, testosterone were analyzed by chemiluminescence technique and compared with the healthy control group. Results: Increased serum hormone levels in women with acne vulgaris were accounted for 29.7%, and hyperandrogenism was accounted for 16.0% of cases. We found significant differences in testosterone levels (mean value, 55.67±25.56 versus 38.37±10.16 ng/dL, p<0.05) respectively in the acne group and the control group. However, the estradiol level of the acne group (323.15±93.31 pmol/L) was lower than the control group (370.94±58.88 pmol/L) with p<0.05). No statistically significant differences were found for progesterone (0.60±0.38 versus 0.50±0.15 ng/mL, p>0.05) levels. Moreover, we did not find the relationship between serum hormone levels and the severity of acne vulgaris. Conclusion: This study showed that the female acne vulgaris patients may have high serum testosterone levels and low serum estradiol levels compared with those of female controls. However, hormone alterations had no correlation with the acne grades.",
"keywords": [
"Acne vulgaris",
"hormone"
],
"content": "Introduction\n\nAcne is a chronic inflammatory disorder of the pilosebaceous unit with various manifestations, including non-inflammation and inflammation lesions. Collier et al. (2008) investigated 1013 Americans aged 20 years and older; 73.3% (744) reported ever having acne, more women suffer from acne than men.1 Four major factors involved in acne pathogenesis are excessive sebum production, follicular hyperkeratinization, hyper-colonization of the duct by Cutibacterium acnes (formerly Propionibacterium acnes), and the production of inflammation.2 Moreover, the hormone plays a crucial role in the pathogenesis of acne. Some studies found that acne had a relationship with hyperandrogenemia in female patients.3 Estradiol, the primary female sex hormone is known as the major active estrogen, forms in absolute serum levels and estrogenic activity during human female reproductive years. Supplying sufficient amounts of estrogens will decrease sebum production and may act by suppressing androgen production by inhibiting the pituitary from secreting gonadotropin.4 The effect of progesterone on sebaceous glands was still disputed. Some authors have blamed progesterone for the change of sebum production in females during the menstrual cycle. However, this theory has not been proved experimentally.5 Therefore, we conducted this study to evaluate the serum testosterone, estradiol, and progesterone levels and the correlation of hormonal alterations with the severity of acne in women with acne vulgaris.\n\n\nMethods\n\nA cross-sectional study was conducted from January to October 2019 to concentrate serum estradiol, progesterone, testosterone levels in female acne patients at the Dermatology department of 103 military hospital, Vietnam.\n\nThe inclusion criteria for acne patients were females aged 16 to 30 years and diagnosed with acne vulgaris.\n\nThe control group’s criteria were healthy females without pregnancy or lactation.\n\nExclusion criteria were: diagnosis with (1) other types of acne; (2) patients with polycystic ovary syndrome; (3) using hormone contraceptives or other hormones; (4) a history of ovarian or pelvic surgery; (5) pregnant or breastfeeding women.\n\nThis was a prospective, cross-sectional descriptive study with control samples.\n\nThe sample size was based on the below formula and the research result of da Cunha (2013),5 we got n = 148.\n\nAll patients for each group were asked about risk factors, clinically examined, were performed tests (control group, acne group), and registered to study records.\n\nThe acne grading score, according to Karen McKoy (2008),6 is as follows:\n\n• Mild: less than 20 noninflammatory lesions or less than 15 inflammatory lesions or less than 30 total kinds of lesions.\n\n• Moderate: 20–100 noninflammatory lesions or 15–50 inflammatory lesions or 30–125 total kinds of lesions.\n\n• Severe: more than 05 papules/cysts or more than 100 noninflammatory lesions/more than 50 inflammatory lesions or more than 125 total kinds of lesions.\n\nAssessment technique of plasma hormone levels: 4 mL of venous blood was collected at 08:00 h and during the follicular phase of the menstrual cycle (2nd to 4th day of menses). Blood samples are contained in a tube with EDTA anticoagulant solution. After being incubated at room temperature for 10–20 minutes, samples are centrifuged for about 20 minutes at 2000–3000 rpm. After centrifuging, taking the plasma part for testing, we used direct chemiluminescent technology for measuring hormone levels in the Unicel® DXI800 machine. Units: testosterone for ng/dL, estradiol for pmol/L, progesterone for ng/mL.\n\nThe data were analyzed by SPSS software version 22.0. Mean SD are in the form: X¯±SD, comparing two means using the student t-test. The research results were compared by the Chi-squared test, and a p-value <0.05 was considered to be of statistical significance.\n\n\nResults\n\n210 female participants were enrolled in the study and divided into 175 female patients with acne vulgaris and 35 healthy controls.\n\nThe mean age of patients and BMI showed no statistically significant difference between the study group and the control group with p>0.05 (Table 1).\n\nThe plasma testosterone level of the acne vulgaris patients was higher than the control group, respectively 55.67±25.56 ng/dL, 38.37±10.16 ng/dL. The difference was statistically significant with p<0.05. On the other hand, plasma estradiol level in acne vulgaris patients was lower than the control group with a statistically significant difference (p <0.05), respectively 323.15±93.31 pmol/L and 370.94±58.88 pmol/l. However, plasma progesterone levels were not different between both groups (Table 2).\n\n52 patients (29.7%) out of 175 acne patients had hormonal alterations, including 28 patients (16%) with hyperandrogenism; 20 patients (11.43%) had increased serum progesterone level, only four patients (2.29%) had increased serum estradiol level, no patient had low hormonal levels (Table 3).\n\nThere were no different hormone levels between the grades of the acne vulgaris group and there were no different testosterone levels between the mild acne and control groups with p>0.05. However, testosterone levels in moderate and severe groups were statistically significantly higher than in the control group (p<0.05). Estradiol levels in the moderate and severe groups were statistically significantly lower than the control group with p<0.05. However, the estradiol level in the mild group was not significantly lower when compared with the control group. Progesterone levels in the mild and moderate groups were similar to the control group, except the severe group was higher than the control group; the difference was statistically significant with p<0.05 (Table 4).\n\n\nDiscussion\n\nThe gonads and the adrenal gland produce the majority of circulating androgens. However, androgens can also be produced locally within the sebaceous gland from the adrenal precursor hormone DHEAS (dehydroepiandrosterone sulfate). The major androgens interacting with the androgen receptor are testosterone and DHT (dihydrotestosterone). In addition, androgen receptors have been localized to the basal layer of the sebaceous gland and the outer root sheath keratinocytes.7\n\nIn 2013, da Cunha et al. investigated androgen levels in 835 female patients with acne vulgaris and found that the rate of androgenism was 10.77%.5 In 2014, Wei et al. studied endocrine disorders in 242 acne patients. The authors showed that serum testosterone levels were significantly increased in the acne patient group compared with controls.8 In this study, we found that the testosterone level of the acne group was higher than controls and the hyperandrogenism rate was 16%.\n\nWe hypothesize that estrogens might impact sebum secretion by three different mechanisms: the opposition of androgens within the sebaceous glands, inhibition of gonadal androgen production via a negative feedback mechanism on gonadotropin release, and has an effect on genes which play a role in sebaceous gland growth and lipid production.9 In 2014, Wei et al. surveyed 118 female acne patients compared with 90 sex-matched controls. The results showed that the estradiol level in the acne group decreased significantly compared with the control group with a p-value less than 0.001, respectively 263.81±14.83 pmol/L; 398.71±26.24 pmol/L.8 This result was also consistent with our result.\n\nTestosterone is converted into a more potent form DHT by 5-ARD (5α-reductase) enzyme causing an excess sebum production, whereas progesterone inhibits the activity of this enzyme and prevents turning testosterone into DHT. So, progesterone itself might be expected to reduce sebaceous gland activity. However, the progesterone effect on acne remains unclear. Although some studies show that progesterone can reduce androgen effects by inhibiting the 5-ARD enzyme or androgen receptors,10 the fluctuation of sebum production in women during the menstrual cycle and premenstrual cyclic flare has partly been associated with progesterone, and some progestins lead to an exacerbation of acne by interacting with androgen receptors.10,11 In our study, there was no statically significant difference between the acne group and controls in terms of serum progesterone levels. However, the progesterone level of the severe acne was higher than the control group; the difference was statically significant with p<0.05.\n\n\nConclusion\n\nThis study showed that the female acne vulgaris patients might have high serum testosterone levels and low serum estradiol levels compared with those of female controls. However, hormone levels differences had no correlation with acne grade.\n\n\nData availability\n\nDryad: Underlying data for ‘Assessment of serum hormone levels in female patients with acne vulgaris’. https://doi.org/10.5061/dryad.bvq83bk9z12\n\nThe project contains the following underlying data:\n\n‐ DATA.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nEthics approval\n\nApproval was obtained from the ethics committee of Hanoi Department of Science and Technology with the code: 01C-08/14-2017-3. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.\n\n\nConsent to participate\n\nWritten informed consent for publication of the patients’ details was obtained from the patients.",
"appendix": "Acknowledgments\n\nThe authors would like to thank the Department of Dermatology and Venereology of 103 Military hospital, Military Medical University, for their support during the study and to the patients for their voluntary participation in this research.\n\n\nReferences\n\nCollier CN, et al.: The prevalence of acne in adults 20 years and older. J. Am. Acad. Dermatol. 2008; 58(1): 56–59. PubMed Abstract\n\nBakry OA, et al.: Role of hormones and blood lipids in the pathogenesis of acne vulgaris in non-obese, non-hirsute females. Indian Dermatol. Online J. 2014; 5(1): S9–S16.\n\nPlaczek M, et al.: Elevated 17-hydroxyprogesterone serum values in male patients with acne. J. Am. Acad. Dermatol. 2005; 53(6): 955–958. PubMed Abstract\n\nThiboutot D: Acne: hormonal concepts and therapy. Clin. Dermatol. 2004; 22(5): 419–428. PubMed Abstract\n\nda Cunha MG , Fonseca FL, Machado CD: Androgenic hormone profile of adult women with acne. Dermatology. 2013; 226(2): 167–171. PubMed Abstract\n\nMcKoy K: Acne and related disorder. Merck and the Merck Manuals Medical Library; 2008.\n\nLiang T, et al.: Immunocytochemical localization of androgen receptors in human skin using monoclonal antibodies against the androgen receptor. J. Invest. Dermatol. 1993; 100(5): 663–666. PubMed Abstract\n\nWei B, et al.: Higher 17alpha-hydroxyprogesterone levels aggravated the severity of male adolescent acne in Northeast China. Dermatology. 2014; 229(4): 359–362. PubMed Abstract\n\nIan Mason J: The 3beta-hydroxysteroid dehydrogenase gene family of enzymes. Trends Endocrinol. Metab. 1993; 4(6): 199–203.\n\nRabe T, et al.: Inhibition of skin 5 alpha-reductase by oral contraceptive progestins in vitro. Gynecol. Endocrinol. 2000; 14(4): 223–230. PubMed Abstract\n\nBitzer J, Tschudin S, Alder J: Acceptability and side-effects of Implanon in Switzerland: a retrospective study by the Implanon Swiss Study Group. Eur. J. Contracept. Reprod. Health Care. 2004; 9(4): 278–284. PubMed Abstract\n\nNguyen CP, et al.: Underlying data for Underlying data for ‘Assessment of serum hormone levels in female patients with acne vulgaris’.2021. Publisher Full Text"
}
|
[
{
"id": "119712",
"date": "02 Feb 2022",
"name": "Berna Aksoy",
"expertise": [
"Reviewer Expertise Acne"
],
"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 evaluates serum hormone levels in women, comparing with a control group. The manuscript evaluated 3 hormones at menstruation period. However, themanuscript needs revision as:\nProgesterone 0,5 vs 0,6 may be better analysed by increasing control size, which is too small (175 vs 35). Additionally severe acne vs control group progesterone levels are significantly different. For a better statistical analysis the control group should be nearly half, and I think, therefore, that increasing control size will be meaningful statistically. The same is applicable to progesterone levels.\nAcne vulgaris is a term up to age 25, what is the rationale that you choose 30 years? Acne adultorum is supposed to be related to hormonal disturbances. Many acne adultorum patients are stressful working women, there is an increased rate of stress hormones such as prolactin and cortisol. It is better you exclude women over 25.\nEstradiol, progesterone and testosterone levels are in fact not enough for hormonal evaluation in women.\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? 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? No source data required\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "7782",
"date": "09 Feb 2022",
"name": "NGUYEN CUONG",
"role": "Author Response",
"response": "1. Progesterone 0,5 vs 0,6 may be better analysed by increasing control size, which is too small (175 vs 35). Additionally severe acne vs control group progesterone levels are significantly different. For a better statistical analysis the control group should be nearly half, and I think, therefore, that increasing control size will be meaningful statistically. The same is applicable to progesterone levels. - This article studied the relationship between acne vulgaris with three degrees of disease and hormone levels. And mild acne was found not in relation to sex hormone disorders. This study tried to find this relationship in the moderate and severe groups, with 35 patients in each group. So we decided to choose the control group of around 35 patients. To be more meaningful statistically, we will increase the number of patients in the control group. 2. Acne vulgaris is a term up to age 25, what is the rationale that you choose 30 years? Acne adultorum is supposed to be related to hormonal disturbances. Many acne adultorum patients are stressful working women, there is an increased rate of stress hormones such as prolactin and cortisol. It is better you exclude women over 25. Acne that occurs in patients over 25 years old is called post-adolescent acne, and the hormone levels in these patients will be affected by external factors such as stress. And Our study first chooses female acne patients ranging from 16 to 30. When we checked our data and found that patients over 25 years old had no change in my statistical data, we could replace the inclusive criteria field that we chose the patients from 16 to 25 years old. 3. Estradiol, progesterone, and testosterone levels are in fact not enough for hormonal evaluation in women. - Thank you for your comment. We will consider changing the article to “Assessment of serum testosterone, estradiol, and progesterone levels in female patients with acne”."
}
]
}
] | 1
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https://f1000research.com/articles/11-23
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https://f1000research.com/articles/12-78/v1
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19 Jan 23
|
{
"type": "Research Article",
"title": "The potency of a free maternal healthcare policy in achieving universal health coverage a cross-sectional qualitative study",
"authors": [
"Peter Twum",
"Eric Besseah Yeboah",
"Peter Agyei-Baffour",
"Kofi Akohene Mensah",
"Eric Besseah Yeboah",
"Peter Agyei-Baffour",
"Kofi Akohene Mensah"
],
"abstract": "Background: The main focus of Ghana’s free maternal healthcare policy under the national health insurance scheme was to reduce the maternal mortality ratio. Aim: This study aims at ascertaining the potency of this policy in the achievement of universal health coverage in Ghana. Method: A cross-sectional qualitative study was conducted in the Bibiani-Anwiaso-Bekwai Municipality from June to December 2021 among women in their reproductive age (15-49 years) to ascertain how the policy has enhanced women’s access to maternal healthcare thereby facilitating the attainment of universal health coverage. Written informed consent and permission to participate in the study was obtained from each participant. In the case of those under 18 years, consent was sought from their parents/guardians A multistage sampling technique was used to select districts, health facilities and study participants. Focus group discussion and four key informants interviews were conducted among two nurses and two midwives who were selected using purposive sampling. The data obtained from respondent was analysed using content analysis. Results: Generally the women included in this study were knowledgeable about the policy as they recounted that, through the policy, health services they could not afford before are now accessible without any financial constraints. This means that the policy has provided many women and neonates access to maternal healthcare and healthcare in general and therefore has contributed to the attainment of universal health coverage in the municipality. Conclusions: The policy has provided financial access to women in maternal healthcare in particular and healthcare in general. This shows that the policy has a strong potential to contribute to the attainment of universal health coverage in the municipality and the country at large. Therefore, women should be encouraged to subscribe to the health insurance policy",
"keywords": [
"Free maternal health",
"health policy",
"Universal health coverage",
"Municipality",
"Ghana"
],
"content": "Introduction\n\nUniversal Health Coverage (UHC) means that all individuals and communities receive the health services they need without suffering financial hardship.1,2 The requirement for this is based on the 1948 World Health Organisation (WHO) Constitution, which declares health a fundamental human right and commits to ensuring the highest attainable level of health for all.3–5 UHC emphasises not only on what services are covered, but also how they are funded, managed, and delivered.6\n\nMany countries are already making progress towards UHC, although everywhere there are challenges of the availability and the ability of health systems to provide undisrupted health services.7 All countries can take actions to move more rapidly towards UHC despite the setbacks or to maintain the gains have already been made.8 Each country is unique and may focus on different areas, or develop their own ways of measuring progress towards UHC.3 However, there is also value in a global approach that uses standardised measures that are internationally recognised so that they are comparable across borders and over time.9–11\n\nTogether with the World Bank, WHO have developed a framework to track the progress of UHC by monitoring both categories, taking into account the overall level and the extent to which UHC is equitable, offering service coverage and financial protection to all people within a population, such as the poor or those living in remote rural areas.12,13\n\nGhana introduced a Free Maternal Health Care Policy (FMHCP) under the national health insurance scheme (NHIS) in 2008.14 Under this policy, all pregnant women are exempted from paying NHIS premiums for new subscriptions or renewal of membership. Expectant mothers are also allowed free access to general medical services that are part of NHIS coverage, and a comprehensive maternal service package including antenatal, delivery, and postnatal care and also neonatal care for infants for the first three months after delivery.15 This focuses on the first category of WHO’s 16 essential health services in four categories as indicators of the level and equity of coverage in countries: reproductive, maternal, newborn and child health. In this study FMHCP is being used to measure progress made in Ghana towards UHC.\n\n\nMethods\n\nWe conducted a cross-sectional study among women in their reproductive age (15-49) who received maternal health care services in three selected health facilities from the sub-district; Bekwai Health Centre, Chirano Health Centre, and Anwhiaso Health Centre in the Bibiani-Anuiaso-Bekwai Municipality from June 2021 to December 2021. The age of the women was confirmed by inspecting their national health insurance cards. A systematic sampling technique was used to select Women who were aged 15-49 years who were within their second and third trimesters as well as nursing mothers within their first three (3) months of birth were included in the study. The women were selected at an interval of three. As patients were admitted they were assigned with numbers up to three and the third person was selected. Women who fell within the reproductive age group and had children aged between three and 12 months were selected to participate in the study. This was repeated at the various health facilities until the required number of 72 was obtained.Women who fall within the reproductive age group but had children older than 12 months were excluded from the study. In addition, in-depth interviews (IDIs) were conducted on Nurses and Midwives within antenatal clinics (ANCs) and child welfare clinics (CWCs) of selected health facilities. Three (3) nurses/midwives from each selected health facility were interviewed, which made a total of nine (9) from all the selected health facilities. Also, a key informant interview (KII) was done on the manager of NHIS at the Bibiani-Anwhiaso-Bekwai municipal office to buttress the information taken from the women.\n\nThe aim was to ascertain the potency of the free maternal health policy under the national health insurance scheme on enhancing women access to maternal health care services thereby contributing to the attainment of UHC.\n\nThe study adopted a multi-stage sampling technique. The health facilities in the municipality were stratified into three sub-districts. The names of the health facilities (Bekwai Health Centre, Chirano Health Centre, and Anwhiaso Health Centre) in each sub-district were written separately on pieces of a paper and folded and were put in a hat and one health facility was selected randomly (lottery) from each of the sub-districts.\n\nWomen who were in their reproductive age and have children aged between three (3) and twelve (12) months and have come to the health facilities to access maternal healthcare services were assigned numbers up to three (3) and every other third person was selected. This process was repeated at the various health facilities until the required number of 72 with 24 participants at each health facility across the three districts was attained.\n\nA purposive sampling technique was used to select nurses, midwives and the municipal national health insurance manager after they have consented to be interviewed. The IDIs on Nurses and Midwives were conducted in enclosed areas of the health facilities, whereas the KII for the manager of the national health insurance scheme (NHIS) at the study area i.e., Bibiani-Anwhiaso-Bekwai municipal office was done in his office.\n\nWomen who were aged 15-49 years who were within their second and third trimesters as well as nursing mothers within their first three (3) months of birth were included in the study.\n\nWomen, who were 15-49 years but were not pregnant or were pregnant but were within their first trimesters, were excluded from the study. The reason for excluding pregnant women in their first trimester is that they have not had enough ANC visits and might not have the needed experience to answer most of the questions for the study.\n\nQuestions for this study included socio-demographic characteristics of participants. The study also helped to find out the health insurance status of mothers. Questions for the study assessed health care services that were covered by the free maternal health care policy in Ghana and ascertained whether the FMHCP could be effective on maternal health-related outcomes. The study also identified some challenges that confronted mothers when they were accessing the FMHCP in Ghana and how these said challenges could be addressed in Ghana.\n\nA focus group discussion guide was prepared based on the study objectives.24 A total of six focus group discussions (FGD) consisting of 12 participants each, were conducted, two in each of the three selected health facilities. The FGDs were done on women during antenatal and postnatal services within enclosed areas of the health facilities. Among the topics considered for discussion during the FGD session were participant’s knowledge about the free maternal healthcare policy in terms of services provided under the policy and how many of the women have registered and benefited from the policy. Matters relating to impact of the policy on maternal healthcare, sustainability and challenges confronting the programme. This allowed the women to freely but critically express their views about the subject matter of the study. It also afforded the researcher the opportunity to probe further on the understanding of the women on the socio-cultural as well as financial components of the policy. The use of a discussion guide also encouraged the researcher to work and engage with study participants rather than simply observing them. It further allowed for full and uncompromising recognition of how the study participants’ experiences create meaning for them and influences their maternal health seeking behaviour and life choices. Focus Group Discussions were audio-recorded, transcribed verbatim, and checked for completeness and accuracy.\n\nNine in-depth interviews and 6 key informant interviews were conducted. The FGD guide was pre-tested in the Atwima Mponua District. This was done to ensure validity, reliability and to check ambiguities. The choice of the district was informed by the fact that it has similar characteristics of the study districts. The results of this pre-test revealed weaknesses in the guide which were subsequently addressed before its application on the field.\n\nQuestions for this study included socio-demographic characteristics of participants. The study also helped to find out the health insurance status of mothers. Questions for the study assessed health care services that were covered by the free maternal health care policy in Ghana and ascertained whether it could enhance women access to maternal healthcare and further help in the attainment of universal health coverage.\n\nQualitative data that emerged from key informant interviews were transcribed verbatim and checked for completeness and accuracy by checking punctuations. Also the focus group discussions were audio recorded, transcribed verbatim and checked for completeness and accuracy. Familiarisation of the data was done by listening to the tape recordings repeatedly to ensure that the correct transcription23 and coding have been done. This was followed by preliminary coding of data by identifying how the respondents conceptualised certain key phrases and words. The document was analysed by using content analysis through identification of general themes that emerged taken into consideration the objectives of the study. All data analysis was completed using NVivo 12 (QSR International, 2020) (RRID:SCR_014802). From the various themes and categories that emerged, the data was analysed thoroughly. The results were presented in a table.16\n\nEthical clearance was obtained from the committee of Human Research, Publications, and Ethics, (CHRPE) of Kwame Nkrumah University of Science and Technology (KNUST) with (Ref: CHRPE/AP/268/21). Written informed consent and permission to participate in the study was obtained from each participant. In the case of those under 18 years, consent was sought from their parents/guardians. The respondents were at liberty to withdraw from the study anytime they deemed it necessary. Moreover, participants were also at liberty to choose not to answer particular questions they were uncomfortable with. Strict confidentiality of the identity of respondents was maintained using unique numeric codes, which were available only to the principal investigator.\n\n\nResults\n\nThe in-depth interview (IDIs) and FGDs revealed that most of the women were knowledgeable about the FMHCP. FMHCP was perceived as a free means by which pregnant women could access NHIS cards, antenatal care, postnatal care, drugs, and other important maternal health services. The following are excerpts from a midwife (Respondent 1) and a pregnant woman attending antenatal care (ANC) (FGD 2):\n\nThis is a policy that helps give pregnant women access to free healthcare under the National Health Insurance Scheme. [Midwife, Participant 1]\n\nAs soon as you get pregnant, you assess the health facility freely as far as you have an NHIS card. [ANC client, FGD 2]\n\nOne other midwife stated emphatically how pregnant women are given priority to obtain NHIS cards for free, which then helps them to have access to free maternal care. According to her:\n\nThis policy allows all pregnant women to have free registration with NHIS after which they will be entitled to free ANC, delivery, and postnatal care. [Midwife, Participant 4]\n\nParticipants were also able to mention some of the services and drugs covered under the FMHCP. Most of them were aware of the fact that without the NHIS card, one could not access these services or obtain routine drugs for free. Regarding the services that pregnant women are given at ANC, most of the respondents affirmed that they were given for free.\n\nThose who come receive antenatal services, Out Patient Department (OPD), laboratory, and postnatal services. [Nurse, Participant 6]\n\nWith Anhwiaso, you would have to do the labs and scan at a different place because they don't have those facilities and that comes with its charges but at the community hospital, the scan is even free. [ANC client, FGD 1]\n\nThe interview with the key informant revealed how awareness was created for the FMHCP within the Municipality. It is therefore not surprising that most of the maternal health clients were appreciably knowledgeable about the FMHCP. According to the key informant:\n\nWe used a lot of means when we started. We were going to the facilities on their ANC days to announce to the pregnant woman there. We used the medium of radio, then we used our community interactions and there were national adverts and other things on the radio and TV too. And also, for the district, we designated a day for pregnant women at our office where they were attended to specifically. [Key informant]\n\nInformal payments were also reported among respondents. It was found that such payments were made for reasons such as the unavailability of drugs at the time the client was at the facility. For some clients, the prescribed drug had to be bought elsewhere. Additionally, both formal and informal fees were charged for services such as laboratory examinations and scans. Some participants made the following complaints during the discussions:\n\nJust like my sister is saying free services are provided for pregnant women at the facility but the services are not entirely free. You would have to pay for some services even with a health insurance card. [ANC client, FGD 1]\n\nThey only gave me folic acid and paracetamol, the other drugs I bought from the drugstore. [ANC client, FGD 2]\n\nYes, I paid (GH¢ 25 cedis for a scan. I was also given a prescription to purchase citrus c the first time I visited the facility, since I was told it was finished, I bought it myself. [ANC client, FGD 3]\n\nAlthough most of the health staff mentioned that clients are not charged any fees, they also affirmed that sometimes, clients are asked to buy drugs elsewhere. This usually occurs when those drugs are not available. According to one midwife:\n\nWe charge nothing, it’s only when drugs are not available in the health centre or they are not covered by NHIS that they are written for them to buy from outside. [Midwife, Participant 1]\n\nWe don’t charge any money from pregnant women. [Midwife, Participant 5]\n\nBoth participants of the focus group and interviewees alluded to the immense benefits of the FMHCP. Cognizance was given to how the policy has improved ANC attendance and reduced mortality. Overall, participants also remarked that, through the FMHCP, women who could not afford to pay for certain services were able to access those services without charge. FGD discussants for instance explained that:\n\nIt has improved the number of pregnant women who come to the health centre to give birth in this community. [Midwife, Participant 1]\n\nI think it’s good. If you do not have an NHIS card and you visit the facility, you will pay for everything, so I think it is good. [ANC client, FGD 2]\n\nAccording to one midwife, the free access to maternal health care came with the benefit of helping pregnant women seek care early enough. According to her, this helped to diagnose some obstetrically important conditions, as well as treat them at their onset to forestall complications. She said:\n\nIt has helped most pregnant women to seek early treatment which helps in the early detection of complications. [Midwife, Participant 4]\n\nAnother midwife also recounted how the policy has helped reduce maternal deaths in the district since the time of its implementation. She said:\n\nIt has improved access to healthcare services and in turn, reduce the maternal mortality rate of this district. [Midwife, Participant 8]\n\nFurthermore, the response of the key informant corroborated all that had been said. The informant indicated that since the implementation of the FMHCP, a downward trend of maternal mortality had been observed over the years. He said:\n\nI think it has worked well because over the years during their annual review which we were invited to, their report, the Ghana Health Service (GHS) indicated that there is a drastic reduction of maternal mortality and many more so I know it has worked. It has also worked because it seems the ladies now feel comfortable attending antenatal than before. [Key informant]\n\nRespondents indicated mixed views regarding the sustainability of the FMHCP. Thus, while some thought that it could be sustained for years to come, others highlighted that there are still gaps that need to be addressed. Otherwise, the sustainability of the policy may dwindle. However, respondents generally of the view that the policy is sustainable. One of the longest-serving midwives indicated that:\n\nI think sustainability is assured because the NHIA pays its debtors or stakeholders regularly. [Midwife, Participant 5]\n\nAnother health staff added that:\n\nI think this policy is averagely sustainable because the government doesn’t provide enough items. [Midwife, Participant 9]\n\nOther respondents, were of a contrary view. According to them, the fact that some services were still being paid for was enough to conclude that the policy is not sustainable.\n\nThe policy in my point of view is poorly sustainable, this is because most of the things to render the services with are mostly not available. [Midwife, Participant 1]\n\nThe key informant also mentioned that:\n\nI’m just being honorable; No. I don’t think it’s sustainable. The cost is quite huge and apart from that, the providers aren’t making the women reach the full benefit of the policy. [Key informant 1]\n\nSeveral challenges regarding the FMHCP were raised during discussions and interviews. It was noticed that the challenges were particular to the category of respondents. For instance, ANC clients mostly complained about informal fees, preferential treatment, and lack of laboratory and scan services. Discussants revealed that:\n\nMy challenge is with the charges. I paid GH¢ 1 for the container for the urine specimen so I asked the midwife if I would be paying GH¢ 1 every time I visit since she will be taking the container back and she said no because I was in nursing uniform. [ANC client, FGD 1]\n\nI have not benefitted from it. I always pay for everything. Some of the drugs I don’t buy if they write for me because my husband always says he doesn’t have money. The labs and the scan are expensive, sometimes I don’t do it because I will not be having money on me. [ANC client, FGD 5]\n\nUnavailability of drugs was also commonly reported as indicated in Table 1. As a result, most of the participants had purchased them from elsewhere. Clients mentioned that sometimes they could not afford those prescribed medications. Two clients lamented that:\n\n< Represents response to key informant interviews.\n\n# Response to focus group discussion.\n\n* Response to in-depth interview.\n\nMost of the drugs too are always not available so they are written for us to buy. [ANC client, Participant FGD 6]\n\nThey only gave me folic acid and paracetamol, the other drugs I bought from the drugstore. [ANC client, FGD 2]\n\nAdditionally, clients complained of preferential treatment that was exhibited by health staff. According to them, student nurses who visit ANC are treated better as compared to other clients.\n\nYou are well attended to when they see you in the nursing uniform but we have individual differences some are good and others are harsh. [ANC client (student nurse), FGD 1]\n\nInterestingly, one of the student nurses agreed to the earlier claim. She recalled:\n\nI was harshly treated one time when I visited in mufti but when next I went in my uniform, she was like, oh so you are a student nurse. They treat you well when you are in nursing uniform but for the other clients, the treatment is a bit harsh. [ANC client (student nurse), FGD 1]\n\nFor health staff, the main challenges of the FMHCP ranged from stock-outs to a low level of education among pregnant women. Some midwives explained:\n\nThere is always a shortage of maternal and child health record books. [Midwife, Participant 6]\n\nThere is always inadequate items and drugs to provide the needed care to pregnant women [Midwife, Participant 7]\n\nThere are no laboratory and scan services in our health center. [Midwife, Participant 8]\n\nThe key informant interview revealed an interesting challenge that was not mentioned at all before. The respondents revealed that some pregnant women have the belief that bad people can cause pregnancy complications for them if they go for their card early. He explained that:\n\nWe also have challenges from the pregnant women themselves. I don’t know from which religious beliefs, some of these women do not come early enough for the cards when they don’t have their own NHIS card. Some think going for the card early, the bad eyes will terminate their pregnancy. [Key informant 2]\n\nParticipants gave recommendations to help address the presently identified challenges of the FMHCP as shown in Table 1. The majority called on the government to do its part to ensure that the needed resources to keep services running are provided. Some clients recommended the following:\n\nGovernment should provide all drugs to the hospital and ensure that it’s given to the pregnant women by health professionals. [ANC client, FGD 4]\n\nLaboratory investigations and scans should be done free of charge for all pregnant women in every facility in Ghana. [ANC client, FGD 1]\n\nSome ANC clients also recommended that all clients be treated irrespective of whether they are student nurses or uninsured.\n\nEvery pregnant woman should be treated well and the same, whether insured or not. [ANC client, FGD 4]\n\nAdditionally, clients indicated that there is a need to ensure that resources for running maternal health services are always available. This is because stock-outs of drugs and other items such as ANC booklets disrupt the effective running of services. In such instances, staff resort to the use of improvised methods to keep services running. Some clients intimated that:\n\nThe scan and laboratories should be free and provided here. [ANC client, FGD 3]\n\nScan and laboratory services should be provided for us for free and should be available at the hospital. [ANC client, FGD 6]\n\nFrom the viewpoint of health staff, it was recommended that apart from communicating with the Health Directorate to do their part, more health staff need to be recruited by the government to match the growing number of maternal health attendants. By doing so, no client will be left untreated. She added again that it is important to educate mothers to know what the FMHCP is about to increase awareness. The following is an excerpt from the interview:\n\nGovernment should post more nurses and midwives to lower-level facilities like the health centres. We educate mothers about the policy to help them know their entitlement to the policy. [Midwife, Participant 1]\n\nFrom the key informant’s perspective, the problem of informal fees collected during maternal health care sessions could be addressed by lodging formal complaints. He explained as follows:\n\nFrom the provider's part where they find ways and means of getting money from these women, we have written to them just about a week or two ago and I’m hoping to get enough evidence and then a formal complaint. We have written to affected facilities to refund the monies taken from those women. [Key informant 3]\n\n\nDiscussion\n\nThe study used qualitative approach to assess how the Free Maternal Healthcare Policy (FMHCP) under the National Health Insurance Scheme could be used to enhance the attainment of the UHC in a municipality in Ghana. In doing this, the knowledge, impact of the policy on access to maternal healthcare services and the challenges of the policy were assessed.\n\nFindings from the study showed that most of the women included had knowledge about the services covered by the FMHCP and therefore are also aware of the services entitled to when they visit health facilities. The services are free NHIS registration or renewal, antenatal care, postnatal care, drugs, and general healthcare services for the mothers and their babies. This may be as a result of intensive public education the National Health Insurance Authority has embarked on over the years.16 This might have contributed to the number of women in their reproductive age registered with the insurance in Ghana being 46% as reported in the 2017 Ghana’s Maternal Health Survey.17 This finding is consistent with other studies conducted among women which affirmed that insurance covers antenatal care, childbirth and postnatal care.14,18\n\nThis study has also demonstrated that, the policy has had impact on both maternal and neonatal health. On maternal health, pregnant women who register or renew their membership with the insurance are exempted from making payments for maternal healthcare. Also, after subscription pregnant women are entitled to free antenatal care, free delivery and post-natal care. Aside these they are also entitled to general medical care.14,18 Neonates, on the other hands are entitled to free medical care for three months before they are registered with the insurance.15 As a result, mothers are able to visit health facilities regularly which makes it possible for early and timely detection of infection and diseases to be treated.14 In this way, women are less likely to have complications and eventually maternal mortality is reduced as well as under five mortality.16 The policy in this way is granting women and neonates, who are mostly vulnerable, access to health without being restricted by financial barriers a key component of UHC.8,9 In Ghana, the health insurance covers 99% of the diseases affecting the population and therefore the policy grants women access to healthcare thereby contributing to the realisation of UHC as reported in earlier studies.16,19,20\n\nIn this study, challenges such as informal fee payment, preferential treatment, and lack of laboratory and scan services were seen as besetting the policy. This could be attributed to factors such as general Ghanaian attitudes where people show gratitude by giving gifts both in kind and in cash to service providers. Also, the unavailability of laboratory and scan services could be as a result of the deprived nature of the study area and not because the policy does not cover them. In areas where these services are lacking and the few that are available are not accredited by the health insurance, women have no other options than to pay from their pockets.16 This is consistent with other studies which showed that pregnant women indicated that they are at certain times have to pay out of their pockets for drugs and services.16,21,22 These challenges could undermine progress towards UHC and therefore needs to be addressed by providing the needed resources to health facilities especially at the primary healthcare level which are mostly located in deprived communities to enhance the realisation of UHC.\n\nThe majority of the respondents were illiterate and could not read nor write hence, there was the need to translate the questions from English to the local language (Twi). The interpretation of the questionnaire to the local language (Twi) might have affected the intended meaning of the questions and could lead to inaccurate result. This however did not affect the findings of the study as effective training was given to field workers.\n\n\nConclusions\n\nIn general, the free maternal healthcare policy has granted access to maternal and neonatal healthcare services thereby contributing to the realisation of the UHC in the municipality and Ghana. It is therefore important to encourage all pregnant women to enrol on the health insurance scheme to have access to ANC, delivery and Post Natal Care (PNC) services. This will go a long way to potentially saving the lives of mothers and babies while achieving the sustainable development goals 3.1 target of reducing the global maternal mortality ratio to <70 per 100, 000 live births and to achieve universal health coverage.\n\n\nData availability\n\nOSF: Potency of Health Insurance in Achieving Universal Health Coverage, https://doi.org/10.17605/OSF.IO/2QTZM.23\n\nThis project contains the following underlying data:\n\n- FOCUSED GROUP DISCUSSION TRANSCRIPTION.docx\n\nOSF: Potency of Health insurance in achieving universal health coverage, https://doi.org/10.17605/OSF.IO/4R63E.24\n\nThis project contains the following extended data:\n\n- f000 focus.docx (Guidelines for focus group)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgement\n\nThe authors thank the committee of Human Research, Publications, and Ethics, Kwame Nkrumah University of Science and Technology for giving us ethical approval for this study.\n\n\nReferences\n\nSanogo NA, Fantaye AW, Yaya S: Universal Health Coverage and Facilitation of Equitable Access to Care in Africa. Front. Public Health. 2019; 7. PubMed Abstract | Publisher Full Text\n\nLoewenson R: Which UHC? Features for Equity and Universalism; Comment on “Universal Health Coverage for Non-Communicable Diseases and Health Equity: Lessons From Australian Primary Healthcare”. Int. J. Health Policy Manag. 2022; 704–707.\n\nNygren-Krug H: The Right(s) Road to Universal Health Coverage. Health Hum. Rights. 2019; 21: 215–228. PubMed Abstract\n\nNampewo Z, Mike JH, Wolff J: Respecting, protecting and fulfilling the human right to health. Int. J. Equity Health. 2022; 21: 36. PubMed Abstract | Publisher Full Text\n\nMeier BM: Human Rights in the World Health Organization: Views of the Director-General Candidates. Health Hum. Rights. 2017; 19: 293–298. PubMed Abstract\n\nIfeagwu SC, Yang JC, Parkes-Ratanshi R, et al.: Health financing for universal health coverage in Sub-Saharan Africa: a systematic review. Glob. Health Res. Policy. 2021; 6: 1. Publisher Full Text\n\nRanabhat CL, Kim C-B, Singh A, et al.: Challenges and opportunities towards the road of universal health coverage (UHC) in Nepal: a systematic review. Arch. Public Health. 2019; 77: 5. PubMed Abstract | Publisher Full Text\n\nAgyepong IA, Abankwah DNY, Abroso A, et al.: The “Universal” in UHC and Ghana’s National Health Insurance Scheme: policy and implementation challenges and dilemmas of a lower middle income country. BMC Health Serv. Res. 2016; 16: 504. PubMed Abstract | Publisher Full Text\n\nBloom G, Katsuma Y, Rao KD, et al.: Next steps towards universal health coverage call for global leadership. BMJ (Clinical research ed.). 2019; 365: l2107. Publisher Full Text\n\nAssefa Y, Hill PS, Gilks CF, et al.: Global health security and universal health coverage: Understanding convergences and divergences for a synergistic response. PLoS One. 2020; 15: e0244555. PubMed Abstract | Publisher Full Text\n\nGrépin KA, Irwin BR, Trakinsky S: On the Measurement of Financial Protection: An Assessment of the Usefulness of the Catastrophic Health Expenditure Indicator to Monitor Progress Towards Universal Health Coverage. Health System Reform. 2020; 6: e1744988. PubMed Abstract | Publisher Full Text\n\nMchenga M, Manthalu G, Chingwanda A, et al.: Developing Malawi's Universal Health Coverage Index. Front. Health Serv. 2022; 1. Publisher Full Text\n\nBoerma T, Eozenou P, Evans D, et al.: Monitoring progress towards universal health coverage at country and global levels. PLoS Med. 2014; 11: e1001731. PubMed Abstract | Publisher Full Text\n\nTwum P, Qi J, Aurelie KK, et al.: Effectiveness of a free maternal healthcare programme under the National Health Insurance Scheme on skilled care: evidence from a cross-sectional study in two districts in Ghana. BMJ Open. 2018; 8: e022614. PubMed Abstract | Publisher Full Text\n\nTwum P, Qi J, Aurelie KK, et al.: Effectiveness of a free maternal healthcare programme under the National Health Insurance Scheme on skilled care: evidence from a cross-sectional study in two districts in Ghana. BMJ Open. 2018; 8: e022614. PubMed Abstract | Publisher Full Text\n\nDalinjong PA, Wang AY, Homer CSE: Has the free maternal health policy eliminated out of pocket payments for maternal health services? Views of women, health providers and insurance managers in Northern Ghana. PLoS One. 2018; 13: e0184830. PubMed Abstract | Publisher Full Text\n\nAmeyaw EK, Dickson KS, Adde KS: Are Ghanaian women meeting the WHO recommended maternal healthcare (MCH) utilisation? Evidence from a national survey. BMC Pregnancy Childbirth. 2021; 21: 161. PubMed Abstract | Publisher Full Text\n\nAzaare J, Akweongo P, Aryeetey GC, et al.: Impact of free maternal health care policy on maternal health care utilization and perinatal mortality in Ghana: protocol design for historical cohort study. Reprod. Health. 2020; 17: 169. PubMed Abstract | Publisher Full Text\n\nAboagye RG, Okyere J, Ahinkorah BO, et al.: Health insurance coverage and timely antenatal care attendance in sub-Saharan Africa. BMC Health Serv. Res. 2022; 22: 181. PubMed Abstract | Publisher Full Text\n\nKipo-Sunyehzi DD, Ayanore MA, Dzidzonu DK, et al.: Ghana's Journey towards Universal Health Coverage: The Role of the National Health Insurance Scheme. Eur. J. Investig. Health Psychol. Educ. 2019; 10: 94–109. PubMed Abstract | Publisher Full Text\n\nAkweongo P, Aikins M, Wyss K, et al.: Insured clients out-of-pocket payments for health care under the national health insurance scheme in Ghana. BMC Health Serv. Res. 2021; 21: 440. PubMed Abstract | Publisher Full Text\n\nAlhassan RK, Nketiah-Amponsah E, Arhinful DK: A Review of the National Health Insurance Scheme in Ghana: What Are the Sustainability Threats and Prospects? PLoS One. 2016; e0165151.\n\nTwum P Dr.: Potency of Health Insurance in Achieving Universal Health Coverage. OSF. [Data].2022. Publisher Full Text\n\nTwum P Dr.: Potency of Health insurance in achieving universal health coverage. [Data].2022. Publisher Full Text"
}
|
[
{
"id": "178425",
"date": "19 Jul 2023",
"name": "Robert Kokou Dowou",
"expertise": [
"Reviewer Expertise Communicable and non-communicable diseases",
"public health policy",
"Health Insurance and maternal and child 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\nThis is an interesting study with the results supported by the literature. However, I have a few comments which if the authors address will help strengthen the manuscript.\nTitle:\nThe authors should put a colon punctuation after universal health coverage/\nSampling technique:\nIf only the names of the health facilities as you mentioned (Bekwai Health Centre, Chirano Health Centre, and Anwhiaso Health Centre) were written separately on pieces of a paper and folded and were put in a hat and one health facility was selected randomly, then that does not clearly describe the sampling method you are seeking to describe in details, there I will suggest you relook at this description to make it more clearer to the reader what exactly was done to arrive at the three health facilities were data was collected. For example, how many health facilities were in each of the sub-district? How many were selected to be part of the sampling frame?\nResults:\nIs there any socio-demographic/profile taken from the participants? It will be very helpful if those characteristics are presented in the results.\nThe quotes should be presented in inverted commas and also the attribution of the quotes should be done with participants job titles and their ages. For example (Nurse, 20 years).\n\nGeneral comments\nIt will be helpful to the readers if the authors provide copies of data collection guides use and ethical approval for the study and the data analysis files.\n\nThe authors should attach the thematic tables for IDI and FGDs.\nIt is also important the authors indicate the reporting guideline used for the reporting of this study and also attached the filled form of the reporting form used\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": "178423",
"date": "26 Jul 2023",
"name": "Tiara Marthias",
"expertise": [
"Reviewer Expertise Health systems research",
"maternal and child health",
"health equity",
"health financing",
"social health insurance."
],
"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 is an important assessment to ascertain the association between the health financing program and maternal health in Ghana.\n\nThere are some very crucial critiques, please see below the section by section comments. And at the end of this review, the general and major revision points are presented to make this article more meaningful and robust.\n\nAbstract:\n\nTypo (no period sign) between \"their parents/guardians A multistage sampling\".\n\nThe findings were quite predictable and so it would be more interesting to also read more nuanced findings in the abstract. I will get back to this once I read the full paper.\n\nIntroduction:\n\nReference to UHC definition should refer to its original source/s, i.e. the WHO. I am referring to references 1-5 used in the introduction section. Also reference 6, which is also not the primary source for the statement.\n\nThis comment refers to the second paragraph of the Introduction. In academic writing, not every sentence needs a reference. A main idea or original statement from the author should also be visible and prominent (no references needed for this type of sentence), and then followed with supporting evidence/statements from the literature.\n\nThird para: \"the WHO\"...\n\nFinal para: would it be possible to get a bit more context on the FMHCP? for instance, is enrolment automatic? (e.g. all pregnant women can automatically can access the free service? Is there any instance where they cannot?). Is the service available in both public and private health facilities? Is there any co-payment or other financial burden that women may have to bear?\n\nMethods:\n\nHow were the health facilities selected? Why the particular three facilities (Bekwai, Chirano, and Anwhiaso)?\n\nWhy 72? It's not usual for a qualitative study to define a set of sample size target, unless there is a particular level/grouping that warrants that.\n\nNo need to repeat the details of the sampling technique in both study design and sampling technique sections.\n\nI believe there is a selection bias that the researchers need to address. I.e. the women interviewed are those who are already accessing the services, so the information obtained is biased because it's only based on the perspective of what possibly are women who are more health-literate, those who have the means to access health insurance and can come to health facilities (having financial and geographical access). Not sampling from outside of the facilities possibly means that there is a breadth of perspective that the research would not be able to assess, e.g. how many women actually know about the program? Are all pregnant women aware and have access to the insurance card? Was it well promoted? Not interviewing women who DID NOT access the health service (that is by coming to their houses and asking whether they access pregnancy care) would miss out on digging deeper information on the coverage of the insurance and who are left behind by the policy/program.\n\nAdditional note: As I read through the Discussion section, I noticed that the coverage level of the insurance is pretty low at 46%, even after 10-years of policy implementation (from 2008, and the 56% data came from 2017 survey). Less than 50% of the target population is not insured. Meaning that the sampling selection is probably skewed towards those with better socioeconomic status, who are the ones most likely to be insured and can access health services. This to me, implies that there is indeed poor socialisation of the program and many pregnant women may not able to get covered under the insurance. I believe this is an important aspect of the UHC (i.e. population coverage) to assess and criticise.\n\nResults:\n\nThe informal payment finding is interesting and applicable to many LMICs settings. How often does this occur? Is there any indication on how often drugs are unavailable and whether the informal payment was found to be debilitating? Or is there any information if women were asked to buy drugs elsewhere, they decide (or cannot afford to) not to buy them? Additional note; as I read through the results section, I noticed that there are more info on this in the \"Challenges\" section. I would suggest to combine these findings (perhaps just under challenges), so that the readers could better understand the whole picture of informal payment.\n\nQuote \"I think this policy is averagely sustainable because the government doesn’t provide enough items\" --> does this imply that the benefit package is very limited? It's not clear just from this excerpt.\n\nQuote \"The cost is quite huge and apart from that, the providers aren’t making the women reach the full benefit of the policy\" --> what does not reaching the full benefit mean? I would suggest that quotes should be put into more context and interpretation or supplemented by other information or observation that the researchers have gathered.\n\nQuote \"I was harshly treated one time when I visited in mufti \" --> What is 'mufti'?\n\nDiscussion:\n\nI believe the most important discussion points would be: how the coverage is still low (less than 50%) and even among those who managed to access health services, there are all these challenges. Does the program really improve maternal health use for its intended target population? Social health insurance is supposed to protect those most vulnerable and who could not otherwise have any access to health services. But in the case of this study, also due to its limitation regarding the sample selection, it seems that it may only benefit certain groups of the population (which could be further assessed using quantitative data, i.e. benefit incidence analysis) and even then, there are structural and managerial challenges remain.\n\nAnd thus, the conclusion is quite misleading. The free maternal health care policy in its current state in Ghana covers only a small proportion of women, many are left out of the program, it has a lot of issues (informal payment, limited benefit package, providers' behaviour that could be improved, etc). So maybe there is a need to rethink the design of the insurance, even if it works, it only works for less than half of the population and even then, those who are covered are not universally covered based on the dimensions of UHC.\n\nI would suggest a rather totally different tone and assessment of the findings and be more critical on the design and implementation of the health insurance program. The equity lens must always be applied in any health research, particularly those assessing the impact of public/social health insurance programs on health care utilisations including maternal health care services.\n\nAnd there is a need to also address the selection bias of the participants, at the very least is by acknowledging this major limitation and cautious interpretation of the findings is very much necessary.\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?\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": []
}
] | 1
|
https://f1000research.com/articles/12-78
|
https://f1000research.com/articles/12-77/v1
|
19 Jan 23
|
{
"type": "Research Article",
"title": "Sepsis decreases lung SVEP1 expression in a murine model",
"authors": [
"Takeo Kurita",
"Takehiko Oami",
"Lisa Fujimura",
"Akemi Sakamoto",
"Ryoko Sato-Nishiuchi",
"Kiyotoshi Sekiguchi",
"Masahiko Hatano",
"Taka-aki Nakada",
"Takeo Kurita",
"Takehiko Oami",
"Lisa Fujimura",
"Akemi Sakamoto",
"Ryoko Sato-Nishiuchi",
"Kiyotoshi Sekiguchi",
"Masahiko Hatano"
],
"abstract": "Background: Genome-wide association studies have identified sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing 1 (SVEP1) polymorphism as a genetic risk factor for sepsis, as well as acute coronary syndrome. However, research on the role of SVEP1 in systemic inflammation, such as surgical invasion and sepsis, remains insufficient. Therefore, we investigated SVEP1 gene expression and protein levels after surgical invasion and sepsis in mice. Methods: We compared the gene expression and protein levels of SVEP1 between the control (no surgery), sham operation model, and sepsis model with cecal ligation and puncture in mice. Samples were collected at 2, 6, and 24 h after surgery. Results: The lungs had high gene expression and protein production of SVEP1 at baseline. Sham operation and sepsis decreased SVEP1 gene expression in the lungs immediately after stimulation. Furthermore, sepsis significantly downregulated the gene expression compared with sham operation. Flow cytometric analysis showed that mice with sepsis had a significantly decreased percentage of CD31high / SVEP1high and lymphatic vessel endothelial receptor 1 (LYVE-1)high / SVEP1high cells and an increased percentage of CD45.2high / SVEP1high cells. Conclusions: Sepsis decreased SVEP1 gene expression in the lungs. Mice with sepsis had a decreased percentage of SVEP1high vascular and lymphatic endothelial cells and an increased percentage of SVEP1high hematopoietic cells.",
"keywords": [
"SVEP1",
"Polydom",
"sepsis",
"vascular endothelial cell",
"lymphatic endothelial cell"
],
"content": "Introduction\n\nSepsis remains the leading cause of death despite the development of acute care and the widespread use of guidelines.1–3 Among the various factors related to the severity of sepsis,4–6 a recent genome-wide association study has revealed that sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing 1 (SVEP1) gene polymorphism is associated with altered mortality and organ dysfunction in septic shock.7,8 The negative impact of genetic polymorphisms of SVEP1 has also been reported in coronary artery disease with promoted inflammation and atherosclerosis.8–10 These findings suggest that SVEP1 plays a critical role in the progression of systemic inflammation. Therefore, investigating SVEP1 following surgical invasion and sepsis may contribute to further elucidation of the pathophysiology and development of novel treatments.\n\nSVEP1 is an extracellular matrix protein containing a signal peptide followed by multiple different protein domains: a pentraxin domain, a von Willebrand factor type A domain, ephrin2-like cysteine-rich repeats, a hyalin domain, domain similar to thyroglobulin type 2 repeats, 10 epidermal growth factor domains, and 34 complement control protein modules.11 SVEP1, with a size greater than 300 kDa, is present in the cytoplasm and is degraded into N-terminal SVEP1 (90 kDa) after secretion into the extracellular space.12 This cell adhesion molecule appears to play a key role in regulating intercellular adhesion and embryonic lymphatic development via the angiopoietin-2 and Tie1/Tie2 receptor systems.12–15\n\nCell adhesion and vascular permeability have been recognized as important elements that alter the pathophysiology of sepsis.16,17 An interaction between angiopoietin and Tie, which modulates endothelial permeability, has an impact on the progression of organ dysfunction and mortality in septic shock.18–23 A previous study showed that inhibition of SVEP1 expression resulted in an increase in the levels of soluble intracellular adhesion molecules (sICAM) and soluble E-selectin in an in vitro model of endotoxemia, implicating that SVEP1 is responsible for regulating vascular permeability in sepsis.24 Despite the potentially strong associations between SVEP1 and sepsis, the role of SVEP1 during systemic inflammation is yet to be determined.\n\nTherefore, in this study, we tested the hypothesis that surgical invasion and sepsis alter SVEP1 gene expression and protein production in a murine model.\n\n\nMethods\n\nC57BL/6 mice were purchased from Japan CLEA (Tokyo, Japan). All mice were housed in a controlled environment with a 12-h day and night cycle under specific pathogen-free conditions. Eight- to 12-week-old male and female mice were used for the experiments. The experimental procedures were approved by the Institutional Animal Care and Use Committee of Chiba University (approval number; 2-88; 3/13/2020). This study was carried out in accordance with the recommendations of the Chiba University Resolution on the Use of Animals in Research. The protocol was approved by the Institutional Animal Care and Use Committee of the Chiba University, School of Medicine. The mice were maintained under specific pathogen-free conditions at the Animal Center of the Chiba University Graduate School of Medicine. All efforts were made to ameliorate harm to animals. If necessary, we sacrificed mice under anesthesia to minimize any suffering of animals.\n\nThe cecal ligation and puncture (CLP) procedure was used to create an intra-abdominal sepsis model. Briefly, a midline incision was made on the abdomen, and the cecum was exposed following anesthesia with 2% isoflurane. The cecum was ligated with a 15 mm length from the tip of the cecum and punctured once with a 20-gauge needle after squeezing feces into the cecum. The abdomen was closed in layers. Next, 1 mL of saline was injected subcutaneously for fluid resuscitation. The same procedures were used in the sham operation model, except for CLP. After the surgery, the mice were sacrificed by cervical dislocation at the time of sample collection under anesthesia. In the control (no surgery), sham operation model, and CLP model, samples were harvested at 2, 6, and 24 h after the surgery without perfusion.\n\nWe compared the gene expression and protein levels of SVEP1 between the control (no surgery), sham operation model, and sepsis model with cecal ligation and puncture in mice. Samples were collected at 2, 6, and 24 h after surgery. We used eight mice in each model for reverse transcription-quantitative polymerase chain reaction and western-blotting, and four mice in each model for flow cytometry. We used a total of 92 mice in all experiments. We did not conduct priori sample size calculation. As we had no pre-defined exclusion criteria, no mice were excluded in each experiment.\n\nTotal RNA was isolated using a RNeasy Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. Single-stranded cDNA was transcribed from total RNA using a SuperScript III™ First-Strand Synthesis System for RT-PCR and random hexamers (Invitrogen, USA). RT-qPCR was performed with a Power SYBR® Green PCR Master Mix (including Dual-Lock™ Taq DNA Polymerase) (Thermo Fisher Scientific, USA) and analyzed using an ABI PRISM® 7000 Sequence Detection System (Applied Biosystems, USA). We used GAPDH as a housekeeping gene. Primers are shown in Table 1. The thermal cycling were run on 95°C for 10 minutes, 40 cycles of 95°C for 15 seconds and 60°C for 1 minute, 95°C for 15 seconds, 60°C for 1 minute, and 95°C for 15 seconds.\n\nRT-qPCR, reverse transcription-quantitative polymerase chain reaction; F, forward; R, reverse.\n\nThe rabbit anti-N-terminal region of mouse SVEP1 (polyclonal N antibody) developed at the Institute for Protein Research, Osaka University12 was used to detect proteins. The proteins collected from the homogenized organs were run on polyvinylidene difluoride gels and transferred onto silver nitrate or polyvinylidene difluoride membranes. For immunoblotting, the membranes were probed with the poly N antibody and peroxidase-conjugated affinity pure donkey anti-rabbit IgG (Jackson Immuno Research, USA) and then reacted with ECL Prime Western Blotting Detection Reagent (GE Healthcare, USA). The signal intensity of SVEP1 in the organs was analyzed using ImageJ software (RRID:SCR_003070) (Bethesda, MD, USA). We showed representative densitometric images of western blotting that were cropped as protein bands corresponding to the size of SVEP1 and GAPDH. We did not splice the images.\n\nWhole lung tissue was collected without perfusion and treated with collagenase to isolate single cells. After labeling with cell-surface antibodies, including anti-mouse CD45.2, anti-mouse CD31 (BD Pharmingen, USA), and anti-mouse lymphatic vessel endothelial receptor 1 (LYVE-1) (LifeSpan Biosciences, USA), the cells were stained with poly N antibody as the primary antibody and goat anti-rabbit IgG-FITC (Santa Cruz Biotechnology, USA) as the secondary antibody. This was followed by permeabilization and fixation using the Foxp3/Transcription Factor Staining Buffer Set® (eBioscience, USA). Samples were run on a FACSCalibur® (BD Bioscience, USA) and analyzed using FlowJo® (RRID:SCR_008520) (BD Bioscience). A freely available alternative for the analysis is R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria, https://www.r-project.org/) using the flowCore package (RRID:SCR_002205).\n\nWe compared the control with the sham operation model and CLP model using the Kruskal-Wallis test with Dunnett’s multiple comparison test. We compared the sham operation model with the CLP model at each point in time using the Student’s t-test or Mann-Whitney test according to normality. We used GraphPad Prism 8 (RRID:SCR_002798) (GraphPad software, USA) for statistical analysis. R version 4.1.2 (R Foundation for Statistical Computing) is a freely available alternative for statistical analysis. Results were considered statistically significant at p < 0.05.\n\n\nResults\n\nWe first evaluated SVEP1 gene expression and protein production in vital organs, including the heart, lungs, liver, spleen, kidneys, and colon, in C57BL/6 mice at baseline. The lungs and spleen had 29.6- and 11.2-fold higher SVEP1 gene expression, respectively, compared with the average expression in the other four organs (Figure 1A).36\n\n(A) Relative SVEP1 gene expression levels in various organs (normalized by the average of four organs: heart, liver, kidneys, and colon) are shown. Data are shown as the mean ± SEM; n = 8 mice in each group. (B) Representative densitometric images of western blotting in various organs at baseline are shown. GAPDH was used for normalization. SVEP1, sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing 1.\n\nSubsequently, SVEP1 protein expression in the organs was evaluated using the poly N antibody. The target band for the lung tissue was approximately 90 kDa, which is the size of the N-terminal SVEP1 secreted into the extracellular space. No target bands were clearly detected for the heart, liver, spleen, kidneys, and colon (Figure 1B). These results demonstrated that the gene expression and protein levels of SVEP1 were relatively high in the lungs at baseline.\n\nSince SVEP1 gene expression and protein levels were higher in the lungs at baseline than in other organs, we focused on the lung and examined the time course of SVEP1 gene and protein expression in the lungs after sham operation and CLP.\n\nIn the lungs, there was a significant decrease in SVEP1 gene expression 2 h after sham operation and 2/6/24 h after CLP surgery. SVEP1 gene expression returned to baseline levels at 6 and 24 h after sham operation. Furthermore, sepsis decreased SVEP1 gene expression until 24 h after CLP surgery. We found that SVEP1 gene expression was significantly reduced in the CLP model at all three time points compared with the sham operation model (Figure 2). These results indicate transiently decreased gene expression of SVEP1 in surgical invasion and persistent suppression of gene expression after sepsis induction.\n\nRelative SVEP1 gene expression in the lungs was compared between control (no surgery), 2 h after sham operation (Sham 2h), 6 h after sham operation (Sham 6h), 24 h after sham operation (Sham 24h), 2 h after CLP procedure (CLP 2h), 6 h after CLP procedure (CLP 6h), and 24 h after CLP procedure (CLP 24h). The data were normalized using the control. Error bars represent the mean ± SEM; n = 8 mice in each group. We compared the control to the Sham and CLP models using the Kruskal-Wallis test with Dunnett’s multiple comparison test (*, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001). We compared the sham operation model with the CLP model at each time point using the Student’s t-test or Mann-Whitney test according to the normality (†, p < 0.05; ††, p < 0.01; †††, p < 0.001; ††††, p < 0.0001). SVEP1, sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing 1; CLP, cecal ligation and puncture.\n\nWe quantitatively evaluated the SVEP1 90 kDa protein in the lungs by western blotting (Figure 3A). There was no change in the SVEP1 90 kDa protein level 2/24 h after sham operation and 2/6/24 h after CLP surgery. The SVEP1 90 kDa protein level was slightly elevated only 6 h after sham operation, and there was a significant difference between the Sham 6 h and CLP 6 h group (Figure 3B).\n\n(A) Representative densitometric images of western blotting in the lungs are shown. GAPDH was used for normalization. (B) Relative expression of 90 kDa SVEP1 protein was compared between control (no surgery), 2 h after sham operation (Sham 2h), 6 h after sham operation (Sham 6h), 24 h after sham operation (Sham 24h), 2 h after CLP procedure (CLP 2h), 6 h after CLP procedure (CLP 6h), and 24 h after CLP procedure (CLP 24h). The data were normalized using the control. Error bars represent the mean ± SEM; n = 8 mice in each group. We compared the control with the Sham and CLP models using the Kruskal-Wallis test with Dunnett’s multiple comparison test (*, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001). We compared the sham operation model with the CLP model at each time point using the Student’s t-test or Mann-Whitney test according to the normality (†, p < 0.05; ††, p < 0.01; †††, p < 0.001; ††††, p < 0.0001). SVEP1, sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing 1; CLP, cecal ligation and puncture.\n\nSince SVEP1 is an extracellular matrix protein,12 we examined the time course of gene expression of other extracellular matrix proteins, such as collagen1 and fibronectin, in the lungs after sham operation and CLP surgery. The gene expression of collagen1 was significantly decreased after sham operation and CLP surgery. At 6 and 24 h after the insult, gene expression was significantly lower in the CLP model than in the sham operation model (Figure 4A). By contrast, the gene expression of fibronectin significantly increased after sham operation and CLP surgery. In the sham operation model, fibronectin gene expression returned to baseline levels after 6 h, whereas gene expression in the CLP model remained significantly higher than that in the sham operation model (Figure 4B). The time course of collagen1, but not fibronectin, showed a similar trend with that of SVEP1 gene expression in sepsis.\n\nRelative gene expression of (A) collagen1 and (B) fibronectin in the lungs was compared between control (no surgery), 2 h after sham operation (Sham 2h), 6 h after sham operation (Sham 6h), 24 h after sham operation (Sham 24h), 2 h after CLP procedure (CLP 2h), 6 h after CLP procedure (CLP 6h), and 24 h after CLP procedure (CLP 24h). The data were normalized using the control. Error bars represent the mean ± SEM; n = 8 mice in each group. We compared the control to the Sham and CLP models using the Kruskal-Wallis test with Dunnett’s multiple comparison test (*, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001). We compared the sham operation model with the CLP model at each time point using the Student’s t-test or Mann-Whitney test according to the normality (†, p < 0.05; ††, p < 0.01; †††, p < 0.001; ††††, p < 0.0001). CLP, cecal ligation and puncture.\n\nNext, we performed flow cytometric analysis to identify the dynamics of SVEP1-expressing cells at the single-cell level in the lungs after surgery. At baseline, SVEP1 was expressed on CD31-positive vascular endothelial cells, LYVE-1-positive lymphatic endothelial cells, and CD45.2-positive hematopoietic cells (Figure 5B, D and F; Control).\n\nThe percentage of (A) CD31high/SVEP1high, (C) LYVE-1high/SVEP1high, and (E) CD45.2high/SVEP1high cells was compared between control (no surgery), 2 h after sham operation (Sham 2h), 6 h after sham operation (Sham 6h), 24 h after sham operation (Sham 24h), 2 h after CLP procedure (CLP 2h), 6 h after CLP procedure (CLP 6h), and 24 h after CLP procedure (CLP 24h). Representative flow plots of (B) CD31high/SVEP1high, (D) LYVE-1high/SVEP1high, and (F) CD45.2high/SVEP1high are shown. The data were normalized using the control. Error bars represent the mean ± SEM; n = 8 mice in each group. We compared the control with the Sham and CLP models using the Kruskal-Wallis test with Dunnett’s multiple comparison test (*, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001). We compared the sham operation model with the CLP model at each time point using the Student’s t-test or Mann-Whitney test according to the normality (†, p < 0.05; ††, p < 0.01; †††, p < 0.001; ††††, p < 0.0001). SVEP1, sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing 1; CLP, cecal ligation and puncture; LYVE-1, lymphatic vessel endothelial receptor 1.\n\nThe percentage of CD31high/SVEP1high vascular endothelial cells was significantly lower at 24 h after sham operation, whereas CLP surgery decreased the percentage at 2 and 6 h after the operation compared with the baseline. We found that the percentage of CD31high/SVEP1high cells was significantly lower at 2 and 6 h after CLP surgery compared with the sham operation (Figure 5A and B).\n\nThe percentage of LYVE-1high/SVEP1high lymphatic endothelial cells tended to decrease over 24 h after sham operation without significance. By contrast, the CLP model had a decreased percentage of LYVE-1high/SVEP1high compared with the control at 6 and 24 h and at all time points compared with the sham operation model (Figure 5C and D).\n\nAlthough the percentage of CD45.2high/SVEP1high lung hematopoietic cells demonstrated no significant differences in the sham operation or CLP model compared with the control, the CLP model had a significantly higher percentage than the sham operation model at 2 and 6 h, which was followed by a return to baseline levels 24 h after the surgery (Figure 5E and F).\n\n\nDiscussion\n\nIn this study, we demonstrated that SVEP1 is highly expressed in the lungs at baseline. SVEP1 expression was decreased over the course of sepsis, with a decreased percentage of SVEP1high vascular endothelial cells and lymphatic endothelial cells and an increased percentage of SVEP1high hematopoietic cells.\n\nSince the 300 kDa full-length SVEP1 protein is secreted into the extracellular matrix and degraded into a 90 kDa protein, we examined the dynamics of 90 kDa SVEP1 protein expression in the lungs after CLP. Because there were no significant changes in the amount of the 90 kDa protein, the expression was potentially regulated at the transcriptional level rather than active degradation or consumption of the extracellularly distributed SVEP1. The present study revealed that SVEP1 gene expression in the lungs decreased not only after the CLP procedure, but also after sham operation. These findings suggest that the gene expression of SVEP1 responds not only to sepsis induction, but also to surgical invasion in the early phase after surgery. In addition, the decreased gene expression of collagen1, resembling the dynamics of SVEP1, was induced by surgical invasion and sepsis. The notable downregulation of SVEP1 by surgical stimulation without sepsis is intriguing. It has been reported that cytokines, such as TNF-α, are activated after surgical invasion and induce biological responses similar to sepsis.25–28 Based on our results, we believe that SVEP1 gene expression may be associated with these cytokines. Although estrogen reportedly regulates the expression of SVEP1,29 the exact mechanisms underlying the regulation of SVEP1 remain to be determined. Our findings that SVEP1 shows similar dynamics to collagen1 following the insult could be a critical clue to clarify the mechanisms underlying the regulation of SVEP1 expression.\n\nSince SVEP1 is highly expressed in lung tissue consisting of heterogeneous cell types, we analyzed the expression of SVEP1 at the single-cell level by flow cytometry. In accordance with the finding that SVEP1 deficiency in coronary artery disease increases endothelial CXCL1 expression and promotes plaque formation,30 the present study suggests that SVEP1 is secreted from endothelial cells. Since SVEP1 is supplied by vascular and lymphatic endothelial cells, the decreased percentage of cells with CD31high or LYVE-1high/SVEP1high after CLP surgery indicates that sepsis reduces intracellular SVEP1 protein production in the vascular and lymphatic endothelial cells or promotes the extracellular release of the protein. In terms of the reduced percentage of cells with CD31high and LYVE-1high after sepsis induction, the endothelial-mesenchymal transition might contribute to decreasing the overall percentage of CD31-positive cells after sepsis induction. The decreased percentage of CD31-positive cells in septic shock patients because of endothelial-mesenchymal transition supports our speculation of the altered specific population.31\n\nIn the time course of SVEP1 expression after surgery in lung cells of mice with sepsis, an increased percentage of CD45.2high/SVEP1high cells indicates that hematopoietic cells containing SVEP1 migrate to the lungs during sepsis. Although blood cells reportedly express less SVEP1,15 our results demonstrated a different pathology of SVEP1 following sepsis. Further analysis is needed to identify the localization of SVEP1 and the cells responsible for producing SVEP1.\n\nIn sepsis, endothelial hyperpermeability because of disruption of the glycocalyx layer16,19 and tight junctions17,32 exacerbates the pathophysiology of sepsis. Angiopoietin-1 and angiopoietin-2 act antagonistically with each other and regulate the function of tight junctions.18–21,33–35 An association between decreased expression of SVEP1 and increased expression of sICAM and E-selectin in a model of endotoxemia has been reported.24 These findings suggest that SVEP1 may regulate vascular permeability in cooperation with angiopoietin and cell adhesion molecules. Although we have not demonstrated the exact role of SVEP1 in sepsis, the time course of SVEP1 expression in vascular endothelial cells and lymphatic endothelial cells indicates that SVEP1 potentially regulates vascular permeability.\n\nThis study has several limitations. First, since we did not perform perfusion fixation prior to tissue collection, blood cells in the tissue potentially affected the whole analysis. Second, we used both male and female mice in this study; therefore, sex-associated differences might have affected the results. Third, the detailed functions of SVEP1 were not investigated in this study. Future research should clarify the significant contribution of SVEP1 in sepsis pathophysiology.\n\n\nConclusions\n\nSVEP1 expression was highly upregulated in the lungs compared with other organs at baseline. Sepsis suppressed SVEP1 gene expression with a decreased percentage of SVEP1high vascular endothelial cells and lymphatic endothelial cells and an increased percentage of SVEP1high hematopoietic cells.",
"appendix": "Data availability\n\nBioStudies: Sepsis decreases lung SVEP1 expression in a murine model. Accession number S-BSST942, https://identifiers.org/biostudies:S-BSST942. 36\n\nThis project contains the following underlying data:\n\n- SVEP1 Author Checklist – Full.pdf (completed ARRIVE checklist)\n\n- SVEP1 Data.xlsx\n\n- SVEP1 Lung GAPDH western-blot all gel.tiff\n\n- SVEP1 Lung SVEP1-90kDa western-blot all gel.tiff\n\n- SVEP1 organs GAPDH western-blot all gel.tiff\n\n- SVEP1 organs SVEP1-90kDa western-blot all gel.tiff\n\n\nAcknowledgments\n\nThe authors thank A. Goda and F. Iida for their technical support.\n\n\nReferences\n\nCecconi M, Evans L, Levy M, et al.: Sepsis and septic shock. Lancet. 2018; 392: 75–87. Publisher Full Text\n\nSinger M, Deutschman CS, Seymour CW, et al.: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315: 801–810. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQu Z, Zhu Y, Wang M, et al.: Prognosis and Risk Factors of Sepsis Patients in Chinese Icus: A Retrospective Analysis of A Cohort Database. Shock. 2021; 56: 921–926. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShimada T, Oda S, Sadahiro T, et al.: Outcome prediction in sepsis combined use of genetic polymorphisms - A study in Japanese population. Cytokine. 2011; 54: 79–84. PubMed Abstract | Publisher Full Text\n\nThair SA, Walley KR, Nakada TA, et al.: A single nucleotide polymorphism in NF-kappaB inducing kinase is associated with mortality in septic shock. J. Immunol. 2011; 186: 2321–2328. PubMed Abstract | Publisher Full Text\n\nGuillen-Guio B, Lorenzo-Salazar JM, Ma SF, et al.: Sepsis-associated acute respiratory distress syndrome in individuals of European ancestry: a genome-wide association study. Lancet Respir. Med. 2020; 8: 258–266. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNakada TA, Russell JA, Boyd JH, et al.: Identification of a nonsynonymous polymorphism in the SVEP1 gene associated with altered clinical outcomes in septic shock. Crit. Care Med. 2015; 43: 101–108. PubMed Abstract | Publisher Full Text\n\nNakada TA, Takahashi W, Nakada E, et al.: Genetic Polymorphisms in Sepsis and Cardiovascular Disease: Do Similar Risk Genes Suggest Similar Drug Targets? Chest. 2019; 155: 1260–1271. Publisher Full Text\n\nMyocardial Infarction G, Investigators CAEC, Stitziel NO, et al.: Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. N. Engl. J. Med. 2016; 374: 1134–1144.\n\nJung IH, Elenbaas JS, Alisio A, et al.: SVEP1 is a human coronary artery disease locus that promotes atherosclerosis. Sci. Transl. Med. 2021; 13: 13. Publisher Full Text\n\nGilges D, Vinit MA, Callebaut I, et al.: Polydom: a secreted protein with pentraxin, complement control protein, epidermal growth factor and von Willebrand factor A domains. Biochem. J. 2000; 352(Pt 1): 49–59. Publisher Full Text\n\nSato-Nishiuchi R, Nakano I, Ozawa A, et al.: Polydom/SVEP1 is a ligand for integrin alpha9beta1. J. Biol. Chem. 2012; 287: 25615–25630. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShur I, Socher R, Hameiri M, et al.: Molecular and cellular characterization of SEL-OB/SVEP1 in osteogenic cells in vivo and in vitro. J. Cell. Physiol. 2006; 206: 420–427. PubMed Abstract | Publisher Full Text\n\nSamuelov L, Li Q, Bochner R, et al.: SVEP1 plays a crucial role in epidermal differentiation. Exp. Dermatol. 2017; 26: 423–430. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMorooka N, Futaki S, Sato-Nishiuchi R, et al.: Polydom Is an Extracellular Matrix Protein Involved in Lymphatic Vessel Remodeling. Circ. Res. 2017; 120: 1276–1288. Publisher Full Text\n\nUchimido R, Schmidt EP, Shapiro NI: The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit. Care. 2019; 23: 16. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee WL, Slutsky AS: Sepsis and endothelial permeability. N. Engl. J. Med. 2010; 363: 689–691. Publisher Full Text\n\nFisher J, Douglas JJ, Linder A, et al.: Elevated Plasma Angiopoietin-2 Levels Are Associated With Fluid Overload, Organ Dysfunction, and Mortality in Human Septic Shock. Crit. Care Med. 2016; 44: 2018–2027. PubMed Abstract | Publisher Full Text\n\nLukasz A, Hillgruber C, Oberleithner H, et al.: Endothelial glycocalyx breakdown is mediated by angiopoietin-2. Cardiovasc. Res. 2017; 113: 671–680. PubMed Abstract | Publisher Full Text\n\nAslan A, van Meurs M , Moser J, et al.: Organ-Specific Differences in Endothelial Permeability-Regulating Molecular Responses in Mouse and Human Sepsis. Shock. 2017; 48: 69–77. Publisher Full Text\n\nFilewod NC, Lee WL: Inflammation without Vascular Leakage. Science Fiction No Longer? Am. J. Respir. Crit. Care Med. 2019; 200: 1472–1476. PubMed Abstract | Publisher Full Text\n\nHilbert T, Dornbusch K, Baumgarten G, et al.: Pulmonary vascular inflammation: effect of TLR signalling on angiopoietin/TIE regulation. Clin. Exp. Pharmacol. Physiol. 2017; 44: 123–131. PubMed Abstract | Publisher Full Text\n\nKorhonen EA, Lampinen A, Giri H, et al.: Tie1 controls angiopoietin function in vascular remodeling and inflammation. J. Clin. Invest. 2016; 126: 3495–3510. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchwanzer-Pfeiffer D, Rossmanith E, Schildberger A, et al.: Characterization of SVEP1, KIAA, and SRPX2 in an in vitro cell culture model of endotoxemia. Cell. Immunol. 2010; 263: 65–70. Publisher Full Text\n\nLin E, Calvano SE, Lowry SF: Inflammatory cytokines and cell response in surgery. Surgery. 2000; 127: 117–126. Publisher Full Text\n\nYan Y, Hu Y, Wang X, et al.: The predictive prognostic values of serum interleukin-2, interleukin-6, interleukin-8, tumor necrosis factor-alpha, and procalcitonin in surgical intensive care unit patients. Ann. Transl. Med. 2021; 9: 56. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMaeda K, Schoeniger LO, Shimada M, et al.: Regulation of acute phase gene expression following surgery and endotoxin administration in the anesthetized pig. Anesthesiology. 1993; 79: 1324–1337. PubMed Abstract | Publisher Full Text\n\nHabes QLM, Linssen V, Nooijen S, et al.: Markers of Intestinal Damage and their Relation to Cytokine Levels in Cardiac Surgery Patients. Shock. 2017; 47: 709–714. PubMed Abstract | Publisher Full Text\n\nShur I, Zemer-Tov E, Socher R, et al.: SVEP1 expression is regulated in estrogen-dependent manner. J. Cell. Physiol. 2007; 210: 732–739. PubMed Abstract | Publisher Full Text\n\nWinkler MJ, Muller P, Sharifi AM, et al.: Functional investigation of the coronary artery disease gene SVEP1. Basic Res. Cardiol. 2020; 115: 67. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTapia P, Gatica S, Cortes-Rivera C, et al.: Circulating Endothelial Cells From Septic Shock Patients Convert to Fibroblasts Are Associated With the Resuscitation Fluid Dose and Are Biomarkers for Survival Prediction. Crit. Care Med. 2019; 47: 942–950. Publisher Full Text\n\nMilam KE, Parikh SM: The angiopoietin-Tie2 signaling axis in the vascular leakage of systemic inflammation. Tissue Barriers. 2015; 3: e957508. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZonneveld R, Jongman R, Juliana A, et al.: Low Serum Angiopoietin-1, High Serum Angiopoietin-2, and High Ang-2/Ang-1 Protein Ratio are Associated with Early Onset Sepsis in Surinamese Newborns. Shock. 2017; 48: 638–643. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchuldt EA, Lieb W, Dorr M, et al.: Circulating angiopoietin-2 and its soluble receptor Tie-2 concentrations are related to inflammatory markers in the general population. Cytokine. 2018; 105: 1–7. Publisher Full Text\n\nZheng W, Nurmi H, Appak S, et al.: Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions. Genes Dev. 2014; 28: 1592–1603. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKurita T:Sepsis decreases lung SVEP1 expression in a murine model. [Dataset]. BioStudies. 2022. S-BSST942.Reference Source"
}
|
[
{
"id": "189449",
"date": "18 Aug 2023",
"name": "Jared S Elenbaas",
"expertise": [
"Reviewer Expertise SVEP1",
"animal models",
"translational 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\nThis study by Kurita et al. is designed to determine the expression of SVEP1 in pulmonary tissue of mice under different conditions that may relate to the protein's disease associations. This is a clear question that could provide meaningful insight into the diseases that associate with SVEP1, including sepsis.\nThe manuscript is well-written, and the statistics are acceptable, except in the cases outlined below. Unfortunately, we have a number of significant concerns regarding the methodology. These cases of inadequate methodology may undermine the major conclusions of the manuscript.\nMajor concerns:\nSeveral experiments rely on an antibody that has not been rigorously validated. Tissues and/or cells from animals lacking SVEP1 are critical for determining the specificity of the antibody in the respective tissue. The full gel images that the authors provide suggest the antibody is widely non-specific, and it is not clear that the band corresponding to 90kDa is truly staining SVEP1. Please see citation for appropriate antibody validation.\n\nGAPDH is used as a reference gene for qPCR, as well as for immunoblot assays in the manuscript. Although GAPDH is frequently used as a reference gene, it is well-recognized that it is not appropriate in certain conditions, including sepsis. Please see citation. Indeed, figure 3 suggests GAPDH may increase in their CLP model. A reference gene and loading control that does not change in response to sham and CLP treatments are necessary to interpret the experiments.\n\nThe authors use flow cytometry to identify changes in SVEP1-expressing cells. The signal along the x-axis purportedly represents SVEP1 staining, yet there is no separation between SVEP1+ and SVEP1- cells, suggesting the staining is non-specific. Neither endothelial cells, nor hematopoietic cells are thought to be major sources of SVEP1 expression, further raising concern about the specificity of the antibody (see point 1). Knockout or heterozygous mouse tissues should be used to validate this assay.\nMinor concerns:\nPlease clarify what the positive control material is in Figure 1.\n\nPlease clarify the significance of comparing SVEP1 expression to collagen1 and fibronectin. Why were these two proteins studied?\n\nThe statement beginning with \"the negative impact of genetic polymorphisms of SVEP1...\" has unclear meaning. Are the authors implying that these polymorphisms are loss of function?\n\nPlease clarify the significance/relevance of the claim, \"Based on our results, we believe that SVEP1...\".\n\nThe authors' claim that \"SVEP1 gene expression returned to baseline levels at 6 and 24 h after sham operation\", but do not use appropriate statistical tests to make this claim. Since they are claiming a decrease at 2 h, they should also test whether 6 and 24 h are significantly different than 2h to support their claim about returning to baseline.\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? 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": "189451",
"date": "18 Aug 2023",
"name": "Gavin E Morris",
"expertise": [
"Reviewer Expertise I have experience in working with SVEP1 and flow cytometry."
],
"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\nKurita and co-authors present the results of a study that investigates the expression of SVEP1 in various organs of mice at baseline and during a model of sepsis. The study concludes that SVEP1 expression changes in SVEP1-expressing cells in the lungs during sepsis. To model sepsis, the authors perform a cecal ligation and puncture (CLP) procedure and examined the effect of CLP upon SVEP1 expression using various gene and protein expression techniques. They find that SVEP1 expression is highest in the lung and spleen at baseline, with significant SVEP1 protein detected in the lung. During sepsis, SVEP1 gene expression decreased in the lungs at different time points. This decrease in SVEP1 expression may associate with changes in specific cell populations; however, further control experiments need to be performed before this can be stated. The study also reveals that SVEP1 protein expression remained relatively stable in the lungs during sepsis, suggesting that SVEP1 expression is regulated at the transcriptional level. Interestingly, surgical invasion without sepsis also led to the downregulation of SVEP1 gene expression, indicating its response to surgical stimuli.\nThis study is part of the group’s ongoing research on the polymorphism in SVEP1 as a genetic risk factor for sepsis, and begins to provide a mechanistic understanding to this genetic association. The findings indicate dynamic regulation of SVEP1 in response to sepsis, supports the validity to the model for further investigations into how SVEP1 specifically contributes to cell inflammatory responses, sepsis, lung function and pathology.\nHowever, there are some concerns and suggestions for the authors to consider:\nFigure 1: While representative blots are shown in B, there is no cumulative data presented as a bar chart (as in Figure 3) to quantitatively demonstrate SVEP1 expression across the organ types.\n\nIn all figure legends, there are P values stated that are not expressed in the data presented (e.g. **** P<0.0001)\n\nThe western blots throughout are cropped significantly, and there are no visible ladders. It would be beneficial to include the antibody catalogue numbers (for westerns and flow cytometry) for others who might wish to reproduce these data with these antibodies.\n\nGiven that SVEP1 is a ligand for integrin α4β1 and α9β1, and that integrins are targets of several pathogen-host interactions, it would be interesting to examine whether the expression of these integrins is also altered upon CLP.\n\nMajor concerns regarding the presented flow cytometric data:\nThe methods section does not specify whether the CD45.2, CD31 or LYVE-1 antibodies were conjugated-primary antibodies, or which secondary antibodies were used (catalogue numbers would help).\n\nIt is unclear why the samples were permeabilised since the proteins are expressed on the cell surface. The use of the Foxp3/transcription factor staining set also appears irrelevant here.\n\nThe data in Figure 5 requires reassurance that the data presented are not due to technical artifacts:\nincluding a live/dead dye would remove dead cells prior to analysis. There is no indication that doublets or red blood cells were removed prior to analysis. Alternatively, staining the nuclei with DAPI (or similar) would serve as a universal control for the cell population, ensuring only nucleated cells are included in the analysis.\n\nTechnical controls such as unlabelled cells (to show any autofluorescence) and IgG control antibodies (to show non-specific antibody binding) should be included to ensure cleaner populations for analysis. These will give reassurance that proper channel compensation has been performed to avoid fluorescence emission bleeding into other channels.\n\nThe cytometry axes are in arbitrary units and are (at best) semi-quantitative. The term “high” expression does not seem to correlate to the fluorescence intensity range within each gate, which makes further analysis redundant. In addition, the use of the term high, medium or low is usually relative to another population of the same (or similar) cell type. It is unclear how the thresholds were determined to categorize e.g. CD45.2+ cells as “high” for SVEP1 expression. Technical controls for each antibody will help determine the threshold in both x and y axis. There also seems to be very few truly high SVEP1 expressing cells in any cell population. For example, the alterations in event percentages in panels D&F do not seem to be due to any high expressing SVEP1 events, but just more LYVE-1 negative (panel D) or CD45.2+ events (panel F).\n\nThe alterations in cell percentages may be meaningless without control over identifying, quantifying, or accounting for the denominator populations. For example, in panel D, have the CD45.2+ events and instrument “noise” been removed from the analysis so that they do not confound the interpretation? Additional controls should be performed and included (see above) before inferring alterations in specific cell types.\n\nDetermining the smooth muscle population and examining whether SVEP1 expression is altered in this cell type could provide additional insight, with SVEP1 highly expressed in this cell type within the vasculature.\n\nThe introduction and results sections are clearly written, but the discussion section needs improvement. The authors make statements or link the current results to the findings of other studies without performing the necessary experiments to validate these claims: i) While the authors “believe SVEP1 gene expression may be associated with these cytokines” due to TNFα activation after surgical invasion, no experiments showing any association between SVEP1 and pro-inflammatory cytokine levels are presented. ii) The significance of both SVEP1 and collagen I gene expression decreasing post CLP as a “critical clue to clarify the mechanisms underlying the regulation of SVEP1 expression” needs to be explained more clearly. iii) The claim that the present study “suggests SVEP1 is secreted from endothelial cells” should be supported by experimental data. iv) Although the current study shows an alteration in SVEP1 expression in vascular endothelial cells, there is no experimental data linking SVEP1 and vascular permeability, and this should be made clear.\nBy addressing these concerns and suggestions, the authors can significantly strengthen their study and contribute valuable insight into SVEP1 expression within the lung in sepsis.\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?\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? No",
"responses": []
},
{
"id": "189446",
"date": "18 Aug 2023",
"name": "Thorsten Kessler",
"expertise": [
"Reviewer Expertise Molecular biology",
"cardiovascular sciences"
],
"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 had the opportunity to review the paper by Kurita and colleagues. The authors investigate the role of the protein SVEP1 in a murine model of sepsis. It needs to be taken into account that not much is known about SVEP1. It was associated with sepsis before but also coronary artery disease. Here, there are contradictory hypotheses which are based on in vivo studies in mice. In my opinion, a key question regarding all SVEP1 studies is how its expression behaves under baseline as compared to disease conditions. As a matter of fact, most of the SVEP1 that is found in the circulation might be produced by fat tissue. However, the role of circulating SVEP1 also remains elusive.\nThe authors add an important point to the SVEP1 research when they show that in sepsis, SVEP1 expression is reduced in lung tissue. A reduction of SVEP1 expression might indeed lead to leakage and characteristic sepsis phenotypes and might be comparable to what happens in atherosclerosis.\nMajor:\nThe manuscript is very focused. It is of descriptive nature and mechanistic insight is lacking. I am in particular not persuaded by the analyses of the SVEP1 90 kDa fragment.\n\nVascular tissue should be included in the gene expression analysis.\n\nThe protein analysis in Fig. 3 is not as clear as the mRNA analysis. What is the half-life of SVEP1?\n\nThe rationale to also investigate collagen 1 and fibronectin remains unclear. Further ECM proteins should be included.\n\nThe FC data in Fig. 5 is limited by the poor quality of SVEP1 antibodies and that they are not able to differentiate between full-length SVEP1 and fragments.\nMinor:\nContradictory results in atherosclerosis should be discussed.\n\nGrammar and orthography should be re-checked.\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? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-77
|
https://f1000research.com/articles/9-589/v1
|
11 Jun 20
|
{
"type": "Research Article",
"title": "Cytological and molecular screening of Chlamydia trachomatis in infertile women attending a maternity teaching hospital in Gezira State, Sudan: a cross-sectional study",
"authors": [
"Hajir Mohammed Hussien Omer",
"Khalid Eltahir Khalid",
"Elhadi Ibrahim Miskeen",
"Madiha Yousif Taha",
"Eylaf Yasir Saleh",
"Elhadi A. Ahmed",
"Omaima Hassan Abdelwahid",
"Mohammed Abdelssalam Hassan",
"Adam Dawoud Abakar",
"Khalid Eltahir Khalid",
"Elhadi Ibrahim Miskeen",
"Madiha Yousif Taha",
"Eylaf Yasir Saleh",
"Elhadi A. Ahmed",
"Omaima Hassan Abdelwahid",
"Mohammed Abdelssalam Hassan",
"Adam Dawoud Abakar"
],
"abstract": "Background: Chlamydia trachomatis (CT) is a sexually transmitted pathogen that threatens reproductive health worldwide. This study aims to screen CT urogenital infection using cytology and molecular methods in women suffering infertility. Methods: In total, 415 women suffering infertility, attending Wad Madani Maternity Hospital were included in this study and then classified into two groups: primary infertile women and secondary infertile women. Both urine (n= 415) and vaginal swab samples (n= 130) were collected and tested using Giemsa stain and Polymerase Chain Reaction (PCR) for detection of CT. Results: CT was detected in 33.7% (140/415) of urine samples and 73.1% (95/130) of vaginal swab samples using Giemsa stain, compared with 44.6% (185/415) and 84.6% (110/130) using PCR, respectively. In the primary infertile group (n= 265), chlamydia was detected in 35.8% (95/265) of urine and 75% (60/80) of swab samples by Giemsa stain compared with 50.9% (135/265) and 75% (60/80) of the samples by PCR. In the secondary infertile group (n= 150), chlamydia was detected in 30% (45/150) of urine and 70% (35/50) of swab samples by Giemsa stain compared with 33.3% (50/150) and 100% (50/50) of the samples by PCR. The associated risk factors were age, lower abdominal pain, and urethritis (p< 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value of Giemsa stain in detecting chlamydia compared to PCR were 86.4%, 100%, 100%, and 83.6%, respectively. Conclusions: Giemsa stain can be used as a screening test for detection of urogenital chlamydia in urine and vaginal samples in places where PCR is difficult to be performed.",
"keywords": [
"Chlamydia trachomatis",
"Infertility",
"Cytology",
"Polymerase Chain Reaction",
"Screening test."
],
"content": "Introduction\n\nChlamydia is the most common bacterial sexually transmitted infection (STIs), with more than 100 million new cases per year, and is caused by an intracellular Gram-negative bacterium named Chlamydia trachomatis (CT)1–3. CT infections of the lower female genital tract are frequently asymptomatic. However, if these infections do not resolve or persist untreated, the organisms can ascend to the upper genital tract, potentially causing salpingitis and functional damage to the fallopian tubes4. The World Health Organization (WHO) estimated that in 2012 there were 357.4 million new global cases of STIs, including CT (130.9 million cases) and Neisseria gonorrhoeae (78.3 million cases)5.\n\nImprovements in screening tests hold promises for increasing screening rates and preventing consequences of silent untreated infections. Until recently, asymptomatic infection and the lack of a simple and sensitive screening test has been a barrier to the accurate detection of CT infection. The prevailing concept was that chlamydia tests were conducted using cervical swabs for women and urethral swabs for men, but, due to the greater sensitivity and specificity of molecular tests, urine for both sexes can be used as a less invasive sampling technique3. Due to the asymptomatic nature of many chlamydia infections, screening is recognized as the most effective approach for reducing the sequela of this disease. Thus, the development of alternative, low-cost, easy-to-use, point-of-care methods for the detection and simultaneous screening of CT infections in clinical settings in a useful time frame remains a critical strategy for improving reproductive genital tract health worldwide1.\n\nSudan is one of the largest countries in Africa and most of its population live in rural areas. This country faces manifold problems including; low socioeconomic status, poor transportation and education, and health problems. One of these health problems is infertility. In Gezira State, Sudan, CT infections are neglected infections and there is no local preventive screening program or exhaustive information about the prevalence of these infections. In addition, to the best of our knowledge, no previous studies have been carried out to determine the size of the problem. This prompted the following study to be performed, which focusses on urogenital CT infections among women suffering infertility, which may be indicator for higher risk for more serious sequela of sexually transmitted diseases.\n\n\nMethods\n\nA cross-sectional hospital-based study was conducted from May 2017 to May 2018, to screen CT in urine and high vaginal swab samples from infertile women attending Wad Medani Maternity Hospital, Medani, Sudan.\n\nTwo permissions were granted to carry out this study; firstly from the Faculty of Medical Laboratory Sciences, University of Gezira, and secondly from the Ministry of Health, Gezira State. Written informed consent was obtained from all study subjects after they had been informed about the study objectives (for participants under the age of 18 years, consent was obtained from the husbands as per Sudanese policy).\n\nIn total 415 Sudanese, married women, suffering infertility were enrolled during the routine clinic of Wad Madani Maternity Hospital. The women were classified into two groups as follow: primary infertile women (n= 265), those failed to become pregnant for at least one year after marriage; and secondary infertile women (n= 150), those failed to become pregnant after a history of abortion and/or successful pregnancy/ies before. Women suffering vaginal bleeding were excluded from this study.\n\nThe study sample size (415) was calculated according to the following equation: (n = (z)2 p (1 – p ) / d2), where n stands for number, z equal 1.96 at 95% level of confidence, p for estimated proportion of the population, and d for margin of error 0.05.\n\nA questionnaire (Extended data6) was designed and filled out before clinical sample collection in order to obtain participant’s demographic characteristics and relevant clinical symptoms.\n\nSocioeconomic status was classified according to the participant’s income, or husband’s monthly income if the participant was not in employment as follows: high status, >30000 SDG per month; moderate, 30000–8000 SDG; low, <8000 SDG.\n\nEducation level was classed according to the last degree achieved by the participant as follows: high for undergraduate and post graduate degrees certificate; medium for secondary school degree certificate; and low for primary and pre-school level.\n\nParticipants were instructed on the proper self-collection of the first-void urine (i.e., the initial 10–30 mL of voided urine) using a sterile plastic wide neck leak-proof cup and transported to the laboratory within two hours. Also, high vaginal swabs were taken using a Dacron swab (COPAN DIAGNOSTICS INC.) by a trained medical officer.\n\nCytological technique. The urine sample was centrifuged to obtain a pellet to make a smear slide. Another smear was performed from the swab sample by rolling the swab gently on a glass slide. All smears were fixed using alcohol and then stained using weak solution of Giemsa stain for a longer staining time. The presence of intracellular inclusions of chlamydia was tested microscopically.\n\nMolecular technique. The DNA was extracted from urine and high vaginal swab samples using the manual chloroform phenol method, as described by Mohammed7. In brief, 500 µl of the sample was added to 500 µl of guanidine chloride, 5 µl proteinase K, and 150 µl ammonium acetate. The mixture was incubated overnight at 37°C, then boiled and cooled at room temperature. One milliliter (1 mL) of pre-chilled chloroform was added, vortexed, and centrifuged for 5 minutes at 3000 rpm. The upper layer was transferred to another tube, and 3 ml of cold absolute ethanol was added and kept at -20°C for 2 hrs. Then the tube was centrifuged at 3000 rpm for 15 minutes. The supernatant was discarded, the tube dried, the pellet was re-suspended with 70% ethanol, and centrifuged at 3000 rpm for 15 minutes. The supernatant was poured off again, the tube was dried and 200 µl of de-ionized water was used to re-suspend the last pellet. Finally, the tube was vortexed gently and stored at -20°C. The DNA purity was measured by spectrophotometer.\n\nThe desired conserved region of cryptic plasmid published DNA sequences for CT species was amplified by PCR using CT forward primer (5’-TAgTAACTgCCACTTCATCA-3’) and CT reverse primer (5’-TTCCCCTTgTAATTCgTTgC-3’), to produce 201 bp length end product. For the PCR setups; 25 ml PCR reaction mixture containing 5 µl of extracted DNA, 0.5 µl of each primer, 5 µl of PCR premix (containing 10 Mm Tris, 50 Mm KCL, 0.01% gelatin, 200 μM deoxynucleoside triphosphate, and 2.5 mM MgCl2), and 14 µl of sterile deionized water (Ready Master mix; MaximeTM PCR pre Mix Kit (i-Taq for 20 ul rxn), iNtRON). The first cycle was optimized to 5 min denaturation at 94°C, followed by 35 cycles each of 30s at 94°C, 45s at 55°C and 30s at 72°C with a final extension for 5 minutes at 72°C. PCR was run on GeneAmp PCR System 9700 version 3.1. 2DNA fragments were visualized in 1.5% agarose gels under UV light using gel documentation system (Ingenus, USA).\n\nData were analyzed using Statistical Package for the Social Science (SPPS) software version 20.0 (IBM, USA). Descriptive statistics including frequencies, mean, range, and standard deviation were calculated for all demographic, clinical, laboratory and other parameters. Specificity, sensitivity, positive and negative predictive values (PPV and NPV, respectively) were also calculated. Chi square test was used to determine the significance and associations. P<0.05 was considered significant.\n\n\nResults\n\nA total of 415 women were tested for CT in urine and high vaginal swab samples, their age range between 17 and 52 years. The study subjects divided into 265 (63.9%) women suffering primary infertility and 150 (36.1%) women suffering secondary infertility. Their mean age was 32.47±7.80 and 31.27±8.02 years, respectively. The majority of the women were between 31–40 years (43.4%) and 21–30 years (46.7%), and were housewives, resided in an urban city, with varying educational levels, and with moderate socioeconomic status (Table 1).\n\nA total of 415 urine samples were collected from participants, and, due to some traditional/social beliefs and the painful nature of the swab sampling, only 130 vaginal swab samples were obtained (Table 2). Using Giemsa stain, 33.7% and 73.1% were positive for CT, compared with 44.6% and 84.6% positive using PCR (Table 3). In the primary infertile group (n=265), chlamydia was detected in 35.8% (95/265) of urine samples and 75% (60/80) of swab samples using Giemsa stain, compared with 50.9% (135/265) and 75% (60/80) of the samples by PCR. In the secondary infertile group (n=150), chlamydia was detected in 30% (40/150) of urine samples and 70% (35/50) of swab samples by cytology, compared with 33.3% (50/150) of urine samples and 100% of swab samples (50/50) by PCR (Table 4). The risk factors associated with genital chlamydia infection were age, lower abdominal pain (PID), and urethritis (p<0.05; Table 5).\n\nThe sensitivity, specificity, PPV, and NPV of cytology in detecting chlamydia compared to PCR were 86.4%, 100%, 100%, and 83.6%, respectively (Table 6).\n\n\nDiscussion\n\nChlamydia is the most prevalent sexually transmitted bacterial infection worldwide2,7–9. Screening of the causative pathogen is important, not only to identify symptomatic individuals for the management of the infection and preventing the more serious sequela caused by the organism, but also to identify asymptomatic individuals who serve as reservoirs for the disease.\n\nAge is shown to be a risk factor for chlamydia infection among the sexually active population. In total, 29 of 34 studies in women have shown a significant relationship between age and chlamydia infection10. This is supported by results reported by Kucinskiene et al.11 and Navarro et al.10, and other studies performed in Sudan6, Brazil12, China13, and Peru14. In a previous study, many women who tested positive for CT reported increased risk of PID, ectopic pregnancy, and infertility (adjusted hazard ratio was 2.36, 1.87,and 1.85 respectively)15. For the current study, 81.1% of women positive for chlamydia were suffering from PID.\n\nThis study attempted to use the Giemsa staining technique as a non-invasive sample to detect CT in order to be used as an approach for screening program in Gezira state, where PCR is difficult to be applied. In our study, participant's swab samples tested by PCR showed that 84.6% of participants were positive, which is higher than that reported by Ortashi et al. (7.3%)16, Mohamed Elawad (49%)17, and Mohammed (22.5%)7,16.\n\nInfertility is a medical problem that affects more than 80 million people worldwide18,19. Although few data exist on infertility in Sudan, 68.9% of Sudanese couples suffering primary infertility, due to various causes, was reported recently20. Some researchers reported the link between chlamydia and both primary and secondary infertility4,9,21. In this study, using PCR, the percentage of positive cases among primary infertile women was 75%, which is higher than that reported by Malik et al. (27%)22 and Gorini et al. (31.8%)21. In addition, in our study, all women with secondary infertility were found to be suffering from chlamydia infection by PCR, which is also higher than that reported by Malik et al. (30.6%)22. This might suggest the role of chlamydia in the infertility cases seen in our study.\n\nTraditionally, detection and diagnosis of CT depends mainly on culturing cervical and urethral swab samples taken from women and men, respectively23. The culture technique is time consuming and requires well trained personnel and access to specialized facilities, which is not easy to be offered as a routine screening technique in Gezira State24. On the other hand, the sampling of both cervical and urethral swab have not been accepted by most patients due to the patients reported pain caused by the invasive nature of the spatula and the swab. In addition, there is resistance due to traditional beliefs (especially in communities that advocate circumcision in women). In order to overcome these drawbacks, we used urine samples in this study as a non-invasive sample to detect CT, which had been reported, evaluated and validated for use in most new techniques directed towards the detection of chlamydia trachomatis25–30.\n\nCytology was used as one of the non-cultural methods to detect intracellular inclusion bodies of CT31–34. This technique is especially useful and easy to perform and is accessible. Ultimately, this technique has established itself as a primary methods35. Giemsa staining is used and accepted by many authors to detect intracellular inclusion bodies of CT in cell lines used for culturing techniques30,35,36. In the current study, the Giemsa staining cytology reported high specificity and sensitivity when compared to PCR, which may suggest this technique as a reliable screening test for use in Gezira State.\n\n\nConclusions\n\nFrom the results of this study, chlamydia may be one of the causes of infertility inf women at Gezira State. The sensitivity and specificity of a cytology technique using Giemsa stain from a urine or vaginal sample can be used to screen urogenital chlamydia infection where PCR may be difficult to perform.\n\nCT screening, especially for Sudanese women, is of the utmost importance and should be performed through local or national screening programs. Screening programs have been shown to significantly decrease CT prevalence in some regions of the United States and Sweden37,38, and subsequently the severe sequela of the infection, including genital damage and infertility.\n\n\nData availability\n\nFigshare: Cytological and Molecular Screening of Chlamydia trachomatis in infertile women-Sudan .xlsx, https://doi.org/10.6084/m9.figshare.11871303.v239.\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: Extended data. Cytological and molecular screening of Chlamydia trachomatis in infertile women- Sudan, https://doi.org/10.6084/m9.figshare.12307331.v26.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nThe authors would like to acknowledge the Department of Medical Microbiology/University of Gezira- Sudan and Prime Medical Center/ Wad Madani- Sudan for the practical part of the study.\n\n\nReferences\n\nChen Y, Premasiri WR, Ziegler LD: Surface enhanced Raman spectroscopy of Chlamydia trachomatis and Neisseria gonorrhoeae for diagnostics, and extra-cellular metabolomics and biochemical monitoring. Sci Rep. 2018; 8(1): 5163. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFoschi C, Laghi L, D'Antuono A, et al.: Urine metabolome in women with Chlamydia trachomatis infection. PLoS One. 2018; 13(3): e0194827. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGaydos CA: Nucleic acid amplification tests for gonorrhea and chlamydia: practice and applications. Infect Dis Clin North Am. 2005; 19(2): 367–86, ix. PubMed Abstract | Publisher Full Text\n\nLi M, Zhang X, Huang K, et al.: Presence of Chlamydia trachomatis and Mycoplasma spp., but not Neisseria gonorrhoeae and Treponema pallidum, in women undergoing an infertility evaluation: high prevalence of tetracycline resistance gene tet(M). AMB Express. 2017; 7(1): 206. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHascoet JL, Dahoun M, Cohen M, et al.: Clinical diagnostic and therapeutic aspects of 221 consecutive anorectal Chlamydia trachomatis and Neisseria gonorrhoeae sexually transmitted infections among men who have sex with men. Int J Infect Dis. 2018; 71: 9–13. PubMed Abstract | Publisher Full Text\n\nOmer H, Kheiralla KEK, Miskeen EI, et al.: Untitled Item(extended data) Cytological and molecular screening of Chlamydia trachomatis in infertile women- Sudan. figshare. Online resource. 2020. http://www.doi.org/10.6084/m9.figshare.12307331.v2\n\nMohammed MA, Omer AFA: Molecular detection of Chlamydia trachomatis among gynecological patients attending Khartoum Teaching Hospital. Journal of Bacteriology Research. 2012; 4(4): 42–45. Publisher Full Text\n\nTamarelle J, Thiebaut ACM, Sabin B, et al.: Early screening for Chlamydia trachomatis in young women for primary prevention of pelvic inflammatory disease (i-Predict): study protocol for a randomised controlled trial. Trials. 2017; 18(1): 534. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMalik A, Jain S, Rizvi M, et al.: Chlamydia Trachomatis Infection in Women With Secondary Infertility. Fertil Steril. 2009; 91(1): 91–5. PubMed Abstract | Publisher Full Text\n\nNavarro C, Jolly A, Nair R, et al.: Risk factors for genital chlamydial infection. Can J Infect Dis. 2002; 13(3): 195–207. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nJensen IP, Fogh H, Prag J: Diagnosis of Chlamydia trachomatis infections in a sexually transmitted disease clinic: evaluation of a urine sample tested by enzyme immunoassay and polymerase chain reaction in comparison with a cervical and/or a urethral swab tested by culture and polymerase chain reaction. Clin Microbiol Infect. 2003; 9(3): 194–201. PubMed Abstract | Publisher Full Text\n\nHaugland S, Thune T, Fosse B, et al.: Comparing urine samples and cervical swabs for Chlamydia testing in a female population by means of Strand Displacement Assay (SDA). BMC Women's Health. 2010; 10(1): 9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMouton JW, Verkooyen R, van der Meijden WI, et al.: Detection of Chlamydia trachomatis in male and female urine specimens by using the amplified Chlamydia trachomatis test. J Clin Microbiol. 1997; 35(6): 1369–72. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKoumans EH, Black CM, Markowitz LE, et al.: Comparison of Methods for Detection of Chlamydia trachomatis and Neisseria gonorrhoeae Using Commercially Available Nucleic Acid Amplification Tests and a Liquid Pap Smear Medium. J Clin Microbiol. 2003; 41(4): 1507–11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSzarewski A, Pompey A, Bertrand J, et al.: Use of the Cytobrush for concurrent endocervical cytology and chlamydia sampling. Genitourinary med. 1990; 66(3): 205–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVinette-Leduc D, Yazdi HM, Jessamine P, et al.: Reliability of cytology to detect chlamydial infection in asymptomatic women. Diagn Cytopathol. 1997; 17(4): 258–61. PubMed Abstract | Publisher Full Text\n\nLevi AW, Beckman D, Hui P, et al.: Comparing Two Methods of Detection for Chlamydia trachomatis in Liquid-Based Papanicolaou Tests. Am J Clin Pathol. 2012; 138(2): 236–40. PubMed Abstract | Publisher Full Text\n\nMartinelli M, Musumeci R, Rizzo A, et al.: Prevalence of Chlamydia trachomatis Infection, Serovar Distribution and Co-Infections with Seven High-Risk HPV Types among Italian Women with a Recent History of Abnormal Cervical Cytology. Int J Environ Res Public Health. 2019; 16(18): 3354. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAsadi-Amoli F, Nozarian Z, Mehrtash V, et al.: Comparison of Direct Immunofluorescence and Giemsa Staining in Chlamydia trachomatis Follicular Conjunctivitis. Zahedan Journal of Research in Medical Sciences. 2015; 17(10). Publisher Full Text\n\nCornetta MdCdM, Gonçalves AKdS, Bertini AM: Efficacy of cytology for the diagnosis of Chlamydia trachomatis in pregnant women. Braz J Infect Dis. 2006; 10(5): 337–40. PubMed Abstract | Publisher Full Text\n\nWelte R, Kretzschmar M, Leidl R, et al.: Cost-effectiveness of screening programs for Chlamydia trachomatis: a population-based dynamic approach. Sex Transm Dis. 2000; 27(9): 518–29. PubMed Abstract | Publisher Full Text\n\nZakher B, Cantor AG, Pappas M, et al.: Screening for gonorrhea and Chlamydia: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014; 161(12): 884–93. PubMed Abstract | Publisher Full Text\n\nOmer HS, Salim ADA, Kheiralla KEK, et al.: Cytological and Molecular Screening of Chlamydia trachomatis in infertile women-Sudan .xlsx. figshare. Dataset. 2020. http://www.doi.org/10.6084/m9.figshare.11871303.v2"
}
|
[
{
"id": "71310",
"date": "19 Oct 2020",
"name": "Jayanti Mania-Pramanik",
"expertise": [
"Reviewer Expertise Immunodiagnostics of sexually transmitted infections",
"Immunogenetics and Immunology of related to Gynecological complications and cancers"
],
"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 a very old ref: ---The World Health Organization (WHO) estimated that in 2012 there were 357.4 million new global cases of STIs, including CT (130.9 million cases) and Neisseria gonorrhoeae (78.3 million cases).\n\nAny reference for the following? The study sample size (415) was calculated according to the following equation: (n = (z)2 p (1 – p ) / d2), where n stands for number, z equal 1.96 at 95% level of confidence, p for estimated proportion of the population, and d for margin of error 0.05.\n\nWhat is SDG? Write the full form.\n\nWhy vaginal samples have been collected? Endo Cervical samples are the best for testing CT.\n\nFor the PCR setups; 25 ml PCR? Any reference for this PCR is followed?\n\nThere is no figure to suggest that Giemsa staining can identify CT.\n\nThere is also no figure on PCR results.\n\nBoth Giemsa staining and PCR used seems to be showing false positives, may be due to contaminations.\n\nEven for interpretation of Giemsa staining and PCR for CT diagnosis, very trained personnel and technical experts are required.\n\nThere were no control groups used in the study.\n\nIn-house PCR should have been compared with a commercially available CT diagnostic kit to evaluate its sensitivity and specificity.\n\nWhat is the prevalence of CT in fertile women?\n\nInfertility may be due to several factors, these are not evaluated in these women.\n\nWhat is the infection rate among the spouses of these women\n\nThere many tables, which could have been represented only in 2 tables\n\nEvaluation of the methods used for the study needs to be verified, before its application in this study population.\n\nWhat other infections are detected in Giemsa staining?\n\nHow the authors have interpreted that the urine samples are adequate and useful for PCR or Giemsa? What denominator was used to test the quality of urine samples for testing?\n\nAny treatment was given to these women and what were the outcomes?\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": "6578",
"date": "16 Apr 2021",
"name": "Hajir Omer",
"role": "Author Response",
"response": "Dear reviewer: Please find enclosed the response to your comments. With Regards, The corresponding author: Hajir Omer 1. This a very old ref: ---The World Health Organization (WHO) estimated that in 2012 there were 357.4 million new global cases of STIs, including CT (130.9 million cases) and Neisseria gonorrhoeae (78.3 million cases). This estimation was cited to a reference published in 2018 Hascoet JL, Dahoun M, Cohen M, et al.: Clinical diagnostic and therapeutic aspects of 221 consecutive anorectal Chlamydia trachomatis and Neisseria gonorrhoeae sexually transmitted infections among men who have sex with men. Int J Infect Dis. 2018; 71: 9–13. PubMed Abstract | Publisher Full Text -------------------------------------------------------------------------------------------------------------------- 2. Any reference for the following? The study sample size (415) was calculated according to the following equation: (n = (z)2 p (1 – p ) / d2), where n stands for number, z equal 1.96 at 95% level of confidence, p for estimated proportion of the population, and d for margin of error 0.05. Jaykaran Charan and Tamoghna Biswas (2013), How to Calculate Sample Size for Different Study Designs in Medical Research? . Indian J Psychol Med. 2013 Apr-Jun; 35(2): 121–126. doi: 10.4103/0253-7176.116232 ------------------------------------------------------------------------------------------------------------------- 3. What is SDG? Write the full form. SDG will be replaced by SDP which used to abbreviate the Sudanese Pounds, and will be corrected in the text (highlighted by the pink color). ------------------------------------------------------------------------------------------------------------------- 4. Why vaginal samples have been collected? Endo Cervical samples are the best for testing CT. The study aimed to use more easier and also simple sample such as vaginal swab samples and urine samples rather than the endo-cervical sample which is usually not accepted by most of Sudanese women due to some traditional/social beliefs. ------------------------------------------------------------------------------------------------------------------ 5. For the PCR setups; 25 ml PCR? Any reference for this PCR is followed? This was a typing mistake and corrected to 25ml (highlighted by the pink color). ------------------------------------------------------------------------------------------------------------------- 6. There is no figure to suggest that Giemsa staining can identify CT. 10.6084/m9.figshare.14406413 ------------------------------------------------------------------------------------------------------------------- 7. There is also no figure on PCR results. 10.6084/m9.figshare.14406494 ------------------------------------------------------------------------------------------------------------------ 8. Both Giemsa staining and PCR used seems to be showing false positives, may be due to contaminations. No false positive results in the study. The PCR was performed by an expert under qualified and accurate conditions to avoid carryover and contamination. The false negative results showed by Giemsa staining method may be due to the low shedding of the epithelial cells in both urine and vaginal swab samples (low number of epithelial cells ‘the cells which carry the inclusion bodies of chlamydia’ in the sample). ------------------------------------------------------------------------------------------------------------------- 9. Even for interpretation of Giemsa staining and PCR for CT diagnosis, very trained personnel and technical experts are required. The authors are experts in the field of: *Microbiology (Hajir Omer and Alhadi Abdalla) *Molecularbiology (Khalid Eltahir and Hajir Omer) and *Cytology (Mohammed Abdelsalam) ------------------------------------------------------------------------------------------------------------------ 10. There was no control groups used in the study. The study designed as cross sectional study aimed to detect the feasibility to use both technique and sample for screening, so, no need to use control group. ------------------------------------------------------------------------------------------------------------------ 11. In-house PCR should have been compared with a commercially available CT diagnostic kit to evaluate its sensitivity and specificity. CT is one of the neglected infections in Gezira state, so absence of screening test prompted us to establish the use of cytology and PCR as screening test. Then, research will be followed further to include other objectives and evaluations. ------------------------------------------------------------------------------------------------------------------ 12. What is the prevalence of CT in fertile women? Using urine sample and PCR, CT was detected in 44.6% of the infertile women.in pilot study conducted before this one, including pregnant women, CT was detected in 9.2% of them. Lack of symptoms makes clinical diagnosis of chlamydial infection difficult. Screening of infertile women for CT is therefore recommended so far early therapeutic interventions. ------------------------------------------------------------------------------------------------------------------ 13. Infertility may be due to several factors, these are not evaluated in these women. The study subjects were selected in routine clinic after being evaluated and suggested for chlamydia infection on the basis of clinical symptoms. ------------------------------------------------------------------------------------------------------------------ 14. What is the infection rate among the spouses of these women Not included and not tested in this study. ------------------------------------------------------------------------------------------------------------------ 15. There many tables, which could have been represented only in 2 tables The tables were presented in this way to be more clear that the study included different techniques and different samples in addition to the table of sensitivity and specificity which need to be presented separately. ----------------------------------------------------------------------------------------------------------------- 16. Evaluation of the methods used for the study needs to be verified, before its application in this study population. (A): The methods used in this study were evaluated and verified by many authors 1.PCR was used by different authors to detect CT. *Ortashi OM, El Khidir I, Herieka E. Prevalence of HIV, syphilis, Chlamydia trachomatis, Neisseria gonorrhoea, Trichomonas vaginalis and candidiasis among pregnant women attending an antenatal clinic in Khartoum, Sudan. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 2004;24(5):513-5. *Mohammed A. Molecular detection of Chlamydia trachomatis among gynecological patients attending Khartoum Teaching Hospital. Journal of Bacteriology Research. 2012;4(4):42-5. (B): In order to overcome the samples' drawbacks, the urine (as non-invasive sample) had been reported, evaluated and validated by different authors for use in most new techniques directed towards the detection of Chlamydia trachomatis. *Paul ID, Caul EO. Evaluation of three Chlamydia trachomatis immunoassays with an unbiased, noninvasive clinical sample. Journal of clinical microbiology. 1990;28(2):220-2. *M Palmer H, B Gilroy C, J Thomas B, E Hay P, Gilchrist C, Taylor-Robinson D. Detection of Chlamydia trachomatis by the polymerase chain reaction in swabs and urine from men with non-gonococcal urethritis1991. 321-5 p. *Jensen IP, Fogh H, Prag J. Diagnosis of Chlamydia trachomatis infections in a sexually transmitted disease clinic: evaluation of a urine sample tested by enzyme immunoassay and polymerase chain reaction in comparison with a cervical and/or a urethral swab tested by culture and polymerase chain reaction. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2003;9(3):194-201. *Haugland S, Thune T, Fosse B, Wentzel-Larsen T, Hjelmevoll SO, Myrmel H. Comparing urine samples and cervical swabs for Chlamydia testing in a female population by means of Strand Displacement Assay (SDA). BMC Women's Health. 2010;10(1):9. *Mouton J, Verkooyen R, Meijden W, Rijsoort-Vos T, Goessens W, Kluytmans J, et al. Detection of Chlamydia trachomatis in male and female urine specimens by using the amplified Chlamydia trachomatis test. Journal of clinical microbiology. 1997;35:1369-72. (C): Cytology was used as one of the non-cultural methods to detect intracellular inclusion bodies of CT in different studies *Szarewski A, Pompey A, Bertrand J, Bradbeer C. Use of the Cytobrush for concurrent endocervical cytology and chlamydia sampling. Genitourinary medicine. 1990;66(3):205-7. *Vinette-Leduc D, Yazdi HM, Jessamine P, Peeling RW. Reliability of cytology to detect chlamydial infection in asymptomatic women. Diagnostic cytopathology. 1997;17(4):258-61. *Levi AW, Beckman D, Hui P, Schofield K, Harigopal M, Chhieng DC. Comparing Two Methods of Detection for Chlamydia trachomatis in Liquid-Based Papanicolaou Tests. American journal of clinical pathology. 2012;138(2):236-40. (D): Giemsa staining cytology was found used and accepted by many authors to detect intracellular inclusion bodies of CT in cell line used for culture technique. *Koumans EH, Black CM, Markowitz LE, Unger E, Pierce A, Sawyer MK, et al. Comparison of Methods for Detection of Chlamydia trachomatis and Neisseria gonorrhoeae Using Commercially Available Nucleic Acid Amplification Tests and a Liquid Pap Smear Medium. Journal of clinical microbiology. 2003;41(4):1507-11. *Asadi-Amoli F, Nozarian Z, Mehrtash V, Beheshtnejad H, Shabani A. Comparison of Direct Immunofluorescence and Giemsa Staining in Chlamydia trachomatis Follicular Conjunctivitis. Zahedan Journal of Research in Medical Sciences. 2015;17(10). *Cornetta MdCdM, Gonçalves AKdS, Bertini AM. Efficacy of cytology for the diagnosis of Chlamydia trachomatis in pregnant women. Brazilian Journal of Infectious Diseases. 2006;10:337-40. --------------------------------------------------------------------------------------------------------------------- 17. What other infections are detected in Giemsa staining? No others were detected, the cases already were selected in the basis of testing profile in the clinic. ---------------------------------------------------------------------------------------------------------------------- 18. How the authors have interpreted that the urine samples are adequate and useful for PCR or Giemsa? What denominator was used to test the quality of urine samples for testing? 1. Urine sample was approved to be useful in screening most of infectious agents using PCR. 2. Urine sample was used widely in detection most of microorganisms using cytological techniques. 3. The positive predictive value was 100% and the negative predictive value was 83.6% using the urine sample, and the positive predictive value was 100% and the negative predictive value was 57.1% using the swab sample (table 6). ---------------------------------------------------------------------------------------------------------------------- 19. Any treatment was given to these women and what were the outcomes? Azithromycin 1 g daily for 7 days was administered to positive cases and they were suggested to be followed by the doctor."
}
]
},
{
"id": "154077",
"date": "11 Nov 2022",
"name": "Philip Giffard",
"expertise": [
"Reviewer Expertise Molecular microbiology",
"genetic analysis methods",
"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\nThe authors compared PCR and a cytology approach to screening infertile women for Chlamydia trachomatis.\n\nThe cytology was significantly less sensitive than the PCR, but apparently quite specific.\nAlthough this study does not make use of modern concepts/genetic methods, it succeeded an answering a clear question, and has some translation potential. The finding was that there is a high prevalence of C trachomaitis in infertile women, and that screening with a low cost cytology assay, while somewhat insensitive, has some value.\n\nA problem with the study design is that there was no validation of the PCR method against a e.g. a fully validated molecular STI diagnostic platform. It would have been OK if such a validation had been done elsewhere/as part of another study. However, unless a critical reference has been omitted, this seems to be a new method, with an unknown performance in regard to a recognized gold standard such as a commercial diagnostics system. I guess total lack of false positive cytology assays lends some credibility to the assay.\n\nTable 6 is difficult to understand, mainly because of using \"Yes\" and \"no\" to mean positive and negative for the cytology assays.\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": "9017",
"date": "18 Jan 2023",
"name": "Hajir Omer",
"role": "Author Response",
"response": "Dear reviewer: Please find enclosed the response to your comments. With Regards, The corresponding author: Hajir Omer Author comments are underlined. The authors compared PCR and a cytology approach to screening infertile women for Chlamydia trachomatis. (Yes) The cytology was significantly less sensitive than the PCR, but apparently quite specific. Although this study does not make use of modern concepts/genetic methods (the limited resources, cost, availability of PCR as a routine test for Chlamydia may influence the author to use the simple method in detection, as the reviewer noticed that one of the study objective was to find more simple and reliable screening test), it succeeded an answering a clear question, and has some translation potential. The finding was that there is a high prevalence of C trachomaitis in infertile women (and this was so important findings because genital C.trachomatis infection is neglected at study area), and that screening with a low cost cytology assay, while somewhat insensitive, has some value. A problem with the study design is that there was no validation of the PCR method against a e.g. a fully validated molecular STI diagnostic platform. It would have been OK if such a validation had been done elsewhere/as part of another study. However, unless a critical reference has been omitted, this seems to be a new method, with an unknown performance in regard to a recognized gold standard such as a commercial diagnostics system. I guess total lack of false positive cytology assays lends some credibility to the assay. (the study depend on previous study conducted by Sudanese scientists ((Mohammed A. Molecular detection of Chlamydia trachomatis among gynecological patients attending Khartoum Teaching Hospital. Journal of Bacteriology Research. 2012;4(4):42-5.)) in the molecular method and on several studies approved the use of Giemsa and cytology to detect the inclusion bodies of CT ((such as: Asadi-Amoli F, Nozarian Z, Mehrtash V, Beheshtnejad H, Shabani A. Comparison of Direct Immunofluorescence and Giemsa Staining in Chlamydia trachomatis Follicular Conjunctivitis. Zahedan Journal of Research in Medical Sciences. 2015;17(10).)). Some modifications was introduced to suit the local used materials) Table 6 is difficult to understand, mainly because of using \"Yes\" and \"no\" to mean positive and negative for the cytology assays. (Yes, and will be replaced by “positive” and “negative”)"
}
]
},
{
"id": "154080",
"date": "15 Nov 2022",
"name": "Fernando Guerra",
"expertise": [
"Reviewer Expertise Sexual transmission diseases",
"Chlamydia",
"HPV",
"Gardnerella vaginalis",
"Mycoplasma spp."
],
"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\nCytological and molecular screening of Chlamydia trachomatis in infertile women attending a maternity teaching hospital in Gezira State, Sudan: a cross-sectional study.\nAfter reading this manuscript, I have some questions. The objective of the manuscript is confusing because the aim, according to the manuscript, is the screen CT urogenital infection using cytology and molecular methods in women who have infertility. If the intention is to evaluate the cytology method is necessary to change the title of the manuscript to Evaluation of Giemsa stain for screening of Chlamydia trachomatis in urine and vaginal samples from infertile women. Afterward, they concluded that Giemsa stain could be used as a screening test for detecting urogenital chlamydia in urine and vaginal samples where PCR is difficult to perform (Background).\nIntroduction section. This section does not describe the sensitivity and specificity of the Cytology method for screening Chlamydia infection, much less the still of Giemsa stain in Chlamydia detection. It is imperative to beef up their results with a good introduction and discussion.\nMaterial and Methods section. In this section, there is no good description of the cytology assay and no cytological description for considered as positive urine or vaginal sample; there are no images of the cytology of these samples.\nResults section. In this section, the patients are grouped into primary and secondary infertility. However, women up to 40 years old are considered infertile. If so, it is necessary that the material and methods section put the definition of infertility. I saw a better classification as women with and without lower abdominal pain. If you change the infertility classification, you must make a new statistical analysis.\nDiscussion section. There is no information about cytology methods in the discussion, such as an assay to screen Chlamydia infection. There are no described sensitivity and specificity of this test. There is no comment about of utility of Giemsa stain; there are no images of positive urine and vaginal samples. It is necessary to put these images. What experience has the technique to identify Chlamydia positive urine smear? Is it straightforward to locate positive urine smears? What is the weakness of the study, and what are its strengths?\nThe authors must remember that the description of the methodology must be well described if someone wants to reproduce this methodology.\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": "9106",
"date": "18 Jan 2023",
"name": "Hajir Omer",
"role": "Author Response",
"response": "Dear reviewer: Please find enclosed the response to your comments. With Regards, The corresponding author: Hajir Omer Author comments in italics After reading this manuscript, I have some questions. The objective of the manuscript is confusing because the aim, according to the manuscript, is the screen CT urogenital infection using cytology and molecular methods in women who have infertility. If the intention is to evaluate the cytology method is necessary to change the title of the manuscript to Evaluation of Giemsa stain for screening of Chlamydia trachomatis in urine and vaginal samples from infertile women. Afterward, they concluded that Giemsa stain could be used as a screening test for detecting urogenital chlamydia in urine and vaginal samples where PCR is difficult to perform (Background). Answer: Yes, the aim of this study was to screen CT using Giemsa stain and molecular method. And this was achieved by the result of positive cases using urine and swab samples. Further analysis was performed for the feasibility and of screening using Giemsa stain due to some reasons: CT is neglected infection in the study area. Molecular detection was confirmed and well established but with cost and applicability restriction. Instead, Giemsa stain is simple, cheap and available in study area. The cytology was confirmed and accepted by many authors but, this is the first study conducted in Sudan and Gezira State, so the need to notify the gynecologists for the test feasibility to screen CT using both simple test and non-invasive sample Introduction section. This section does not describe the sensitivity and specificity of the Cytology method for screening Chlamydia infection, much less the still of Giemsa stain in Chlamydia detection. It is imperative to beef up their results with a good introduction and discussion. The sensitivity and specificity of Giemsa stain was 38% and 97% respectively as described by Asadi and colleague in 2015. (Asadi-Amoli F, Nozarian Z, Mehrtash V, et al.: Comparison of Direct Immunofluorescence and Giemsa Staining in Chlamydia trachomatis Follicular Conjunctivitis. Zahedan Journal of Research in Medical Sciences. 2015; 17(10).) An extra description will be added to the new version of the introduction and discussion about Giemsa stain Material and Methods section. In this section, there is no good description of the cytology assay and no cytological description for considered as positive urine or vaginal sample; there are no images of the cytology of these samples. The following citation will be added to the references: Omer, Hajir (2021): Giemsa stain for C.trachomatis. figshare. Figure. https://doi.org/10.6084/m9.figshare.14406413.v1 Results section. In this section, the patients are grouped into primary and secondary infertility. However, women up to 40 years old are considered infertile. If so, it is necessary that the material and methods section put the definition of infertility. I saw a better classification as women with and without lower abdominal pain. If you change the infertility classification, you must make a new statistical analysis. The infertility definition was mentioned in methodology section. Discussion section. There is no information about cytology methods in the discussion, such as an assay to screen Chlamydia infection. There are no described sensitivity and specificity of this test. There is no comment about of utility of Giemsa stain; there are no images of positive urine and vaginal samples. It is necessary to put these images. What experience has the technique to identify Chlamydia positive urine smear? Is it straightforward to locate positive urine smears? What is the weakness of the study, and what are its strengths? The description of Giemsa stain will be mentioned in more details in methodology section. The description of Giemsa sensitivity will be mentioned in discussion section. The image (figshare) will be added in the references as follow: Omer, Hajir (2021): Giemsa stain for C.trachomatis. figshare. Figure. https://doi.org/10.6084/m9.figshare.14406413.v1 Thank you."
}
]
}
] | 1
|
https://f1000research.com/articles/9-589
|
https://f1000research.com/articles/10-324/v1
|
27 Apr 21
|
{
"type": "Opinion Article",
"title": "Data management challenges for artificial intelligence in plant and agricultural research",
"authors": [
"Hugh F. Williamson",
"Julia Brettschneider",
"Mario Caccamo",
"Robert P. Davey",
"Carole Goble",
"Paul J. Kersey",
"Sean May",
"Richard J. Morris",
"Richard Ostler",
"Tony Pridmore",
"Chris Rawlings",
"David Studholme",
"Sotirios A. Tsaftaris",
"Sabina Leonelli",
"Hugh F. Williamson",
"Julia Brettschneider",
"Mario Caccamo",
"Robert P. Davey",
"Carole Goble",
"Paul J. Kersey",
"Sean May",
"Richard J. Morris",
"Richard Ostler",
"Tony Pridmore",
"Chris Rawlings",
"David Studholme",
"Sotirios A. Tsaftaris"
],
"abstract": "Artificial Intelligence (AI) is increasingly used within plant science, yet it is far from being routinely and effectively implemented in this domain. Particularly relevant to the development of novel food and agricultural technologies is the development of validated, meaningful and usable ways to integrate, compare and visualise large, multi-dimensional datasets from different sources and scientific approaches. After a brief summary of the reasons for the interest in data science and AI within plant science, the paper identifies and discusses eight key challenges in data management that must be addressed to further unlock the potential of AI in crop and agronomic research, and particularly the application of Machine Learning (AI) which holds much promise for this domain.",
"keywords": [
"data science",
"plant science",
"crop science",
"agricultural research",
"machine learning",
"data management",
"data quality",
"data sharing"
],
"content": "1. Introduction\n\nData science is central to the development of plant and agricultural research and its application to social and environmental problems of a global scale, such as food security, biodiversity and climate change. Artificial Intelligence (AI) offers great potential towards elucidating and managing the complexity of biological data, organisms and systems. It constitutes a particularly promising approach for the plant sciences, which are marked by the distinctive challenge of understanding not only complex gene-environment (GxE) interactions that span multiple scales from the cellular through the microbiome to climate systems, but also their interaction with rapidly shifting human management practices (GxExM) in agricultural and other settings, whose reliance on digital innovations is growing at a fast pace (Wang et al. 2020; Harfouche et al. 2019). Accordingly, examples of useful applications of AI – and particularly Machine Learning (ML) – to plant science contexts are increasing, with the Covid-19 pandemic crisis further accelerating interest in this approach (King 2020).\n\nNevertheless, we are still far from a research landscape in which AI can be routinely and effectively implemented. A key obstacle concerns the development and implementation of effective and reliable data management strategies. Developing reliable and reproducible AI applications depends on having validated, meaningful and usable ways to integrate large, multi-dimensional datasets from different sources and scientific approaches. This is especially relevant to the development of novel food and agricultural technologies, which rely on research from diverse fields including fundamental plant biology, crop research, conservation science, soil science, plant pathology, pest/pollinator ecology and management, water and land management, climate modelling, agronomy and economics.\n\nThis paper explores data-related challenges to potential applications of AI in plant science, with particular attention paid to the analysis of GxExM interactions of relevance to crop science and agricultural implementations. It brings together the experiences of an interdisciplinary set of researchers from the plant and agricultural sciences, the engineering and computational sciences and the social studies of science, all of whom are working with complex datasets spanning genomic, physiological and environmental data and computational methods of analysis. The first part of the paper provides a brief overview of contemporary AI and data science applications within plant science, with particular attention paid to the UK and European landscape where the authors are based. The second part identifies and discusses eight challenges in data management that must be addressed to further unlock the potential of AI for plant science and agronomic research. We conclude with a reflection on how transdisciplinary and international collaborations on data management can foster impactful and socially responsible AI in this domain.\n\n\n2. AI in plant research: current status and challenges\n\nFollowing wider trends in the biosciences, both basic and applied plant sciences have increasingly emphasised data-intensive modes of research over the last two decades (Leonelli et al. 2017; Leonelli 2016, 2019). The capacity to measure biological complexity at the molecular, organismal and environmental scales has increased dramatically, as demonstrated by: advances in high-throughput genomics and norms and tools that have supported the development of a commons of publicly shared genomic data; the development of platforms for high-throughput plant phenotyping in the laboratory, the greenhouse and the field; and the proliferation of remote sensing devices on-farm (Tardieu et al. 2017). Such platforms and associated data generation have contributed to a booming AI industry in commercial agriculture, focused on the delivery of “precision” farming strategies, with estimates that the market will be worth US$1.55 billion by 2025.1 Indeed, AI applications in plant research and agriculture have so far primarily benefited large-scale industrial farming (Carbonell 2016), with R&D investment focused on commodity crops such as wheat, rice and maize; high-value horticulture crops such as soft fruits; and the enhancement of large-scale orchards and vineyards. In addition to this, however, the amount and type of data being collected, alongside advancements in AI methods, offer the opportunity to ask and address new questions of great importance to plant scientists and agricultural stakeholders around the world (Tsiligiridis & Ainali 2018).\n\nAI is the field of study and development of computer hardware and software that perform functions, such as problem-solving or learning, which have traditionally been considered properties of intelligent life. A range of research fields have contributed to the development of AI, currently the most prominent of which is machine learning (ML), the design of algorithms for data processing, prediction and decision support that are able to learn from a priori (“supervised”), inductive (“unsupervised”), and reward-based (“reinforcement”) experience (Mitchell 1997). This approach is particularly significant for applications that do not require an exact understanding of how the algorithm has reached its decision, as long as it has predictive power and it is possible to reproduce it (Napoletani et al. 2015).\n\nML has been the dominant AI technology applied to plant and agricultural research so far. Many successful examples come from bioinformatics, where researchers may not need to worry about why a sequence of amino acids was classified as alpha-helical in structure as long as we know how reliable that prediction is, for instance. Indeed, ML has been widely used in the analysis of sequence data, for example to identify signal peptides and functional domains in amino-acid sequences via neural nets and profile hidden Markov models, such as Pfam and SMART (El-Gebali et al. 2019, and see Larrañaga et al. 2006 for other classic examples). One key example from genomics that goes back to the 1990s is the use of models to identify genes and predict their functions based on training data from multiple species (Hayes & Borodowski 1998; Birney et al. 2004; Zou et al. 2019). This has ongoing relevance for orphan and non-model crop research, where experimental approaches such as CRISPR knockouts to identify and validate gene function for individual species may not be feasible or cost-effective, but results may be inferred from experiments in model species (Zou et al. 2019). Other challenges in genomics that can be addressed include the inference of gene regulatory networks (Mochida et al. 2018) and the identification of pathogen virulence effector genes from genomic sequence data (Sperschneider 2019), for example. Thus, ML can help to identify correlations not readily picked up by more traditional approaches and in turn suggest fruitful directions for further research. To date, whether or not correlations have biological meaning typically needs to be ascertained via experiment and/or observational data (Leonelli 2014; Smith & Cordes 2019). Efforts towards explainable AI are, however, gaining momentum and both methodological and computational techniques are emerging which promise to support biological use of ML (Schramowski et al. 2020).\n\nAlongside applications in genomics, AI offers new opportunities for linking genotypes to phenotypes (Wang et al. 2020). Image-based plant phenotyping has proven a particularly fertile area for the application of ML techniques, with the rapid development of non-destructive methods for the evaluation of plant responses to biotic and abiotic stress (Singh et al. 2016; Mohanty et al. 2016; Ramcharan et al. 2017) and estimation of photosynthetic capacity (Fu et al. 2019), as well as a variety of feature detection, counting, classification, and semantic segmentation tasks (Jiang & Li 2020). With the arrival of deep supervised convolutional networks, progress in the performance of ML algorithms in predicting leaf counts increased considerably (Dobrescu et al. 2017). Convolutional Neural Networks (CNNs) were also shown to be capable of performing challenging tasks of point feature detection (Pound et al. 2018) and pixelwise segmentation (Yasrab et al. 2019, Soltaninejad et al. 2020) on both roots and shoots in a variety of imaging modalities in both laboratory and field environments (Gao et al. 2020). These technologies pose substantial new opportunities for analysing and understanding GxExM interactions through the integration of high throughput phenotyping data with other forms of research data, including genomic, field evaluation and climatic data. As well as addressing fundamental research questions, AI applications in this area offer the opportunity to understand and improve a range of practical activities from crop breeding through agricultural management (see Boxes 1 to 3).\n\nGenomic Selection (GS) is an approach for estimating breeding values for individual plants that can guide breeders’ decisions for selection and crossing (Crossa et al. 2017), based on modelling associations between quantitative traits and a genome-wide set of markers. Accuracy of predictive models for GS and rate of genetic gain can be increased by employing ML, although the utility of ML in comparison to existing statistical models vary depending on the characteristics of the trait of interest (Gonzalez-Camacho et al. 2018). A promising opportunity for the improvement of GS lies in using ML for the integration and the analysis of data from different omics layers (such as proteomics, metabolomics, metagenomics) that mediate between genotype and phenotype, facilitating the prediction of quantitative traits based on biological mechanisms rather than genetic marker associations and thereby increasing the reliability and utility of models for a wider range of populations than is currently possible (Harfouche et al. 2019).\n\nLong-term experiments (LTE), where the same crop or crop rotation is grown for many years subject to a range of different management or treatment options, have an important place in agricultural research. Data from these experiments enable separation of agronomic and environmental (weather) influences on crop yield, and soil health over time and have done much to influence modern farming practices (e.g. Poulton et al. 2018; Jensen et al. 2020). The \"Classical Experiments\" at Rothamsted Research (Parolini 2015, Macdonald et. al. 2018) are important examples. The data from these experiments, some of which were started in 1843, are available and documented in the e-RA data resource (Perryman et al. 2018). Data from LTEs continue to be the subject of new analytical methods (e.g. Addy et al. 2020), yet remain a relatively untapped resource for knowledge discovery, in part because of the complexity of the experimental designs and the difficulty in accounting properly for the changes that might have occurred during their lifespans. To make LTEs more accessible for knowledge discovery, a recent initiative was launched by the Global Long Term Experiment Network to catalogue LTEs using a standard meta-data schema. The use of ML methods combining data from LTEs with local weather data might, for example, reveal hidden patterns in the data linked to long-term or higher order interactions within the data which could provide useful insights into the impact of future climate change.\n\nAI offers many opportunities to improve the cost and labour efficiency of longstanding research and monitoring tasks in research and agricultural settings. While such possibilities are most developed in commercial agricultural settings, there are many opportunities too for the public research sector as well as for small or non-commercial farmers, for example in agricultural settings where there is limited access to relevant scientific expertise.\n\nExample (1): Assessing soil health is a key driver of crop yields, yet wet soil chemistry analyses are both expensive and time-consuming and generally not accessible by growers in low and middle-income countries. Using near-infrared (NIR) and mid-infrared (MIR) soil spectroscopy data, ML models can be developed to predict soil characteristics and nutrient content that are faster and cheaper to run (Data Study Group Team 2020). Such models could be integrated with plant physiology models in the future to predict optimal crop performance in a given soil, and open the possibility of the development of hand-held soil devices for use directly by farmers or local advisors in countries where lab access and resources are limited.\n\nExample (2): Conventional methods such as suction and light traps for monitoring the appearance and migration of airborne insects, including crop pests, which currently need manual identification can also be augmented by ML models trained to recognise and classify insect species based on bioacoustic data (e.g. Potamitis et al. 2015, and under development by the Rothamsted Insect Survey), connected to in-field sonic sensors. Such developments are directed at increasing the scalability of the insect pest monitoring networks and also potentially removing the need for manual steps for some insect species.\n\nNevertheless, the effective implementation of AI in plant and agricultural science depends in large measure on establishing a favourable data landscape, consisting of the networks and practices of sourcing, managing and maintaining data. This is particularly important for research undertaken outside of resource-intensive commercial sites, including research in and for the Global South. Identifying the primary challenges faced by users and would-be users of AI in the contemporary data landscape of plant science is necessary in order to understand the possibilities and limitations afforded by AI for public as well as private plant and agricultural research. Here we build on the experiences of leading UK-based researchers in these areas to identify and discuss eight key data challenges, summarised in Table 1. These challenges span technical, social and governmental domains, and will require concerted, international and transdisciplinary efforts from a range of stakeholders to address. In the remainder of the paper, we review these challenges in detail, drawing on a range of examples from fundamental and translational plant science. Several of the challenges are shared with the biosciences more broadly, reflecting the conditions and complexity of biological research, while others are specific to plant science and agriculture. In the conclusion, we offer some reflections on how these challenges could be overcome.\n\n\n3. Data challenges\n\nBiological research tends to be very fragmented compared with other sciences, and biological data is highly heterogeneous as a result (Hey et al. 2009; Marx 2013; Leonelli 2019; Strasser 2019). A key reason for this is the attention paid by biologists to the unique characteristics of the target systems that they are studying: different species of mushrooms, bacteria, trees, ferns and mammals can behave and interact with their environment in fundamentally different ways, which in turn affects their different structures, functioning and reproduction. Biodiversity thus encourages the production of research methods and instruments specifically tailored to the ‘endless forms most beautiful’ in question—with different laboratories producing data in a wide variety of ways. Added to this, there is the multiplicity of purposes for which biological research is conducted, which in the plant and crop sciences include the production of genetically engineered crops, understanding growth conditions, improving crop yield and identifying medically useful compounds; many of which also require the study of key environmental features such as soil and climate conditions. Moreover, the translation of plant research into agronomic spaces is made especially complex by the multiplicity of stakeholders, with breeders focused on the specific conditions in their target markets, farmers producing a large variety of data of potential research interest as part of their everyday work, and many companies working in agritech (including companies producing sensing devices for farms), although many data producers remain secretive around their own data practices and datasets. Furthermore, there is a divergence between the large emphasis on omics data within academic plant science and the equally strong focus on phenotypic data for crop evaluation favoured in more applied domains, which is only partly mitigated by ongoing efforts to bridge this gap and exploit the complementary nature of these data resources through integration and interoperability. Last but not least, there is no consensus on data formats, standards and methods of analysis. Datasets are typically collected with a specific hypothesis or practical use in mind, with much data not generated in machine-readable formats and data standards rarely prioritized when developing new methods or technologies. Data circulation is also limited, due to a lack of targeted incentives and necessary infrastructures as well as a general reluctance from researchers to share their data beyond their immediate communities of collaborators. Many research funders and institutions do not yet provide concrete incentives to make data publicly available, including rewards and resources to match the significant labor involved. This has significant implications for researchers, especially given the competitive culture predominant within the life sciences and the well-founded fear that spending resources on data curation may lower the publication rate of any one group, with negative effects on their reputation and future endeavors (Leonelli et al. 2017; European Commission 2017).\n\nThis fragmented data landscape limits the opportunities for the application of AI to plant research and agronomy. For example, when object recognition software is applied to human faces, relatively homogeneous reference sets of photographs are available for training, but equivalent data is not available when the same technologies are aimed at identifying morphological traits in plants. The introduction of the FAIR principles (Wilkinson et al. 2018), stating that data should be Findable, Accessible, Interoperable and Reusable, has greatly helped to address some of these issues.2 Some organisations are promoting the “FAIRification” of data using semantic web technologies (e.g. https://www.go-fair.org), but even more limited forms of annotation, semantification and standardisation would significantly facilitate applications within more restricted domains. Many molecular biology data are already integrated in structured, curated and interlinked public repositories (Rigden & Fernández 2020), which are widely used by the research community. This is not surprising given the historical ties between the development of sequencing technologies and the emergence of computation (November 2012; Stevens 2013; Strasser 2019) and related database standards and classification initiatives (Mackenzie et al. 2013) - often starting with data from model organisms grown in standard conditions like Arabidopsis thaliana with large associated research communities (Leonelli & Ankeny 2012).\n\nAt the same time, many other types of data are not as standardised, and the heterogeneity of data formats and methods across different areas of the life sciences is likely to affect the ways in which FAIR principles are implemented. Such differential adoption of FAIR principles and resources may, again, constrain the potential for ML to integrate data across multiple domains. Indeed, while the FAIR data principles are increasingly being applied across the plant sciences (Rodriguez-Iglesias et al. 2016; Pommier et al. 2019; Reiser et al. 2018), different projects have developed different elements of FAIR depending on their specific goals and context. Some applications, such as FAIDARE (FAIR Data-finder for Agronomic REsearch)3 have focused on Findability. Others, such as the Crop Ontology and related ontologies in the Planteome project, have focused on interoperability and semantic standards. AI and ML applications depend heavily on the Interoperability and Reusability dimensions of FAIR, but these have received less attention overall than Findability and Accessibility. As well as the semantic efforts mentioned above, more recent initiatives such as BrAPI (Breeding API; Selby et al. 2019) and MIAPPE (Minimum Information about a Plant Phenotyping Experiment; Papoutsoglou et al. 2020) have addressed these aspects in a more targeted way.\n\nAcknowledging and rewarding those who generate data would go a long way towards encouraging effective data sharing. One approach to this issue is exemplified by the Annotated Crop Image Database, which is set up to show only fragments of annotated images of plant phenotypes, without necessarily showing the detailed metadata that would allow others to re-use those images for biological research.4 This encourages biologists to share their data as early as possible to support the development of methods such as feature detection, while at the same time protecting those data from re-use by other biologists for as long as it is needed for the original data producers to publish their own results. This is only one among many possible solutions to adequate acknowledgement of data sourcing, with other approaches favoring early data publication (for instance in data journals) as a way to reward data producers while also fast-tracking data sharing. The Research Data Alliance is one among many organizations engaged in developing conventions and methods to reassure those providing data that their own research and publications will not be adversely affected, such as for instance the CARE and the TRUST principles (Lin et al 2020).5 It is imperative that such guidance is visibly implemented and that researchers are trained to understand its significance for their own work and data management strategies.\n\nGiven the wide variety of data types, formats and sources in the plant sciences, determining which data resources could be selected for AI-informed analysis constitutes a serious challenge. Are there data sets of immediate potential if suitably curated, and what metadata is needed to describe data sets so that their suitability for inclusion in a given analysis can be assessed? The achievement of clear criteria and priorities for data selection is a crucial issue given the considerable amount of work required to digitise, curate and process datasets and related metadata. Such criteria should consider the ML task at hand, the scientific goals as well as the concerns of individuals and groups holding the data.\n\nConsider herbarium specimens as a promising potential substrate for ML. Collectively, the world’s herbaria contain an estimated 392,353,689 plant specimens as of December 2019 (Thiers 2020), associated with metadata describing the place and time of their collection. ML can be used to infer useful information from the physical and molecular characteristics of the specimens to support automatic identification of plants (Carranza-Rojas et al. 2017), or to find material with potentially useful traits (Younis et al. 2018). Recent efforts have combined specimen images, their associated metadata including descriptive labelling, and associated field images (Carranza-Rojas et al. 2017). These approaches could be used to monitor ex situ conservation efforts, to track changes in natural and farmed distribution of species in response to environmental changes, to trace the spread of invasive weeds, or many other applications not strictly related to crop research. However, many herbaria are only partially digitised, if at all. Most specimens have not been imaged or subject to molecular analysis, and even basic metadata is often not databased, but only exists in the form of hand-written or typed annotations attached to the physical specimen, meaning that even taking an inventory of stock is not possible, and access to the material is only possible via physical visit. Thus, while the new technologies of imaging, molecular analysis and ML have created new possibilities to exploit these historic collections (Soltis 2017), these will remain unrealised until the information they contain is extracted, digitised, and made publicly available, tasks which are very labour-intensive. Interestingly, ML itself may be able to help solve this problem: the transcription of physical herbarium labels may be supported by the use of ML to interpret handwriting. A useful step towards this is the recent production of a benchmark dataset of transcribed herbarium labels (Dillen et al. 2019), which could be used to assess the performance of algorithms. This does not however help to address questions of data selection. Researchers still need to decide which specimen and related data/metadata to prioritise given limited resources and the vast scale of existing collections. In turn, the selection of usable and relevant data and digitisation of records is tightly associated with the prioritization of research problems and questions on which to work. There is relatively little investment in improving procedures and methods in this area, and yet there is a need for processes through which researchers explicitly consider and debate which data should take precedence and why. Without such processes, the ensemble of data being curated risks being patchy and fragmentary, the random result of individual efforts by separate and uncoordinated projects rather than of a community effort to locate and invest on data of most relevance to all. Indeed, without such processes, pressure to use automatic methods, and to be seen using them, can aggravate the problem with researchers investing resources in the creation of large datasets without considering whether and how those data could be used.\n\nClear reporting on the relation between digital data and material samples – the seeds, germplasm and other biological sources to which data are associated - is vital to the interpretation, re-use and reproducibility of results (Leonelli 2016, Strasser 2019), as well as constituting a major source for data in the first place (Bebber et al. 2012). Moreover, the use of plant science to inform agriculture and related domains such as forestry is predicated on understanding and utilizing the widest possible range of biological variation between and within species. For example, crop breeding is dependent on having access to a large pool of traits that can be incorporated in new varieties that are resistant to changing climates, diseases and stresses (Hufford et al. 2019). Applications of AI to plant and related data must be designed in such a way that data, models and other outputs can be linked back to the material samples on which scientific research and biotechnological applications depend.\n\nThis has proved to be problematic. While a vast number of accessions of crops and crop wild relatives are held in genebanks worldwide, the corresponding data records for this global resource are often limited at both a scientific and operational level. Some progress has been made in promoting data deposition and thereby indexing of resources in overarching international plant genetic diversity databases such as EURISCO, which provides information about more than 2 million accessions of crop plants and their wild relatives, preserved ex situ by almost 400 institutes including both passport data and phenotypic data.6 However, meeting the disparate needs of users, donors, funders and other stakeholders in such indexing databases remains difficult. Within the international phenotyping community, information systems are developing which require all objects, including individual plants, to be allocated a persistent URI (Neveu et al. 2019). This increase in specificity has the potential to increase connectivity between phenomic data and the samples from which it was obtained, but comes with a significant overhead cost and to date is only feasible in indoor, highly mechanised environments.\n\nLegacy systems do not always lend themselves to easy integration and can make consistent matching of appropriate terms and datatypes between originating resources difficult. There can be competing arguments for the most appropriate, efficient, or scientifically accurate representation or classification of data and characteristics to meet perceived audiences. A reluctance or inability to re-invent domain specific resource catalogues is also understandable given the range of operational concerns that inform the management of live resources. Genebank databases have been iteratively customised to user requirements and/or contractual constraints over a period of many decades. There may be significant conflicts between visibility and dissemination drivers for commercial and public collections and even for separately donated materials within those resources. There may also be concerns about third party use of collated data or perceived availability of materials, particularly where there may be implicit or implied intellectual property, or regulatory compliance benchmarks for benefit sharing obligations. A precautionary principle not to include portions of the biobank collection may also apply when downstream use of data or implied ownership of downstream discovered characteristics are considered by the biobank review panel considering inclusion in such an external index.\n\nWithin plant phenotyping facilities, the legacy problem arises from the historic variations in metadata collection. In particular, useful linkage of phenomic data to samples requires details of the growth environment to also be collected. This is now attracting significant interest, and methods and standards for e.g. illumination conditions are emerging (Cabrera-Bosquet et al. 2016). Inclusion in some databases is now conditional on capture of specified levels of environmental information. Legacy data, however, often lack such information, and the variations in plant structure and performance introduced by environmental conditions - even within well-controlled environments - means that simple linking of genotype to phenotype is insufficient.\n\nBetween them, these issues can make reduce data donation to a lowest common denominator of permitted and approximated metadata overlap for a subset of holdings – often a simple index or indicator of materials which merely points to the originating collection and may not permit broader aggregation of recorded characteristics. This can be insufficient for useful exploitation of the resource by specialist researchers and will often render an aggregation site unpopular or secondary to the primary biobanks. The problem is even further exacerbated when considering the very large number of valuable land races, crop wild relatives (CWRs) and heritage varieties preserved in-situ at herbaria, botanical gardens and conservation sites. Moreover, and despite significant work invested in creating genotyping panels and populations for many different species, a lack of phenotypic data about accessions has limited the utilisation of this diversity and constrained understanding of the genetics of complex traits, leading to a phenomics “bottleneck” (Araus & Cairns 2013). An increasing number of high-throughput phenotyping platforms are being constructed, in which large quantities of data about individual plants are collected, integrated and analysed with the help of ML techniques (especially on multispectral and RGB imaging data). These phenotyping platforms are at the forefront of materials-data linkage and biodiversity studies in plant science, and yet they are often unavailable beyond the institute or research group that developed them, for reasons ranging from data size to commercial protections.\n\nThe challenges of managing the relationship to material samples are not limited to datasets, but also include models. The accuracy of Genomic Selection (see Box 1) for a given breeding population is strongly dependent on genotypic and phenotypic data collected from closely related populations, which are used to train models (Spindel & McCouch 2016). Robust linkage between models and the material samples for which they have been optimised, combined with pedigree data and made available via public infrastructures, will be important to enhance the accuracy and utility of GS modelling through greater transparency, comparison and reuse of models for related breeding materials or traits. Thus, the usefulness of AI-informed analysis of digital data is tied to investments in the development and maintenance of material samples - including those kept in seed banks and herbaria - and key germplasm metadata such as those captured by the Multi-Crop Passport Descriptors (Alercia et al. 2015).\n\nStandards ensure that data are collected in formats and with labels that can be understood by users, whether human or machine, as well as ensuring that a necessary minimum of contextual information (or metadata) is recorded about the methods through which data were generated and the environmental and experimental conditions in which they were acquired. Consider this example from orchard management. A two-year study of 19 orchards in New York state collected data on the effects of conventional pesticide use on the wild bee community visiting apple (Malus domestica) within a gradient of percentage natural area in the landscape (Park et al. 2015). ML techniques, such as hidden Markov models, can effectively be used to model the behaviour of pollinators based on movement data, especially between orchards and natural habitats. This in turn could inform decision support tools for scheduling the use of pesticides to limit their effect on pollinators, using data collected from individual trees by remote sensing technology. However, the dataset presents several issues for reuse. Each orchard was going to be visited twice for data collection, once before and once after blossoming, but the first year some data were not collected due to cancelled visits. While this was not a problem for this study, where the focus was on the bee count in the second year, for a study with a different objective the incomplete data could be problematic. Moreover, dates are annotated relative to bloom rather than to calendar dates; and a key variable is the Bee Impact Quotient (BIQ) for each individual pesticide, and other scores derived from these. These measures are appropriate for a study on pollinators, but may be less suitable for a study measuring different impacts on the ecosystem, such as plants or biodiversity. Without a preliminary discussion of standards for future data reuse at the start of the study, and incentives to ensure that the scientists involved are given credit for developing data resources of wider interest than for their own project, such considerations are not taken into account, and data collection cannot yield standardised, machine-readable labels for data that can be aggregated and reused within other projects.\n\nTo counter such issues and help researchers to signpost more clearly the characteristics and expected utility of datasets, there has been considerable progress in developing semantic standards by a variety of transnational organisations and initiatives. For phenomic research, such efforts include the Ontologies community of practice of the CGIAR (Arnaud et al. 2020), which manages the Crop Ontology, and the Food and Agriculture Organization’s AGROVOC thesaurus. Distinctive to both initiatives is not only the standardisation of terms for field studies, but also the attempt to develop terminologies that bridge the expertise of the multiple stakeholders in agricultural field trials, including farmers, breeders and scientists, and link different languages.7 Initiatives such as ELIXIR, the Research Data Alliance Agricultural Data Interest Group, GODAN and the project PHENOME-EMPHASIS provide precious collaborative venues to improve plant data standards beyond molecular omics and experiments. Notable concrete examples include projects such as the Breeding API (BrAPI; Selby et al. 2019) and MIAPPE (Minimum Information about a Plant Phenotyping Experiment; Papoutsoglou et al. 2020), the latter fostered by ELIXIR as a way to improve consensus on ways to annotate data generated by phenotypic experiments; the Working Group on Integrating Genomic and Phenotypic Data for Crop and Forest Plants coordinated by ELIXIR-EXCELERATE8; and the efforts to standardise the collection and interoperability of field data in the CGIAR’s AgroFIMS, the open-source FieldBook application (Rife & Poland 2014) and the Grassroots information infrastructure of the BBSRC Designing Future Wheat programme. Efforts such as the COPO platform also implement semantic standards, including MIAPPE, in user interfaces to aid data brokering which underpins the availability of well-described datasets that can in turn power AI/ML studies (Shaw et al., 2020).\n\nThese initiatives, and a shift in research culture more generally, are playing a central role in establishing wider attention to and use of best practice in standards to deliver impact through AI/ML (cf. Leonelli et al. 2017). Ensuring that these standards are not implemented retrospectively, but rather they are adopted before data are actually produced, remains a key challenge. In this respect, companies that develop scientific instruments and research software have a crucial role to play. This is particularly evident in the case of data generated by remote sensing technologies, where the most prominent standards concern the technical levels of imaging and data processing rather than data curation. For example, a recent study of the impact of oil palm plantation in Indonesia based on a range of sources of satellite imagery attempted to assess the impact that historical changes in land use had on greenhouse gas emissions (van Beijma et al. 2018). An outcome of the study was that comparing the outputs from different remote sensing sources was severely compromised not because of any challenges of changes to satellite technology but rather because there was no consistency in the classification of land use between the different remote sensing campaigns.\n\nDeveloping reliable ML tools is dependent on having adequate reference data (also referred to as ground-truth or training data) for model validation. Obtaining or accessing reference data for complex field environments poses a distinct challenge, due to the scale of data collection required and the associated problem that the high value of such data means that it is frequently held behind restrictions on access or licensing agreements (see section 3.7). Purpose-built platforms such as Rothamsted Research’s North Wyke Farm Platform allow the monitoring and control of multiple agricultural and environmental variables, from plant growth through soil health and water flows, generating detailed, multi-scalar data (Orr et al. 2016). Such facilities are expensive and few, however.\n\nGiven that the generation of new data specifically for the purpose of training and benchmarking can be expensive and time-consuming, re-using already published data for these purposes is desirable. Implementing good data and metadata standards can reduce the cost and time of reuse, but standardisation alone does not allow the creation of benchmark datasets on demand. The utility and accuracy of algorithms is dependent on the quality of the datasets used to train them. Without sufficiently broad and unbiased training sets, algorithms will not have wide general applicability. It is therefore necessary to address statistical aspects of data sets in addition to the data management and stewardship principles described in the previous section. Data quality benchmarking has played a central role for example in genomics, with projects such as the MAQC/SEQC (SEQC/MAQC III Consortium 2014), the MicroArray/Sequencing Quality Control initiative by the FDA, but quality standards also depend on the potential implications of decisions taken based on the information contained in the data. For example, the evaluation of ecological risks associated with GM crops or pesticide use need to happen based on more robust data than those procured via fundamental research. While published data sets such as those in genomics repositories, citizen science platforms or ecological data banks typically have undergone some quality checks, these are tailored to the requirements of the original context of the data collection. Re-using data sets to develop an algorithm serving a changed purpose requires a fresh assessment of the suitability and quality of the data set. The following questions can provide guidance for finding out whether representativeness and resolution requirements are fit for the specific context and purpose of the algorithm that is being trained with the data.\n\n1. Are the variables used by the algorithm (or sufficiently close surrogates) included in the data set? Are the measurement methods sufficiently accurate and precise for this purpose? Have they been taken on a sufficiently elementary unit rather than on an aggregated level only? If the data collection covers a time period, have the measurements been taken sufficiently frequently?\n\n2. Are the records complete? If not, are records simply missing at random or are there any patterns in the absence that might skew the results obtained by the algorithm?\n\n3. Is the sampling method used to collect the data subject to any selection biases that were negligible for the conclusions of the original study, but could impact the results or interpretation of the algorithm?\n\n4. Where data has been gathered from human experts (e.g. in image annotation for phenotyping), has subjective bias been identified? Is the set of experts used sufficient to capture possibly conflicting views? Have the annotators understood and been provided with appropriate tools for the task?\n\nOne example to illustrate quality issues in data reuse concerns the British Farm Scale Evaluations (FSE), which analysed the effect of genetically modified herbicide-tolerant varieties of beet, oilseed rape and maize and that of comparable conventional varieties on the abundance and diversity of arable plants and invertebrates (Firbank et al. 2003).9 The data set consists of complex time courses reliant on farmers’ assessments. While measurement of weed cover, crop cover, crop height and pollinators followed protocols, the schedule for taking the measurements throughout the year was chosen by the individual land managers, which made comparisons difficult. It was pointed out that: extra data assessing \"whether there is evidence of biodiversity harm from the use of the GM crop and herbicide regime\" should have been collected (Environmental Audit Committee 2004); no definitive yield component had been included, which makes it difficult to use this data set for trade-offs between environmental and economic targets; and pesticide data is given as product application rates, which makes interpretation of these numbers difficult for future studies. Another major issue is missing data due to vandalism, a foot and mouth disease outbreak and unknown reasons, in some cases showing systematic patterns of incompleteness.\n\nIndeed, a related issue is the breadth of data used to train models: whether they sufficiently represent the variation and diversity of target species or populations. Use of computer-generated images of plants in order to enlarge the image datasets used to train deep learning computer vision algorithms for phenotyping is increasingly common (e.g. Ubbens et al. 2018; Humphreys et al. 2018; Toda et al. 2020; Atanbori et al. 2020). Whether or not such methods could feasibly be used to generate training data that sufficiently reflected the complexity of field environments is another question. The expansion of field phenotyping, including attempts to capture, integrate and analyse imaging captured by drones and other sensing technologies, is likely to be necessary for this task. Progress in the latter area is rapid, although it is still constrained by the expensive and technically challenging nature of both experiments and associated data annotation practices (Fahlgren et al. 2015; Coppens et al. 2017; Rosenqvist et al. 2019).\n\nWhen developing effective AI solutions in plant-related research, access to adequate software and modelling platforms is as necessary as access to high-quality data. Software and models need to be implemented on digital environments that its users have access to or are willing to pay for. Accessibility, especially for large-scale AI, is key: researchers need access to the computing and data platforms needed to power AI at a reasonable price, in order for such research to be scalable. Where possible, software should also be portable for use across digital environments, so as to accommodate researchers working in different systems; and it should be approachable by users with a range of experience in handling and analysing data.\n\nA key obstacle here is the fact that researchers who can formulate the biological problems are often not those developing ML algorithms. An example is the use of targeted software to explore existing data in search for new targets for experimental investigation. The KnetMiner resource for instance assembles a suite of software and data integration methods aimed at sifting through the biological literature and public data resources to explore relationships between datasets and species, especially in cases where multiple traits are connected to multiple genes. The application of these exploratory methods to key crops such as wheat, sorghum and sugarcane has already resulted in the identification and further study of important agronomic traits (Hassani-Pak et al. 2020). At the same time, it requires expert tailoring whenever targeting a new species, including biologically informed assessment of which datasets used for key crops can be applied to other crops. Indeed, not all models will work directly off the shelf on a new dataset/problem. Giuffrida et al. (2019) devised an algorithm that adapts a leaf counting model on new data without requiring annotations and without requiring the availability of the original training dataset. As model complexity increases, however, so does the opacity of the models. Dobrescu et al. (2019) sought to develop mechanisms that help peek into what ML models learn in tasks of object counting (and in particular leaves) – part of a growing research field which promises to make CNN methods better understood, increasing trust in the insights they provide.\n\nIt is then not enough to provide researchers with software alone. Rather, this must be supported with workflows that incorporate the whole life cycle of data preparation, validation and analysis, and which can be operationalised with minimal friction (Bechhofer et al. 2010). Algorithms and data models must also be articulated at the right level of abstraction, to resolve what could be perceived as a new form of ‘translation gap’ between the cutting edge of data science and the frontiers of plant research. Software and models created for very particular uses will have higher requirements for data quality and annotation, creating a barrier to reuse (Tiwari et al. 2020; Stanford et al. 2015). Some models need to be flexible enough to work across the multiple scales that characterise both biological work in general and agricultural research in particular, including between species and between different environments. An example is the John Innes Centre’s work to create data resources with the appropriate software that enable the transfer of learning from model organisms (e.g. Arabidopsis) to non-model organisms (e.g. Brassica crops) (Jones et al. 2018, 2020; Calderwood et al. 2020a, 2020b).10 Many crops have large complex polyploid genomes, one of many factors that can make the direct transfer of knowledge problematic. Machine learning approaches are being developed that allow for large transcriptomic and phenotypic datasets being collected from many individuals, populations and species. This in turn can be exploited to identify similarities and differences in the regulation of developmental transitions in response to environmental stimuli (Calderwood et al. 2020a, 2020b). Bringing foundational plant science into the crop space is crucial, yet key challenges remain at every level from gene activity and function through networks, tissue behaviour and plant physiology to field-level behaviour.\n\nThe need to operate across multiple scales has long been acknowledged to require trade-offs between accuracy and generality (Levins 1966). Indeed, most models are designed to address specific questions and will not be applicable across scales. This raises questions around whether and how the results of such modelling efforts can be linked and integrated. The goal of ML is not to ensure how the model will do on the training data but instead how it will perform on a testing set. The testing set is used to ascertain how well the model will generalise to an unseen data source and thus “in the wild”. After all, we do care about creating AI/ML that will generalise well either in unseen data or unseen tasks. For example, how will a model that is trained to count plant leaves perform when tasked to count leaves in different images of the same plant family (different illumination), or a different plant family or even a different task (e.g. seed counting)? The ability for models to generalise is largely governed by the quality of the internal data representations the model has learned to fulfil the task. If one relies on supervised machine learning, then these representations will be tuned to the specific task and will have difficulty in generalising. Here multi-task and meta-learning can help as they tend to learn representations that can more easily generalise (Dobrescu et al. 2020).\n\nHowever, if we rely on annotations to drive this supervised learning of data representations, one must readily ask whether data quality and annotation play a key role. In ML, data cleaning and preparation take a considerable amount of time. Even more time consuming is data annotation. Approaches to relieve the data annotation effort include semi-supervised, self-supervised and multi-task learning. These methods aim to learn representations by leveraging unlabelled data, or correlations and self-similarity of the data themselves, or correlations between tasks. Considerable and notable improvements have been made outside and within plant sciences, and particularly in image-based phenotyping. Yet even these methods rely on some annotations. Thus, one must consider whether noise (errors) in annotation have an effect. Learning with label noise, as it is colloquially known in ML, is a mathematical framework that aims to learn a good model even when labels may be noisy, i.e. have errors (Natarajan et al. 2013). Recently, Giuffrida et al. (2018) went to the extreme of assessing such levels of noise amongst expert and even novice annotators (citizen scientists). The findings are promising: Despite the presence of noise, as long as multiple annotations of the same datum by diverse individuals exist, models can be learned.\n\nOne must consider errors in annotation not only in providing labels for ML but in how ML outputs will be used to support statistical hypotheses. In this aspect, an error in labelling the data of a mutant as control will create considerable propagation of error in the pipeline. Thus consistent records of experimental conditions will help ensure that such errors are minimised. Here ML can also help identify errors (Schramowski et al. 2020). An ML algorithm can actually act as a calibration method: outputs of an ML model which are suddenly inconsistent point to data inputs that are out of distribution. Whether such out of distribution data are due to errors in the data or because the ML is encountering data not trained with (but could be updated), necessitates human intervention and this in turn creates a viable checkpoint in the development of robust data processing pipelines.\n\nAccess to appropriate datasets is necessary for the application of AI tools to complex environmental and biological research topics, yet it clearly depends on factors well beyond scientific need, including intellectual property regimes, data governance by specific institutions, and consideration of the rights and risks involved in data sharing for those who produce the materials from which data are extracted and/or may suffer the social and economic consequences of specific applications of data analysis. Legal constraints such as intellectual property controls and licensing regimes can and often do put the data beyond the financial means of lower-resourced researchers and institutions, or place restrictions on the use of the data that makes the kind of wide-ranging data mining required for AI application difficult if not impossible to implement (Jefferson et al. 2015). Given the distinctive landscape of intellectual property rights, contracts and the need to find incentives for data sharing that respond to imperatives of commercial competition, finding ways to make data usable to a range of actors without necessarily sharing it is likely to become increasingly important. In biomedicine, initiatives such as DataSHIELD have been developed in which users are able to run analyses on a dataset via an intermediary platform without having direct access to the source data (Murtagh et al. 2012). Such efforts allow the anonymisation of data and removal of patient/volunteer personal information, which are recognised as important issues in biomedical research. Similar initiatives such as the Open Algorithms (OPAL) project, developed in relation to commercially sensitive data (Roca & Letouze 2016), have recently been promoted in agricultural research forums such as the CGIAR Big Data in Agriculture Convention, but their uptake remains to be determined.\n\nResearch institutions including universities have often kept data from widespread access, with even data produced by publicly funded studies remaining either unknown or inaccessible to other researchers. This is partly explained by lack of investment in the platforms, curation expertise and training required to ensure data sharing and facilitate analysis, and partly due to enduring confusion around legal accountability of research institutions vis-a-vis the requirements of governments, data protection laws, private sponsors (including public-private-partnerships) and public funders - not to speak of the fact that researchers often operate within international networks where different national legislation and expectations may apply.\n\nData access must also be balanced against ethical concerns that have recently arisen around the re-use of data and materials collected in low-income countries and/or low-resourced research environments. With reference to the longer history of colonial exploitation of indigenous agricultural knowledge to support market-driven growth in the Global North (e.g. Carney 2001), international institutions including the World Data Systems, CODATA and the CGIAR have pointed to the potential for indiscriminate data access to accelerate so-called “digital feudalism”; the exploitation of more vulnerable members of the agricultural research network by better-resourced and more powerful actors (such as Alphabet/Google) who can effectively appropriate such data. The opportunities afforded by AI, while holding the potential to benefit many stakeholders, also create new commercial incentives for such exploitation.\n\nKey areas for negotiation include access and benefit sharing agreements and the protection of sensitive data, for example where they include location or certain kinds of farm production data. In the biomedical field, strong regimes of governance and ethics have been developed for data protection and legislating the acceptable uses of data (Hilgartner 2017), and these may provide a model for the plant sciences. However, plant data poses several different challenges to human biomedical data, notably the fact that much of the data utilised in basic and translational plant research does not come under the more protected category of personal data, but is frequently covered instead by contract law (Wiseman et al. 2018).\n\nDespite the increased use of ML expertise and tools and the example set by some highly visible projects, collaboration between cutting-edge data science research groups and plant science communities is not yet commonplace (Henkhaus et al. 2020; Department of Energy 2020). On the one hand, this is due to the poor visibility of plant science datasets and problems to the data science community, in comparison to more prominent biomedical or environmental data and challenges. On the other hand, plant researchers need a better understanding of how algorithms work and what can legitimately be expected from the outputs of AI and ML. It is necessary to up-skill researchers with expertise about the available types and minimum necessary semantic annotations that datasets must be labelled with in order to make them machine-readable, in the first instance, and usable with specific algorithms. Providing researchers in the plant sciences with a minimum fundamental knowledge about such matters, preferably from an early stage in their careers, will facilitate the deployment of AI in the field and assisting decision-making around the issues of data selection and management described above, while also acting as an incentive towards the implementations of standards in the production and use of plant data.\n\nOne example of combining community-wide incentives with collaboration and upskilling are the “data challenges” organised in conjunction with the Computer Vision Problems in Plant Phenotyping (CVPPP) workshops, held at various international computer vision conferences since 2014. The first challenges were built around a curated dataset of images of rosette plants, including Arabidopsis and tobacco, taken in a controlled experimental setting, that could be used to test algorithms for leaf detection, segmentation and counting. This dataset, provided with expert annotation and full metadata, was presented alongside clear problem statements for computer vision researchers to work with and scripts for preprocessing and to code performance metrics, thereby minimising the costs of engagement. Phenotyping problems were mapped onto appropriate computer vision terminology, for example leaf segmentation to multi-instance segmentation, and the workshops were organised to facilitate research likely to lead to publications for participants. These efforts resulted in wider visibility of the Arabidopsis dataset among the CV community as an important benchmark in the development of multi-instance segmentation and object counting tools (Tsaftaris & Sharr 2019); educated ML researchers in the potential of plant data; and highlighted the potential of computer vision (and AI tools more generally) in addressing long-standing plant research questions.11 At the same time, this example highlights the significant effort involved in developing closer collaboration between these two research communities, since presenting the dataset required extensive preparation by the organisers (who needed an understanding of both areas of work to effectively set up the challenge). In addition to supporting access and use of specific software, hardware and workflows, there are benefits to be gained from supporting engagement with tools around which a community has developed, particularly when the users may lack technical background in ML/software engineering. Access to other users’ experiences and opinions is likely to be very valuable here, whether it is informal or through training material and events.\n\nIt is crucial to extend this engagement beyond the sphere of professional scientists to include other stakeholders in food systems, including farmers, agronomy advisors, plant breeders, food manufacturers and suppliers, nutritionists and others. Without dialogue with and among stakeholders, it is hard to identify the priority areas — the social-scientific needs and challenges — where there is greatest opportunity for AI applications to achieve impact. Mapping the stakeholder networks for specific forms of data-intensive plant research is a labour-intensive but important endeavour (The Open Research Data Taskforce 2018), as demonstrated in large projects such as Elixir that devoted significant efforts towards developing transparent and robust mapping services. Government representatives, funding agencies and industrial partners need to be engaged in the development of any data infrastructures and services. The involvement of industrial partners in particular is crucial given their ownership of key data resources, and also for their use of the tools and applications of their outputs. There is strong need for increased governance and related norms ensuring the delivery of public goods from those organisations that see data as a key part of their commercial activities - similarly to what the Food and Agriculture Organisation has been spearheading in the case of plant genetic resources. If the field is to provide advantages to a wider range of socio-economic actors, SMEs also need to be represented in future discussions and governance strategies around data access and protections. In developing its Agri-tech strategy,12 the UK government identified the key role of data and placed the development of an Agri-tech centre dedicated to data integration and access (Agrimetrics)13 as central to its wider development of centres of agricultural innovation.14 Such collaboration has also been envisioned, for instance, in the work of the Agrisemantics working group within the Agricultural Data Interest Group of the RDA15 and the CGIAR Communities of Practice bringing together stakeholders to discuss data standards and semantics (Arnaud et al. 2020). This engagement is crucial to ensure that academic expertise is informing and contributing to food security on the ground. Equally important is for public academic research, typically targeted to a wider range of topics, crops and applications, to be directed towards stakeholder needs. For instance, PlantVillage Nuru, a free smartphone app that uses automated image analysis and recognition with a phone camera for immediate disease diagnosis in several other crop species (Ramcharan et al. 2019), is targeted at farmers in the developing world and was specifically designed, in consultation with farmers’ representatives, to be usable offline and with minimal external input. This resulted in wide uptake and positive feedback due to the accessibility of the app to farmers and the usefulness of its contents and design.\n\n\n4. Conclusion: what data landscape do we need for plant-related AI?\n\nWe have reviewed eight data challenges that need to be urgently confronted in order to support the application of AI and ML tools to plant-related research (see Table 1). With specific reference to the UK and Europe, where our work is based, we discussed examples of good practice, including efforts to articulate data standards, algorithms and models at the right level of abstraction, in order to fit existing research questions and also address the gaps separating cutting edge data science from the frontiers of plant research. Building on such examples, we pointed to the need for a more systemic change in how research in this domain is conducted, incentivised, supported and regulated. We highlighted the importance of developing data services aiming to make data available and usable to people. This is particularly important in relation to environmental data of relevance to plant research, on which there has been much less focus compared to the tools already present to cope with genomic data. We pointed to the need for substantive investment in the development and maintenance of data infrastructures, standards and software, as well as: venues and training programmes aimed at fostering collaboration among the diverse expertise required (and especially exposure to data science for plant scientists and breeders); the identification of relevant stakeholders including industry, governmental agencies, local breeders and indigenous communities as relevant; and substantive engagement with those stakeholders. We stressed the difficulties in implementing these approaches within the highly fragmented biological data landscape, and the even more complex ensemble of public and private sponsors involved in research on crops. Despite marked advances in data availability, infrastructures and analytics, many plant researchers remain unaware of the extent to which AI tools could support their work, and do not actively participate in the effort to produce reliable data for the community.\n\nOne way to shift incentives and support a substantive culture change among researchers could be to foster international and transdisciplinary collaboration around big projects with clear use cases - a “moonshot” equivalent to the Human Genome Project or the search for the Higgs particle in physics. Big science of this kind has a strong track record in driving the development of standards and epistemic cultures, as well as bringing together international partners to maximize the strengths of different regions and approaches (Leonelli & Ankeny 2015). The agronomic domain may need one such big project to create traction and new forms of collaboration, especially given the importance of driving adoption of common standards across as diverse research communities as those of data scientists working on algorithms, molecular biologists focused on genetic engineering and crop scientists engaged in field experiments. Targets for such a moonshot project could be: addressing the phosphate crisis and its impact on agricultural yield; developing a fully digital farm modelling an existing experimental station; or the development of ecosystem services using multiple metrics.\n\nAn alternative approach would be to focus on a key feature of ML that has been lacking in previously dominant technologies: its ability to both generalise and transfer between domains. Once a machine learning strategy has been identified for a given task exposure to further examples of that task typically improves performance, even when the details and environment are significantly different. Rather than identify a moonshot biological challenge, which runs the risk of creating more tools tuned to specific research questions, an explicit search for capabilities needed across a range of plant and agricultural science scenarios could inform the identification of Technological Grand Challenges facing this community. These could be used both to spread innovation across the community and to engage colleagues from other disciplines. This approach could learn from other areas of research who have fared better in the development and application of AI, such as biomedicine. Repurposing some of the insights and infrastructures created in that domain would also be very useful for plant-focused science, including in tackling ethical and governance issues associated with the protection, sharing and reuse of plant data.\n\nAny future strategy for the development and application of AI in plant-focused research will need to have data curation at its centre, rather than as an afterthought. Making plant data FAIR is crucial. This in turn requires both technical work on standards, reference data, software and modelling, and organisational work towards establishing norms and venues for appropriate data governance (including on the terms of ownership, access to and reuse of data) as well as engagement with the widest possible spectrum of relevant stakeholders. Most importantly, it requires collaboration towards tailoring the technologies to the challenges posed by the green domain and the role of plants in relation to food systems and environmental sustainability. The opportunities immediately available in terms of AI applications may not necessarily be what plant research and agronomy need. There is a need to foster collaboration between fundamental researchers, data scientists, algorithm developers and end users in order to identify and maximise opportunities in this domain. Notably, while overcoming challenges to the effective use of AI will require changing practices and networks, it is important that such changes should not detrimentally affect what has already been successful. Existing communities of practice (such as the ELIXIR plant science community in Europe and the RDA agriculture-related groups at the global level) provide valuable sources of expertise and collaboration, and disrupting these risks creating more obstacles to good practice than benefits.\n\nLast but not least, improvements in data management may help identify and account for ethical and societal issues of relevance to agronomy and food production. There has been widespread concern that the adoption of ML tools implies a decrease in the oversight and control retained by humans on the interpretation of results, including the assessment of the potential implications of any resulting actions for stakeholder communities such as farmers, breeders and consumers. This has been flanked by worry around documenting the provenance of data and rewarding the efforts involved in generating the materials and conditions for data collection, especially where results are extracted from farming communities in deprived areas. Practical solutions to these concerns require concerted effort from data producers and curators, research institutions, data infrastructures and international governance. For instance, the impact of specific crop varieties on diverse landscapes is considered by AgroFIMS and other tools developed by the CGIAR, while the allocation of ownership claims and rewards attached to discovery is incorporated into the Global Information System (GLIS) of the International Treaty on Plant Genetic Resources for Food and Agriculture. Thus, data management strategies can help to ensure that the environmental, social and economic impact of AI tools is built into all applications.\n\n\nData availability\n\nNo data are associated with this article.",
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Reference Source\n\nOrr RJ, Murray PJ, Eyles CJ, et al.: The North Wyke Farm Platform: effect of temperate grasland farming systems on soil moisture contents, runoff and associated water quality dynamics. Eur J Soil Sci. 2016; 67: 374–385. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPapoutsoglou EA, Faria D, Arend D, et al.: Enabling reusability of plant phenomic datasets with MIAPPE 1.1. New Phytol. 2020; 227(1): 260–273. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPark MG, Blitzer EJ, Gibbs J, et al.: Negative effects of pesticides on wild bee communities can be buffered by landscape context. Proc Biol Sci. 2015; 282.1809: 20150299. PubMed Abstract | Publisher Full Text | Free Full Text\n\nParolini G: The Emergence of Modern Statistics in Agricultural Science: Analysis of Variance, Experimental Design and the Reshaping of Research at Rothamsted Experimental Station, 1919-1933. J Hist Biol. 2015; 48: 301–335. 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Publisher Full Text\n\nYounis S, Weiland C, Hoehndorf R, et al.: Taxon and trait recognition from digitized herbarium specimens using deep convolutional neural networks. Botany Letters. 2018; 165(3-4): 377–383. Publisher Full Text\n\nZou Q, Sangaiah AK, Mrozek D: Editorial: Machine Learning Techniques on Gene Function Prediction. Front Genet. 2019; 10: 938. PubMed Abstract | Publisher Full Text | Free Full Text\n\n\nFootnotes\n\n1 https://www.marketreportsworld.com/global-artificial-intelligence-ai-in-agriculture-market-13268433.\n\n2 In short, the existence of the data should be published, procedures for accessing the data should be available, sufficient metadata should be provided to allow the data to be understood and appropriately repurposed and common formats and APIs should be used to facilitate the integration of different data sets.\n\n3 https://urgi.versailles.inrae.fr/faidare/.\n\n4 https://plantimages.nottingham.ac.uk/.\n\n5 https://www.gida-global.org/care#.\n\n6 https://eurisco.ipk-gatersleben.de/.\n\n7 Semantic standards that recognise and incorporate this diversity of knowledge will be a necessary bedrock for any applications of AI and ML that are envisioned to work for diverse user bases, and to preventing implicit bias towards the terminology, scope or aims of dominant research groups (Arnaud et al. 2020).\n\n8 https://elixir-europe.org/about-us/how-funded/eu-projects/excelerate/wp7.\n\n9 The datasets are published by CEH as a collection here https://catalogue.ceh.ac.uk/documents/876358e4-62f7-4386-99e1-7d3eac223e03. Each crop dataset has its own DOI and the metadata gives a summary of measurements/data available, plus an extra dataset for management data.\n\n10 http://order.jic.ac.uk.\n\n11 Another successful initiative by the CVPPP is the Global Wheat Detection Kaggle Competition launched to broaden engagement in summer 2020, which received over 2000 entries (https://www.kaggle.com/c/global-wheat-detection).\n\n12 https://www.gov.uk/government/collections/agricultural-technologies-agri-tech-strategy.\n\n13 https://agrimetrics.co.uk/.\n\n14 (https://www.agritechcentres.com/.\n\n15 See e.g. https://www.rd-alliance.org/system/files/documents/SEMANTICS-RICE_poster_LD.jpg."
}
|
[
{
"id": "95850",
"date": "18 Oct 2021",
"name": "Daphne Ezer",
"expertise": [
"Reviewer Expertise Machine learning in plant biology",
"transcriptomics"
],
"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 good summary of data management and curation challenges in the plant science community. Initially, I was a bit skeptical for the need of this article, because the data management challenges listed were the same as those that are required across biology and across both data analysis AND AI. After reading this more carefully, I do think that this is useful, but mostly because of the list and description of excellent examples and case studies across each of the challenge areas addressed by the article.\nI would recommend that they maybe make a supplementary table of these examples for ease of reference.\n\nIn addition, I would be a bit careful about the definition of AI. I generally agree, but some people have strong feelings that ML and AI are distinct, because ML requires some level of manual feature extraction and so may be considered more of a set of statistical method than an \"artificial intelligence\". For instance, it is easy to argue that linear regression is ML, but very few people would call that AI. You use HMMs as an example of AI, which I think would be considered quite controversial. I would acknowledge that this is an area of controversy, but then stick with the definition you've set here.\nThe biggest area that I think you need to be careful about though is the distinction between labelling individual \"data points\" (such as individual images) and metadata about the overall dataset. Metadata about the experimental conditions, species, etc is often easier to come by (and already required by many data repositories), but adding labels to enough data points to enable supervised learning is an order of magnitude harder. You address this when you talk about reliability, but in other places these concepts are slightly conflated.\n\nOne issue with data management for AI is that there is often a lot of data collected about a single or small amount of observations (one species, one or two experimental conditions, etc). However, this kind of thing isn't suitable for machine learning/AI, since AI relies on there being a large number of observations.\n\nAnother issue is the lack of standardisation of experimental profiles. Even if all the meta-information were present, it would still be incredibly challenging to extract batch effects from experiments across labs, given the number of variables that people are changing. Do the authors really believe that making the data FAIR and including metadata would help overcome this problem? It seems like doing a meta-analysis of data across labs using AI will always be somewhat problematic, even if the data was all FAIR.\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? Yes\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? Yes",
"responses": [
{
"c_id": "9155",
"date": "17 Jan 2023",
"name": "Sabina Leonelli",
"role": "Author Response",
"response": "This is a good summary of data management and curation challenges in the plant science community. Initially, I was a bit skeptical for the need of this article, because the data management challenges listed were the same as those that are required across biology and across both data analysis AND AI. After reading this more carefully, I do think that this is useful, but mostly because of the list and description of excellent examples and case studies across each of the challenge areas addressed by the article. I would recommend that they maybe make a supplementary table of these examples for ease of reference. We have added a supplementary table listing the major examples of machine learning and AI discussed in the paper. We have not included examples of databases where the potential for application of ML/AI methods has been discussed, but no work has yet been attempted or published. In addition, I would be a bit careful about the definition of AI. I generally agree, but some people have strong feelings that ML and AI are distinct, because ML requires some level of manual feature extraction and so may be considered more of a set of statistical method than an \"artificial intelligence\". For instance, it is easy to argue that linear regression is ML, but very few people would call that AI. You use HMMs as an example of AI, which I think would be considered quite controversial. I would acknowledge that this is an area of controversy, but then stick with the definition you've set here. We have added a footnote in section 2 recognising that there is disagreement over the classification of ML as AI. The biggest area that I think you need to be careful about though is the distinction between labelling individual \"data points\" (such as individual images) and metadata about the overall dataset. Metadata about the experimental conditions, species, etc is often easier to come by (and already required by many data repositories), but adding labels to enough data points to enable supervised learning is an order of magnitude harder. You address this when you talk about reliability, but in other places these concepts are slightly conflated. We have added an additional comment at the start of section 3.4 on the differences between labelling metadata and labelling individual data points. In subsequent sections we have clarified where the discussion concerns labelling of metadata and labelling/annotating individual data points, especially in section 3.6 where the discussion shifts from data annotation to errors in metadata. One issue with data management for AI is that there is often a lot of data collected about a single or small amount of observations (one species, one or two experimental conditions, etc). However, this kind of thing isn't suitable for machine learning/AI, since AI relies on there being a large number of observations. The whole paper concerns attempts to pool datasets (large and small), so we agree with the idea that very small datasets are not amenable to AI approaches, but this is not what we are discussing here. We clarified this further in the paper. Another issue is the lack of standardisation of experimental profiles. Even if all the meta-information were present, it would still be incredibly challenging to extract batch effects from experiments across labs, given the number of variables that people are changing. Do the authors really believe that making the data FAIR and including metadata would help overcome this problem? It seems like doing a meta-analysis of data across labs using AI will always be somewhat problematic, even if the data was all FAIR. We agree that this challenge remains, and have inserted a paragraph in the conclusion of the paper (right after the suggestions that all data should be FAIR) pointing this out. Many thanks for this and the above suggestions!"
}
]
},
{
"id": "154789",
"date": "14 Nov 2022",
"name": "Joeri Witteveen",
"expertise": [
"Reviewer Expertise Philosophy of science"
],
"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 opinion article presents a solid overview of the state of the art of AI in plant research and provides a comprehensive analysis of current challenges in (and solution for) bringing AI approaches in plant research to full fruition.\nWhile each of the identified challenges is to the point, there is considerable overlap between them. This could have been avoided to some extent by embedding the discussion of these challenges in a clearer analytic framework, instead of by presenting them as more or less randomly ordered list. That said, this is a minor shortcoming and I don't think the article requires any major restructuring to prove its merits. Thus, I approve of the overall article in its current form and have only a few suggestions for minor corrections and further improvements:\nFirst, regarding the current status of the uses of AI in plant research, it would be helpful if the authors could expand their brief introduction of ML approaches by elaborating on which of these approaches are actually being used in plant research. It looks like the examples they go on to describe are all instances of (semi-)supervised learning. Are the other approaches to ML that they present also employed in plant science? If so, examples would be welcome. If not, it would be useful to signpost the more limited scope of AI approaches in plant science. Relatedly, I was slightly puzzled by the characterization of supervised learning as ‘a priori’ and of unsupervised learning as ‘inductive’. Both approaches are often considered inductive, and it is unclear why supervised learning should count as ‘a priori’. A final note on this point is that a reference to more recent literature (>1997) on ML would be appropriate here.\nAnother suggestion for improvement concerns the relation between Table 1 and the main text. While the table as such provides a very useful summary of the challenges and solutions being discussed, I found that the contents of some of the cells does not adequately reflect the material from the main text. The characterization of challenge #5 in the ‘data challenges’ column is a case in point. In the table, this challenge is labeled “Access to computing and modeling platforms, and related expertise” whereas in the main text the corresponding subsection is entitled “Using software and models across scale, species and environment.” Only the first paragraph of this subsection discusses questions of accessibility. In the remainder, issues relating to the *use* of models across contexts and scales are the focus. This is one of several instances for which there appears to be an opportunity to ensure a better fit between the contents of the table and the main text.\nA further small issue about the table: the meaning of the contents in the “risks” column is ambiguous and inconsistent: in some rows, the risks pertain to the data challenge (when left unaddressed), whereas in others rows the risks pertain to the proposed solution. This should be easy to address, e.g. by introducing a further ‘tradeoffs’ column that lists the risks related to implementing the solutions (as opposed to leaving the challenges unaddressed).\nFinally, I was puzzled by this remark in the conclusion: “Once a machine learning strategy has been identified for a given task exposure to further examples of that task typically improves performance, even when the details and environment are significantly different.” This optimistic conclusion seemed to me to be somewhat at odds with the main message of the article. Unless we construe a ‘task’ in plant science artificially narrowly, it seems that that challenges that have been identified and discussed demonstrate that we encounter considerable difficulties in establishing reliable performance of ML across research contexts.\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? Yes\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? Yes",
"responses": [
{
"c_id": "9156",
"date": "17 Jan 2023",
"name": "Sabina Leonelli",
"role": "Author Response",
"response": "First, regarding the current status of the uses of AI in plant research, it would be helpful if the authors could expand their brief introduction of ML approaches by elaborating on which of these approaches are actually being used in plant research. It looks like the examples they go on to describe are all instances of (semi-)supervised learning. Are the other approaches to ML that they present also employed in plant science? If so, examples would be welcome. If not, it would be useful to signpost the more limited scope of AI approaches in plant science. Relatedly, I was slightly puzzled by the characterization of supervised learning as ‘a priori’ and of unsupervised learning as ‘inductive’. Both approaches are often considered inductive, and it is unclear why supervised learning should count as ‘a priori’. A final note on this point is that a reference to more recent literature (>1997) on ML would be appropriate here. In response to reviewer 1’s comments, we have included an additional table (Table 2) documenting the examples of ML and AI applications discussed in the paper. As part of this table, we have also listed the key ML methods associated with those examples. Another suggestion for improvement concerns the relation between Table 1 and the main text. While the table as such provides a very useful summary of the challenges and solutions being discussed, I found that the contents of some of the cells does not adequately reflect the material from the main text. The characterization of challenge #5 in the ‘data challenges’ column is a case in point. In the table, this challenge is labeled “Access to computing and modeling platforms, and related expertise” whereas in the main text the corresponding subsection is entitled “Using software and models across scale, species and environment.” Only the first paragraph of this subsection discusses questions of accessibility. In the remainder, issues relating to the *use* of models across contexts and scales are the focus. This is one of several instances for which there appears to be an opportunity to ensure a better fit between the contents of the table and the main text. Thank you for the useful comment, in some cases (such as that cited) this was a question of what we meant by ‘expertise’. We now improved the table to better match the contents of the paper. A further small issue about the table: the meaning of the contents in the “risks” column is ambiguous and inconsistent: in some rows, the risks pertain to the data challenge (when left unaddressed), whereas in others rows the risks pertain to the proposed solution. This should be easy to address, e.g. by introducing a further ‘tradeoffs’ column that lists the risks related to implementing the solutions (as opposed to leaving the challenges unaddressed). Agreed and implemented, thank you. Finally, I was puzzled by this remark in the conclusion: “Once a machine learning strategy has been identified for a given task exposure to further examples of that task typically improves performance, even when the details and environment are significantly different.” This optimistic conclusion seemed to me to be somewhat at odds with the main message of the article. Unless we construe a ‘task’ in plant science artificially narrowly, it seems that that challenges that have been identified and discussed demonstrate that we encounter considerable difficulties in establishing reliable performance of ML across research contexts. We corrected the sentence and added an additional sentence at the end of this paragraph to signal that this kind of success cannot always be expected or generalised. Real challenges remain, as identified in this paper, but addressing the challenges as suggested here does help to develop effective, targeted uses of ML (what the referee rightly labels a ‘narrow task’)."
}
]
}
] | 1
|
https://f1000research.com/articles/10-324
|
https://f1000research.com/articles/12-68/v1
|
17 Jan 23
|
{
"type": "Research Article",
"title": "The experience of using Alpha-Stim AID cranial electrotherapy stimulation (CES) for symptoms of anxiety",
"authors": [
"Chris Griffiths",
"Kate Walker",
"Harmony Jiang",
"Kate Walker",
"Harmony Jiang"
],
"abstract": "Background: Alpha-Stim AID is a self-administered, cranial electrotherapy stimulation (CES) device with evidence of effectiveness in treating symptoms of anxiety. In this study, Alpha-Stim AID was offered through a United Kingdom (UK) primary care social prescription service to patients with symptoms of anxiety. This study explored the experience and impact of using Alpha-Stim AID cranial electrotherapy stimulation (CES) through in-depth interviews. Methods: Out of a sample of 57 using Alpha-Stim AID, fifteen participants consented to be interviewed. The age range of the participants was 26–65 years (M = 46.6); 10 (67%) were female and 5 (33%) male. Data were analysed using thematic analysis. Results: There was support for the acceptability and useability of Alpha-Stim AID. Most participants described a positive impact in their lives and would recommend it to others. Themes that emerged offered insights into how people used the Alpha-Stim and their experiences of the effects. Conclusions: It is important to identify anxiety symptoms and offer patients choice of treatment options. The results support the use of Alpha-Stim AID as a treatment option for people with symptoms of anxiety. Access to Alpha-Stim AID should not be restricted by being able to afford to buy it. An appropriately designed randomised control trial (RCT) is required.",
"keywords": [
"Social prescribing",
"primary care",
"general practice",
"Alpha-Stim",
"cranial electrotherapy stimulation",
"anxiety"
],
"content": "Background\n\nAnxiety is a common psychiatric disorder associated with fear, nervousness, apprehension, and panic, and physical responses such as cardiovascular, respiratory, and gastrointestinal (Martin, 2003). Anxiety disorders (generalised anxiety disorder [GAD], phobias, and panic disorders) have a 13.6% to 28.8% lifetime prevalence in Western countries (Michael et al., 2007). The most common anxiety disorder is GAD, defined as excessive and difficult-to-control anxiety or worry about life events or activities (APA, 2013), which can impair activities of daily living and reduce quality of life (Locke et al., 2015).\n\nIndividuals with anxiety will commonly experience comorbidity; over three quarters of people with an anxiety disorder have an additional chronic disease (Kessler et al., 2010; Merikangas & Swanson, 2010). There is a strong and unique association between anxiety disorders and physical health disorders, and the presence of both may result in a greater level of disability (Sareen et al., 2005). People with anxiety disorders often experience somatic symptoms (poor sleep, low energy levels, fatigue, headaches, pain, chest pain, shortness of breath, and gastrointestinal issues) and many individuals with anxiety disorders present to primary care with these somatic complaints rather than seeking help for anxiety symptoms (Wittchen et al., 2002; Wittchen & Hoyer, 2001).\n\nAnxiety disorders are associated with fewer healthy behaviours (Hearon et al., 2014) and increased healthcare utilisation across multiple healthcare settings (Horenstein & Heimberg, 2020). High rates of healthcare use among individuals with anxiety disorders may partly be due to poor recognition of somatic symptoms as anxiety-related and a subsequent lack of effective anxiety treatment (Horenstein & Heimberg, 2020). Anxiety symptoms can often be detected when more in-depth primary care patient assessment is undertaken, such as in social prescribing services (NHS England, 2021).\n\nMedication is used as a treatment for anxiety disorders, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine uptake inhibitors (SNRIs), benzodiazepines, buspirone, and tricyclic antidepressants (TCAs) (Bespalov et al., 2010). While there is evidence of effectiveness for some (Muntingh et al., 2016), compliance can be an issue due to adverse side effects, which can include nausea, fatigue, weight gain, tremors, sexual dysfunction, insomnia, and gastrointestinal symptoms (Bandelow et al., 2017). There can be a high treatment dropout, for example, the dropout rate of SSRIs is between 18% and 30% (Mochcovitch et al., 2017). Medication prescription may be associated with a high risk of relapse (Culpepper, 2009) and benzodiazepines are only recommended for severe anxiety symptoms and short-term use (two to four weeks) due to dependence and withdrawal issues (NICE, 2019a).\n\nPsychotherapy is recommended for anxiety and can be effective, but is costly and lengthy: delivered over multiple sessions over a period of time, with non-response rates of 60-66% (Gyani et al., 2013; Griffiths & Griffiths, 2014; NICE, 2019b). Uptake and attendance in psychotherapy can be affected by mobility issues, travel costs, or work or caring responsibilities (Bandelow et al., 2017). It is important for alternative home-based treatment options to be available to enhance patient choice of treatment.\n\nCranial electrotherapy stimulation (CES) is a non-invasive treatment method involving the application of pulsed low-intensity electrical current to the head to cause changes in the brain (Nardone et al., 2014). CES can significantly reduce anxiety symptoms and patients tolerate CES well (Ching et al., 2022). In a RCT with 115 participants diagnosed with anxiety disorder using the Alpha-Stim AID (Anxiety, Insomnia and Depression) CES there was a 32% reduction in anxiety (Barclay & Barclay, 2014). A review that examined five randomized, double-blind placebo-controlled studies found that Alpha-Stim AID reduces symptoms of anxiety; it concluded that Alpha-Stim AID is safe, based on an absence of any serious side effects (Shekelle et al., 2018).\n\nHealth service-based Alpha-Stim AID studies with an open label cohort and no control group design indicated positive outcomes. A study in primary care NHS patients experiencing anxiety symptoms reported significant improvements in anxiety, depression, and quality of life (Griffiths et al., 2021), as did a study set in an NHS Improving Access to Psychology Treatment (IAPT) service with patients diagnosed with GAD (Morriss et al., 2019). Providing Alpha-Stim AID through a nurse-led primary care clinic to university students with a diagnosis of anxiety or depression delivered improvements in anxiety and depression symptoms (Royal et al., 2022). These studies indicate that Alpha-Stim AID is safe, well-tolerated, and acceptable to the majority of patients, and the majority of patients will conform to the required treatment protocol.\n\nThe Medical Research Council (MRC) recommend using qualitative methods to capture people’s experience and feedback of an intervention (Moore et al., 2015). Qualitative research has been undertaken regarding a different form of electrical treatment: transcranial direct current stimulation (tDCS) (Gordon et al., 2021; Grycuk et al., 2021); which while not the same as CES, shares similar characteristics including being a non-invasive brain stimulation given via a portable device that administers weak electrical currents to the brain. Grycuk et al. (2021) explored the experiences and perceptions of tDCS for patients with schizophrenia though interviews with 12 participants and evidenced motivations, concerns, factors reducing fear, experience, and perceived effects. Acceptability, side effects, outcomes, and barriers and facilitators to engagement for patients having tDCS for binge eating disorder have also been successfully investigated (Gordon et al., 2021). In addition, qualitative approaches have been an effective approach to understanding the experience of patients with anxiety and the use of medication (Bosman et al., 2016) and psychotherapy (Pedersen et al., 2020).\n\nPrior to recommending Alpha-Stim AID for adoption, the United Kingdom’s (UK’s) National Institute for Health and Care (NICE) stated the need for collection of real-world data to better understand issues around people’s treatment preferences, treatment completion rates, and impact on quality of life (NICE, 2021). There is no research to date that has explored the experiences and impact of using Alpha-Stim AID through in-depth interviews. This study takes a qualitative approach to examine and understand the experience and impact of using Alpha-Stim AID for patients with symptoms of anxiety.\n\n\nMethods\n\nThis was a qualitative approach employing semi-structured interviews with patients experiencing symptoms of anxiety, who used Alpha-Stim AID for six weeks. The interview questions chosen were informed by the research literature and the data were analysed together.\n\nEthical approval was granted by the review panel of Northamptonshire Healthcare NHS Foundation Trust, whose researchers led the study, and approved by the NHS primary care provider consortium; reference: IFAS009. All participants provided informed written consent.\n\nFollowing informed consent, demographic information (gender, date of birth) was extracted from clinical records containing routinely collected data.\n\nParticipants were recruited through a social prescribing service, which is where a general practice (GP) patient is referred to a primary care-based Social Prescribing Link Worker (SPLW), who assesses their needs and goals, provides practical and emotional support, and makes appropriate links and referrals to healthcare and community-based resources and services; seeking to facilitate behaviour change to healthier lifestyles (NHS England, 2021). The participants were part of a group who had originally taken part in a project funded by East Midlands Academic Health Network’s (EMAHSN) ‘Innovation Pipeline’ funding stream.\n\nParticipants were identified as having symptoms of anxiety by SPLWs and asked if they would like to try using the Alpha-Stim AID for the management of their anxiety. In total 57 participants agreed to try the Alpha-Stim AID. The inclusion criteria for participants were patients: 18 years or over; under the care of SPLWs; and reporting symptoms of anxiety. Patients were excluded if they: lacked the capacity to consent; experienced seizures; or had a pacemaker/any other implanted electrical device.\n\nOf the 57 participants who used the Alpha-Stim AID, 15 were interviewed: the age range was 26–65 years (M = 46.6, SD = 12.0); 10 (67%) were female and 5 (33%) were male. All participants reported ethnicity as ‘White British’. The reasons given for the use of the Alpha-Stim AID, and frequency of use are presented in Table 1.\n\nOnce the participants provided informed consent to try the Alpha-Stim AID (marked as a class IIa medical device by Conformite Europeene [CE]), they were sent it or given it by their SPLW with instructions on how to use it. They were advised to use it once a day for an hour for six weeks, and to use the device at level 1 (2 bars on screen) (0.5 Hz, 100-500 μA, 50% duty cycle, biphasic asymmetrical rectangular waves). Alpha-Stim AID is a mobile phone-sized device worn via a neck lanyard which delivers small electric currents via metal clips (which are soft pad covered) attached to both earlobes. Light activities can be performed whilst in use, but the person is advised not to drive a vehicle. SPLWs could be contacted to ask any questions about the device and its effects. Patients remained on any prescribed medication they were taking and continued any other medical or psychological interventions. Following 6 weeks’ use they were required to return the Alpha-Stim AID.\n\nPatients who completed 6 weeks use of the Alpha-Stim AID were contacted and asked if they would undertake an interview. Those who gave oral informed consent to this were phoned at a prearranged time and interviewed. The interviews followed a semi-structured format. Interviews lasted between 13.52 minutes and 50.07 minutes (M = 30.57, SD = 9.33). They were recorded on a digital audio recorder, and then were transcribed verbatim. Once transcribed and anonymised, the recordings were deleted. NVivo 13 (a qualitative data analysis software package) was used for supporting data analysis. Data were collected between November 2021 and August 2022.\n\nThe ontological and epistemological positionings were critical realism; this is ontologically realist based on the assumption that there is an external reality, independent of human minds, and epistemologically relativist, i.e., different methods produce different perspectives on reality, and reality is a finite subjective experience (Denzin & Lincoln, 2005). A critical realist approach therefore is grounded in the assumption that data are informative of reality, but that data need to be interpreted to enable access to underlying structures embedded in it (Willig, 2012). As there were no studies exploring experiences of using an Alpha-Stim AID, thematic analysis was seen to provide the best methodological framework, as theories can be applied flexibly (Braun and Clarke, 2006), without any a priori theoretical assumptions (Willig, 2001). Thematic analysis enables the researcher to interpret the patients’ experiences as well as the situations and contexts within which they arise.\n\nThe thematic analysis was data-driven and inductive (to explore experiences, perspectives and meanings of the participants in relation to Alpha-Stim AID) and focused on the semantic level to capture explicitly expressed meaning (Braun and Clarke, 2021). The six-phase guide advocated by Braun and Clarke (2006) was implemented and comprised: (i) familiarisation with the data, through transcription, reading and noting initial analytical observations; (ii) generating initial codes from important features in the data; (iii) searching for themes – coherent and meaningful patterns relevant to the research question; (iv) reviewing the themes, assessing for consistency and ensuring that they reflected the whole data set; (v) defining and naming themes; and (vi) writing up coherent accounts of the data, utilising excerpts to capture the essence of the theme. Thematic networks (Attride-Stirling, 2001) were used as a heuristic in the thematic analysis, and not a separate method, to present the themes generated and illustrate their relationships, through the development of global, organising and basic themes.\n\nCoding was undertaken by two members of the research team. To ensure rigour of the coding and strength of the interpretation and theorising, a third member of the research team reviewed and provided feedback on the analysis and findings. Analysis of the data was supported by an individual with lived experience of anxiety, who undertook initial reading and coding of a proportion of the interviews (phases i and ii of thematic analysis), and assisted with reviewing the themes and assessing them for consistency, and naming and defining the themes (phases iv and v of thematic analysis). Verbatim quotes were reported to promote verifiability (Silverman, 2015). To promote credibility and confirmability of the research, and to make sure that the findings were the experiences of those interviewed, Shenton’s (2004) strategies (credibility, transferability, dependability, and confirmability) for ensuring trustworthiness were followed.\n\n\nResults\n\nBased on the narratives of the participants, three global themes were developed, and associated organising and basic themes created. Figure 1 presents the thematic network that was developed, of the different levels of themes.\n\nThis global theme is made up of two organising themes (Enablers and Obstacles). This global theme represents the different factors that support or hinder engagement with and use of the Alpha-Stim AID.\n\nEnablers\n\nThis organising theme is made up of five sub-themes.\n\nAccessible, easy to use, go-to device\n\nThe device was easily accessible, could be used as and when required.\n\nP1: The fact that, it’s there, it’s by my bed, I could just use it if I'm having a rubbish day. I could just sit in my bed and do it while I’m lying there. I haven’t got to go anywhere.\n\nP7: I think with medication, obviously, it takes a while for it to work, whereas the, the Alpha-Stim is instant … in regards to like talking therapy that takes a while also I think. Just because obviously, it's instant.\n\nAlpha-Stim AID offered an element of psychological support, from the knowledge it could be accessed at any time.\n\nP6: I think knowing that I've got something that I could go to, if I was feeling particularly anxious – I knew I could go to it, and it made me feel better … it just helped knowing it was there and I could come home and use it.\n\nThe Alpha-Stim AID was simple and easy to use.\n\nP5: It is good because it is simple to use, I understood how to use it. Press the button and it just went and I didn’t feel negative about it.\n\nNo prohibitive reactions or side effects\n\nMost participants reported no side effects using the Alpha-Stim AID: feeling little, or no physical sensations whilst using it.\n\nP10: The first time I used it I felt a little bit [of tingling], but the more I used it, the more I didn’t feel anything after that. It just calmed me, seemed to calm me down to a really good level without having any side effects.\n\nA few experienced side-effects, but these were all manageable and could be tolerated, so were not prohibitive for use.\n\nP4: Just a little shock. Like an electric shock, I suppose. It wasn’t an electric … you felt there was like a sting, really. It doesn't mean I can't use it because of that.\n\nP9: It was a bit, sort of like pin pricks in my ear lobes … but it wasn’t, too bad. And it wasn’t all the time, it was just every now and then.\n\nA couple of participants reported that they experienced feelings of dizziness, but this did not prevent its use. One participant reported how it was not ‘bothersome, more like a very relaxed dizziness’ [P7], whereas for another it was only initially a problem.\n\nP12: The first couple of times I used it I felt quite dizzy. You know like when you’re on a boat? Just dizzy, in my head. Just a bit dizzy. That went after probably about the third time I was using it, that had gone.\n\nEmbeds and integrates into daily routine\n\nAlpha-Stim AID could easily be embedded and integrated into daily routines.\n\nP1: The thing is good – as well, it’s the fact it's, it's something you have to do every day. It's like, it's, it's sort of a habit that I've done, that I’ve hooked into.\n\nParticipants developed a regular time as part of their routine, for some it was at the start of the day:\n\nP6: I used it routinely in the morning, and I picked that just because I thought it would help me through the day.\n\nWhereas others found it better fitted into their evening and bedtime routine:\n\nP3: I tend to use it in the evening, when I'm just sitting at home, sitting at home relaxing, and then after I've used it, I'm tired and sleepy.\n\nParticipants could use it while continuing with other tasks and activities, thereby reducing disruptions.\n\nP10: It’s not, it’s only an hour, and you can still … it’s not intrusive, you can still do other things … so you don’t have to sit still … you can still go about your routine and your daily life with that, you know, it’s not a problem.\n\nReliable machine, no technical issues\n\nParticipants all found that the Alpha-Stim AID was reliable.\n\nP1: It never stopped working, it's very reliable.\n\nP5: The Alpha-Stim never stopped working, there were no technical issues with it.\n\nP12: The Alpha- Stim always worked, it never stopped, and it was always completely reliable – you could guarantee that it was working and ready to use at any point.\n\nOpenness and willingness to try something new and different\n\nEngagement with and use of the Alpha-Stim AID was furthered by individuals’ willingness and openness to try something new.\n\nP2: Yeah, I know everyone is different but it’s always worth a try. Like I thought maybe it's not, maybe it is … but I tried it. I tried it and it worked.\n\nP8: I am open to trying something a bit different. I just want to help myself really. So, I'm trying anything.\n\nFor several participants, their willingness and openness came from having tried other interventions with no or little success.\n\nP13: I'm willing to sort of give anything a try if I am honest with you. I have literally tried CBT, I’ve tried the pills I've tried CAMHS, and I have tried every, everything been offered to me before. I am willing to give it a try.\n\nThere was a feeling of ‘nothing ventured nothing gained’.\n\nP10: My thoughts were, if it didn’t, I haven’t lost anything by at least trying it and giving it a go … if I hadn’t had tried it, I would’ve regretted it … so I thought, giving it a try is the least I can do and hopefully it’ll work. If it doesn’t, it doesn’t, and I haven’t lost anything by that.\n\nObstacles\n\nObstacles were not widespread; however, there were two identified in a minority of the narratives, which formed two themes.\n\nDelays getting the device and starting\n\nThree of the participants experienced delays in the process of getting started due to supply and communication issues, that were successfully resolved:\n\nP7: It wasn't easy to receive to begin with, because there wasn't many about so I had to wait for one to become available, so it took a bit longer than you would have liked.\n\nEncountering barriers that interfere with use\n\nFactors were identified that resulted in participants delaying using it, or a temporary or permanent stoppage of use. These obstacles were practical:\n\nP12: I didn’t use it like I was supposed to. So, it was a timing thing. I was just really busy … so it was really just kind of life getting in the way that stopped me using it.\n\nOr they involved having other priorities:\n\nP7: Obviously, having children. Not so much priorities but obviously, I had to. Yeah, it was more of just being around the children really, not being able to actually sit and relax and use it.\n\nOr they were to do with time.\n\nP4: I just felt you know having to sit there for an hour, finding time really. And I'm quite [a] fidgety person. You know it is time-consuming doing it. You know you sit there, having to peel them off, put them on … it’s just time-consuming.\n\nOr they were to do with psychological barriers:\n\nP8: I didn't use it for a while when it was sent to me … probably a bit of anxiety, probably, I just don't know, it was just left in its box on my table, sitting in front of me and I was looking at it every day.\n\nSome of the patients wanted to use it longer than the 6-week loan, but the cost of the Alpha-Stim AID was prohibitive.\n\nP5: Once that goes back, I am going to be lost … if I could afford it, I would but with the disability, with the money I get, I … there is no way I would be able to afford it. But I will be lost without it.\n\nThis global theme is made up of four sub-themes capturing the participants’ perceptions and opinions.\n\nPrecipitates a belief that something could help\n\nBeing given this opportunity, and trying something different, precipitated a belief and hope that they had something that would help.\n\nP15: It gave me a belief that it would help me, thought it would help me, not be so stressed and depressed.\n\nP1: But I mean the great thing with the Alpha-Stim is it gives you hope. I try not to go into these things going, it's magic, it’s going to make me better. But it's just because you know, you hope that it might, it might not make you better, but it might help you on the way. And I feel that's what it’s done.\n\nP5: It just gives you positive thoughts. That there is something in life which is actually there to help you. And it’s the thought that you know, it’s out there and you [are] getting to try it.\n\nParticipants felt that the device added value to their lives, that they wanted to keep it and were reluctant to give it back.\n\nP8: Because I don't want to let it go and I want to get the best benefit I could over the last few days. I like the Alpha-Stim. I don't want to give it back … [SPLW’s name] got me an extra week or two.\n\n‘It’s brilliant’ – reluctant to give it back\n\nAcross the narratives, the experience of the Alpha-Stim was simply described as brilliant, e.g., ‘I think it's incredible, it’s brilliant’ [P1]; ‘It was brilliant, to be honest. It's brilliant’ [P2]; ‘The instrument itself is brilliant’ [P5].\n\nThe device added value to their lives, supporting them so much, that they wanted to keep the Alpha-Stim, and were reluctant to give it back.\n\nOne participant bought one.\n\nP3: Because I am going to invest. I've chatted with my family and my friends, and they've all seen the difference that it's made to me. So yeah, I'm going to be getting one.\n\nPreferred alternative to medication\n\nParticipants preferred Alpha-Stim AID as an alternative to medication for treating their anxiety.\n\nP8: Well, I was really interested because it's not medication … I do take medication, but I don't like to take medication. So, this was a lot more helpful for me because it isn't medication. I liked having an alternative to medication.\n\nP15: I prefer to try something that’s not tablets. More natural than tablets.\n\nP6: I do like the fact that it is a non-medicated intervention and is very safe.\n\nP4: The main thing was a replacement for medication … I think with, with not going down the chemical route of prescription drugs. Having the freedom of having something where you can just sit there, and you need to just try. [Alpha-Stim] can mean that you perhaps don't go down the medication route, which is, you know, a positive thing.\n\nFor some, using the Alpha-Stim AID meant they were able to stop using medication:\n\nP3: But the Phenergan it was, I don't really want to take [it], I don't really want to take more chemicals I don’t want to take more meds. Since using the Alpha-Stim, I haven't taken a single one Phenergan, because I haven’t needed it.\n\nRecommendable, advise others to give it a go\n\nAll participants would recommend Alpha-Stim AID based on their positive experiences.\n\nP5: It's brilliant, and I'd recommend it to anyone that was struggling.\n\nP2: I would recommend it to other people, definitely, hundred percent.\n\nP3: I have suggested [name] try it. She suffers with mental health, and she's been put on, I think it's called Propranolol for anxiety, and I said you want to see if you can go on, try this machine. See if you can get on a trial, see if you can use it. I said because it's really worked and I’ve noticed a difference, she said yes, I've noticed a difference in you as well.\n\nOne participant found the Alpha-Stim AID did not work for them, but they would still recommend people try it.\n\nP9: I’d recommend it to people who are thinking about doing it, do it, because it might work. Just because it doesn’t work for me, you know, not everything works for everyone. But some things do for some people, some things work. Yeah, I think it’s a good idea.\n\nOutcomes in terms of impact, progress and recovery were divided into both positive and negative.\n\nCumulative positives supporting recovery\n\nThis organising theme is made up of seven basic interlinked themes (Figure 1). The seven themes represent different positive outcomes experienced: reduced anxiety, clearer thinking and better thought processes, socialising more, engaging in activities, better sleep, positive outlook, and better coping. How these are interlinked and the order in which they are experienced is individualised. Some participants felt the Alpha-Stim AID reduced their anxiety, this increased their ability to do things they enjoyed, and in doing so they felt better and more positive about themselves. Others felt the Alpha-Stim AID improved their sleep, as a result they were better able to cope, and they felt this then reduced their anxiety. A combination of interlinked factors produced positive outcomes.\n\nCalm, relaxed, reduced anxiety\n\nThe majority of patients felt they experienced a positive impact; their anxiety was reduced and more manageable:\n\nP1: My anxiety is going down; I’ve gone out in the garden. I'm not worried about it …\n\nP14: I noticed a change, in, in some of my anxiety levels. I think it has reduced the severity of that constant feeling of anxiety.\n\nP15: I have not so much depression, stress and anxiety.\n\nSeveral of the participants reported the Alpha-Stim AID had a relaxing effect, which helped with anxiety.\n\nP4: I did feel a lot calmer I think, with it, I think when I used it, I didn't get so anxious. I felt calmer in myself, I didn't sort of race, or I felt a little bit more sort of on an even keel.\n\nP3: You've got into that better cycle I think of feeling more relaxed, less anxious, therefore able to sleep. So, then the next day you feel better … I’ve lost the anxiety so I can engage more and enjoy being with my friends … because I'm not as anxious … my mood is at a better level.\n\nExperiencing better quality of sleep\n\nSeveral participants talked about the positive effect on their sleep, including improved sleep:\n\nP12: After about a week or two my sleep had really improved. I think the sleep had a really big impact and it’s definitely the most successful thing I think I’ve found from using the Alpha-Stim. And I think that’s really been quite life-changing.\n\nLonger sleep was commented on:\n\nP2: I found it, well actually [it] helped me sleep as well. Instead of maybe about two or three hours sleep a night and napping in the daytime I sleep maybe about six hours now [at night].\n\nLess broken sleep was seen too:\n\nP5: Now I am getting a little more sleep to what I was having … waking up less during the night.\n\nThere was more ease getting off to sleep:\n\nP14: I think it's made it easier for me to go to sleep … it used to take me longer before I could settle down to sleep.\n\nBetter quality sleep was also observed:\n\nP8: I feel I’m getting a better quality of sleep since the Alpha-Stim.\n\nP3: It makes me want to sleep … the only way I can describe it is that I'm getting a better quality, I sort of slept well, but I think I got a better quality of sleep, which helped anxiety … the more sleep, the more, better quality of sleep I'd had, was resulting in a better mood and lower anxiety.\n\nOne participant compared their sleep when using the Alpha-Stim AID and when not, and was convinced better sleep could be attributed to it.\n\nP13: I even thought, is this psychological? Am I thinking it's working because I want it to work. So, I stopped using it for three days, and noticed my sleep pattern wasn't as good again. So, I put it back on, and I thought no, it's not psychological. It really is working.\n\nClearer more positive thinking, reductions in harmful/unhelpful thoughts\n\nThis theme is about improvements in thought processes, including the removal of negative thoughts.\n\nP12: I used to be very bad for, ‘it’s the end of the world’, ‘something’s wrong’ or ‘I’m useless’ and all that, those kind of horrible thoughts. They’ve definitely improved.\n\nP5: Before I started taking that [Alpha-Stim], I was feeling suicidal and everything. Now those thoughts yeah, those thoughts are going. I have even stopped hearing voices in my head. That’s calmed that down, I still have those days. I have calmed down.\n\nSeveral participants reported changes in their ‘mindsets’, being able to think more clearly, utilising positive self-talk, ‘taking their thoughts to court' [P3], or generally thinking more rationally and in a helpful way.\n\nP2: Is it about the way I’m thinking.] I don't sort of automatically go into a panic meltdown mode. It’s hard to describe really. It’s like I'm able to talk to myself and get over that. Where, I would try to talk to myself before and I wouldn't, I'd just come back inside. So, it is helping the way that I am thinking. The Alpha-Stim helps with my mindset.\n\nP6: It just stopped me overthinking and stopped my thoughts racing. I'm able to stay calm, which then helps me look at things more practically rather than just go into a downward spiral, which I did last time. I think it helps my emotions. I’m not as erratic, not thinking the worst and then you go the other way.\n\nP8: I have got all these thoughts that stop me going to sleep, and since using the Alpha-Stim I still have them, but that's still the same, but they're not so intense. I have managed to get rid of that intensity of those thoughts and things like that. And so, I’m getting to sleep better.\n\nConfident to interact and make connections with others\n\nThe theme is about changes in ability, desire and confidence to socialise with others.\n\nP12: I think there’s been an improvement … I was always kind of afraid to ask to meet up with my friends, like there was always something niggling in my head like: “Oh… don’t do it.” Now I’m definitely more confident with that.\n\nP6: Whereas usually, I'd have caught up with my sisters, and I wasn't wanting to do that. But I think once my mood improved, I was able to go and see them. From using the Alpha-Stim, I felt better in myself, and it meant that I would talk to family and socialise.\n\nP5: Well, it must have helped me to be able to go out and socialise because I have just asked [SPLW’s name], he has just helped me get a, some voluntary work.\n\nP8: I have started this group, the Kins, Kintsugi group. It's just a wellbeing group. So, I've been offered group therapy throughout the years, and I've always turned it down. But not this time.\n\nP3: And then just being with my friends and actually speaking with them sitting with a cup of coffee, just chatting with them. And not, just not constantly looking around me. It is almost impacting on my anxiety; I’ve lost the anxiety so I can engage more and enjoy being with my friends.\n\nAble to engage in and enjoy activities and tasks\n\nAnxiety prevented engaging in day-to-day activities and tasks. Following a reduction in anxiety, individuals reported an ability to take on and undertake tasks they previously hadn’t.\n\nP1: I’ve just gone, wow, I’ve been doing the washing up, doing the garden, being tidying up, you know, washing stuff.\n\nP15: More, well, I have had more showers. If I didn’t, if I weren’t going out, I wouldn’t bother before. But it’s hard though. But I am taking a bit more care of myself.\n\nParticipants were able to do and enjoy activities which were previously meaningful and important to them.\n\nP3: I’ve got back into some of the stuff that I enjoy doing, but I'd stopped doing because I just had no interest in it. You know, I’ve started reading books again, and crocheting and doing cross stitch. It's just enabling me to do things that I enjoy that then make me feel better.\n\nAlpha-Stim AID acted as a catalyst, changing a negative cycle of experiencing poor mental health into a positive cycle:\n\nP2: I was almost in a cycle of, this black cloud, that I couldn't do anything, and because I wasn’t doing anything that obviously didn't make me feel good. But I’ve now changed that cycle to I feel better in myself, so I can do more stuff, and that then makes me continue to feel better. Alpha-Stim kind of kicked me off for the starting-to-do stuff, and now I seem like I can do more.\n\nFeeling better equipped to cope\n\nParticipants noted they felt more equipped to manage and cope: ‘I'm feeling a lot more equipped, well equipped to deal with things’ [P1]; ‘I'm able to cope a lot better with things’ [P2]; ‘I am able to just cope with things that are normal day-to-day‘[P10]; ‘I'm probably like, finding it easier to cope with things’ [P8]. Participants reported reductions in OCD behaviours, feelings of sadness, breakdowns, and anxiety; through this, participants felt they could then cope and manage better.\n\nP12: It is a good tool to help with my anxiety. I think it was good for me as someone who just needed to be brought down to a level where I could cope and manage with whatever life throws at me.\n\nP14: There's been subtle or marginal improvements. Or even with the ability to cope with daily living, which in itself would be … could be seen as an improvement in quality of life also, as it's making the days more manageable\n\nUplifted mood, positive outlook\n\nParticipants experienced a noticeable improvement in how they were feeling.\n\nP1: I feel probably more positive at the minute.\n\nP2: I don't feel so harmful towards myself anymore. I’ve got a lot more energy. Just, well, happy that I can actually go out by myself as well. It's just a lot happier.\n\nP6: It did improve my mood, and it made me want to get up and do the normal thing. My mood felt better, and I didn’t have so much of the depression, so because of that I am more likely to do things around the house and look after myself.\n\nP12: Normally I would stress [over mistakes made] and really overthought the whole situation. That’s a good example of how I’ve changed. I’ve almost just let go of the stress … and have a bit more of a brighter outlook.\n\nNegative or no effect\n\nThis organising theme is made up of two sub-themes representing where the Alpha-Stim AID was deemed to have no effect or a negative effect.\n\nNo identifiable or noticeable change\n\nOnly two participants reported no differences in anxiety, mood, sleep, wellbeing, or any mental health symptoms.\n\nP11: And part of me wants to profess to having some sort of really positive or significant result from the use of it. But I’m not conscious, at least, of any significant, or any sort of change in my overall state.\n\nFor two other participants, whereas they reported positive impacts, they felt there were one or two areas where they would have liked to have experienced benefit but didn’t; for example, finding the Alpha-Stim AID did not help with their sleep: ‘it made no difference to sleep at all’ [P15), or their mood: ‘I don’t think it had much of an impact on my mood’ [P13].\n\nNegative psychological effects\n\nThis theme was only evident in the narratives of the two individuals who experienced no effects: there was a negative psychological effect as their high expectations of the device being something that would help them did not materialise. They had the realisation that this was another thing that had not worked, and they would still be experiencing anxiety.\n\nP9: I don’t know if it made me a bit worse. Cause, I was, I was expecting it to be good, and sort me out. But it’s just another thing that doesn’t work for me. It’s more that you were thinking: “Oh hopefully this can help.” And then, of course it hasn’t, and that has been difficult.\n\n\nDiscussion\n\nThis is the first research to qualitatively examine through in-depth interviews the experience and feedback of individuals with symptoms of anxiety who have used the Alpha-Stim AID. It provides support for acceptability, useability, and positive outcomes. The themes that emerged offered insights into what worked well, positive experiences, engagement, and beneficial outcomes; and what did not work well, barriers to using the device, and lack of impact (in a couple of cases).\n\nThere were fewer prior feelings of uneasiness about receiving Alpha-Stim AID treatment and less discomfort reported than has been reported for using tDCS (Gordon et al., 2021; Grycuk et al., 2021). Participants found engagement with the Alpha-Stim AID was enabled through the useability of the device, in that it was accessible, easy to use, reliable, could be embedded into their daily routine, and did not have any adverse side effects preventing use; these factors promoted treatment compliance. The findings add to and align with evidence of useability, feasibility, ease of use, and lack of side effects found in other studies (Barclay & Barclay, 2014; Griffiths et al., 2021; Morriss et al., 2019; Royal et al., 2022; Shekelle et al., 2018). Medication side-effects can cause treatment failure (Sundbom & Bingefors, 2013); and the lack of Alpha-Stim AID side effects meant that some participants perceived the Alpha-Stim AID as a preferred alternative to medication.\n\nPositive impact was experienced by the majority of the participants, who associated positive benefits with using the Alpha-Stim AID. The participants described reductions in their anxiety and panic attacks, and increases in feelings of calmness and relaxation. This supports evidence from quantitative research, which found Alpha-Stim AID significantly reduces anxiety symptoms (Barclay & Barclay, 2014; Griffiths et al., 2021; Morriss et al., 2019; Royal et al., 2022; Shekelle et al., 2018). Participants reported improvements in sleep quality and duration. This finding is aligned to studies that have quantitatively measured CES and its impact on sleep (Kirsch & Gilula, 2007; Kirsch et al., 2019; Wagenseil et al., 2018). The positive experiences described by the participants were interlinked, giving insight into factors related to experiencing wellbeing and a good quality of life. The Alpha-Stim AID was associated with breaking negative cycles of mental illness and promoting positive cycles of mental health, well-being, and recovery. Further research could investigate how Alpha-Stim AID is directly and/or indirectly linked to these factors through its effects on anxiety, sleep, thoughts, or mood.\n\nParticipants described changes in their thoughts and thought processes: a mindset shift. Some reported a reduction in harmful and unhelpful thoughts (which are known to be associated with distress), and an increase in their ability to make connections with other people and to participate in activities. Some participants reported cognitive reframing (Robson & Troutman-Jordan, 2014) which enabled them to shift their mind-set to look at situations and experiences from a constructive perspective and find more constructive ways of perceiving ideas, events or situations. This seemed to be a key recovery factor and linked to self-reflection and greater resilience.\n\nSome participants experienced no effect following the use of the Alpha-Stim AID, and it is not effective for all people (Barclay & Barclay, 2014; Griffiths et al., 2021; Morriss et al., 2019; Royal et al., 2022; Shekelle et al., 2018). Those who did not experience a positive impact, experienced psychological distress due to the failure of hopes that it would work. Practitioners need to be aware of this and prepare patients for this potential outcome and ensure that patients receive ongoing support, and to suggest other solutions for their anxiety. Patients need to be informed of possible treatment not working and trajectories before the initiation so they know that they may need to try a number of options until an effective treatment is found (Toledo-Chávarri et al., 2020). Further research could be conducted to understand factors that influence impact, and why some do and some do not experience benefits.\n\nDue to recruitment having taken place though NHS primary care social prescribing services in a single county of the UK, generalisability to other settings is reduced; however, the sample was drawn from both rural and urban areas. All participants reported as being White British, limiting generalisability to other ethnic groups. Participants self-selected, which can introduce bias, as their experiences and perceptions may differ from those who did not wish to be, or felt unable to be interviewed. There was a relatively small sample size limiting generalisability; however, the sample size was deemed appropriate for an in-depth interview study, as saturation often occurs at around 12-15 participants in relatively homogeneous groups (Guest et al., 2006). A larger proportion of the participants were female and so results are less generalisable to males; however, this reflects the larger percentage of females presenting to primary care who report symptoms of anxiety.\n\n\nConclusions\n\nIt is important to identify anxiety symptoms and offer patients a choice of various treatment options. The results support the use of Alpha-Stim AID as a treatment option for people with symptoms of anxiety. In many countries people can buy and use Alpha-Stim AID themselves and some private clinicians prescribe use, but the awareness of this device is low, and cost is prohibitive for many (around £600 GBP) (Electromedical Products International Inc., 2022). Availability through free-to-access universal healthcare systems such as the UK’s NHS exists in only a couple of areas. An appropriately designed and powered RCT on the effectiveness of Alpha-Stim AID for anxiety symptoms compared to cognitive behavioural therapy (CBT), anti-anxiety medication or a combination of both is required (NICE, 2021). If Alpha-Stim AID is an effective treatment for anxiety, then access should not be restricted by being able to afford to buy it.\n\n\nAuthors' contributions\n\nAll authors contributed to the design of the study and interpretation of results. All co-authors contributed to critically revising the manuscript, read and approved the final manuscript, and agree to be accountable for all aspects of the work.",
"appendix": "Data availability\n\nThe datasets generated and analysed during the current study consisting of the transcripts of patients’ interviews are not publicly available due to confidentiality and privacy for participants, but the data collection tools are available from the corresponding author on reasonable request.\n\n\nAcknowledgments\n\nWe would like to thank the social prescription service lead for their support.\n\n\nReferences\n\nAPA: Diagnostic and statistical manual of mental disorders. American Psychiatric Association. 2013; 21(21): 591–643.\n\nAttride-Stirling J: Thematic networks: An analytic tool for qualitative research. Qual. Res. 2001; 1(3): 385–405. Publisher Full Text\n\nBandelow B, Michaelis S, Wedekind D: Treatment of anxiety disorders. Dialogues Clin. Neurosci. 2017; 19: 93–107. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBarclay TH, Barclay RD: A clinical trial of cranial electrotherapy stimulation for anxiety and comorbid depression. J. Affect. Disord. 2014; 164: 171–177. PubMed Abstract | Publisher Full Text\n\nBespalov AY, van Gaalen MM , Gross G:Antidepressant treatment in anxiety disorders.Stein MB, Steckler T, editors. Behavioral neurobiology of anxiety and its treatments. Springer;2010; (pp. 361–390).\n\nBosman RC, Huijbregts KM, Verhaak PF, et al.: Long-term antidepressant use: A qualitative study on perspectives of patients and GPs in primary care. Br. J. Gen. Pract. 2016; 66(651): e708–e719. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBraun V, Clarke V: Using thematic analysis in psychology. Qual. Res. Psychol. 2006; 3(2): 77–101. Publisher Full Text\n\nBraun V, Clarke V: Thematic analysis: A practical guide. Sage;2021.\n\nChing PY, Hsu T, Chen G, et al.: Efficacy and tolerability of cranial electrotherapy stimulation in the treatment of anxiety: A systemic review and meta-analysis. Front. Psych. 2022; 13(899040). PubMed Abstract | Publisher Full Text | Free Full Text\n\nCulpepper L: Generalized anxiety disorder and medical illness. J. Clin. Psychiatry. 2009; 70(2): 20–24. Publisher Full Text\n\nDenzin NK, Lincoln YS:Introduction: The discipline and practice of qualitative research.Denzin N, Lincoln Y, editors. The SAGE handbook of qualitative research. 3rd ed.Sage;2005; pp. 1–32.\n\nElectromedical Products International Inc:2022.Reference Source\n\nGordon G, Williamson G, Gkofa V, et al.: Participants' experience of approach bias modification training with transcranial direct current stimulation as a combination treatment for binge eating disorder. Eur. Eat. Disord. Rev. 2021; 29(6): 969–984. PubMed Abstract | Publisher Full Text\n\nGriffiths C, Leathlean C, Smart D, et al.: Alpha-Stim cranial electrotherapy stimulation (CES) for anxiety treatment: outcomes in a United Kingdom (UK) primary care practice. Open Journal of Psychiatry. 2021; 11: 186–201. Publisher Full Text\n\nGriffiths CA, Griffiths LJ: Recovery and reliable change rates for patients scoring severe on depression, anxiety or impaired functioning in a psychological therapies service: IAPT. Ment. Health Rev. J. 2014; 20(1): 28–35. Publisher Full Text\n\nGrycuk L, Moruzzi F, Bardjesteh E, et al.: Participant experiences of transcranial direct current stimulation (tDCS) as a treatment for antipsychotic medication induced weight gain. Front. Psychol. 2021; 12(694203) PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuest G, Bunce A, Johnson L: How many interviews are enough? An experiment with data saturation and variability. Field Methods. 2006; 18(1): 59–82. Publisher Full Text\n\nGyani A, Shafran R, Layard R, et al.: Enhancing recovery rates: lessons from year one of IAPT. Behav. Res. Ther. 2013; 51(9): 597–606. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHearon BA, Quatromoni PA, Mascoop JL, et al.: The role of anxiety sensitivity in daily physical activity and eating behavior. Eat. Behav. 2014; 15(2): 255–258. Publisher Full Text\n\nHorenstein A, Heimberg RG: Anxiety disorders and healthcare utilization: A systematic review. Clin. Psychol. Rev. 2020; 81: 101894. Publisher Full Text\n\nKessler KC, Ruscio AM, Shear K, et al.:2010.Epidemiology of anxiety disorders.Stein MB, Steckler T, editors. Behavioral neurobiology of anxiety and its treatments. Springer;2022; (pp. 21–35).\n\nKirsch D, Gilula M: CES in the treatment of insomnia: A review and meta-analysis. Practical Pain Management. 2007; 7(8): 28–39.\n\nKirsch TB, Kuhn J, Price LR, et al.: A novel medical device that relieves anxiety, depression and pain while improving sleep in a population of teachers. Journal of Depression and Anxiety. 2019; 8(2): 334.\n\nLocke AB, Kirst N, Shultz CG: Diagnosis and management of generalized anxiety disorder and panic disorder in adults. Am. Fam. Physician. 2015; 91(9): 617–624. PubMed Abstract\n\nMartin P: The epidemiology of anxiety disorders: A review. Dialogues Clin. Neurosci. 2003; 5(3): 281–298. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMerikangas KR, Swanson SA:Comorbidity in anxiety disorders.Stein MB, Steckler T, editors. Behavioral neurobiology of anxiety and its treatments. Springer;2010; (pp. 37–59).\n\nMichael T, Zetsche U, Margraf J: Epidemiology of anxiety disorders. Psychiatry. 2007; 6(4): 136–142. Publisher Full Text\n\nMochcovitch MD, da Rocha Freire RC , Garcia RF, et al.: Can long-term pharmacotherapy prevent relapses in generalized anxiety disorder? A systematic review. Clin. Drug Investig. 2017; 37(8): 737–743. Publisher Full Text\n\nMoore GF, Audrey S, Barker M, et al.: Process evaluation of complex interventions: Medical research council guidance. BMJ. 2015; 350(1258). PubMed Abstract | Publisher Full Text | Free Full Text\n\nMorriss R, Xydopoulos G, Craven M, et al.: Clinical effectiveness and cost minimisation model of Alpha-Stim cranial electrotherapy stimulation in treatment-seeking patients with moderate to severe generalised anxiety disorder. J. Affect. Disord. 2019; 253: 426–437. PubMed Abstract | Publisher Full Text\n\nMuntingh AD, van der Feltz-Cornelis CM , van Marwijk HW , et al.: Collaborative care for anxiety disorders in primary care: a systematic review and meta-analysis. BMC Fam. Pract. 2016; 17(1): 1–15. Publisher Full Text\n\nNardone R, Höller Y, Leis S, et al.: Invasive and non-invasive brain stimulation for treatment of neuropathic pain in patients with spinal cord injury: A review. J. Spinal Cord Med. 2014; 37(1): 19–31. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNICE: Benzodiazepine and z-drug withdrawal.2019a.Reference Source\n\nNICE: Generalised anxiety disorder and panic disorder in adults: management. Clinical guideline [CG113].2019b. Reference Source\n\nNICE: Alpha-Stim AID for anxiety disorders. Medical technologies guidance.2021. Published: 8 March 2021.Reference Source\n\nNHS England: Social prescribing (2021). NHS England;2021.Reference Source\n\nPedersen MK, Mohammadi R, Mathiasen K, et al.: Internet-based cognitive behavioral therapy for anxiety in an outpatient specialized care setting: A qualitative study of the patients’ experience of the therapy. Scand. J. Psychol. 2020; 61: 846–854. Publisher Full Text\n\nRobson JP Jr, Troutman-Jordan M: A concept analysis of cognitive reframing. Journal of Theory Construction & Testing. 2014; 18(2): 55–59.\n\nRoyal S, Keeling S, Kelsall N, et al.: Feasibility, acceptability and costs of nurse-led alpha-stim cranial electrostimulation to treat anxiety and depression in university students. BMC Primary Care. 2022; 23(97): 1–14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShekelle PG, Cook IA, Miake-Lye IM, et al.: Benefits and harms of cranial electrical stimulation for chronic painful conditions, depression, anxiety, and insomnia. Ann. Intern. Med. 2018; 168: 414–421. PubMed Abstract | Publisher Full Text\n\nShenton AK: Strategies for ensuring trustworthiness in qualitative research projects. Educ. Inf. 2004; 22(2): 63–75. Publisher Full Text\n\nSilverman D: Interpreting qualitative analysis. Sage;2015.\n\nSareen J, Cox BJ, Clara I, et al.: The relationship between anxiety disorders and physical disorders in the US National Comorbidity Survey. Depress. Anxiety. 2005; 21(4): 193–202. Publisher Full Text\n\nSundbom LT, Bingefors K: The influence of symptoms of anxiety and depression on medication nonadherence and its causes: A population-based survey of prescription drug users in Sweden. Patient Prefer. Adherence. 2013; 7(7): 805–811. PubMed Abstract | Publisher Full Text | Free Full Text\n\nToledo-Chávarri A, Ramos-García V, Torres-Castaño A, et al.: Framing the process in the implementation of care for people with generalized anxiety disorder in primary care: a qualitative evidence synthesis. BMC Fam. Pract. 2020; 21(1): 1–12. Publisher Full Text\n\nWagenseil B, Garcia C, Suvorov AV, et al.: The effect of cranial electrotherapy stimulation on sleep in healthy women. Physiol. Meas. 2018; 39: 114007. PubMed Abstract | Publisher Full Text\n\nWillig C: Introducing qualitative research in psychology adventures in theory and method. Open University Press;2001.\n\nWillig C:Perspectives on the epistemological bases for qualitative research.Cooper H, editor. The handbook of research methods in psychology. American Psychological Association;2012; (pp. 1–17).\n\nWittchen HU, Hoyer J: Generalized anxiety disorder: nature and course. J. Clin. Psychiatry. 2001; 62 Suppl 11: 15–21. PubMed Abstract\n\nWittchen HU, Kessler RC, Beesdo K, et al.: Generalized anxiety and depression in primary care: prevalence, recognition, and management. J. Clin. Psychiatry. 2002; 63(suppl 8): 7712."
}
|
[
{
"id": "226771",
"date": "23 Jan 2024",
"name": "Tony Sparkes",
"expertise": [
"Reviewer Expertise Mental health",
"personal recovery",
"suicide",
"qualitative 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\nThank you for asking me to review this paper. I feel this is a relevant and important piece of empirical work in this domain and progresses what is known about this particular intervention.\n\nI felt that the article was disciplined and well-written. That said, I would have preferred little more on the evaluation of more 'traditional' interventions (especially the psychotherapy section) in the introduction. Nevertheless, the introduction was logical, informative and the rational underpinning the study was clear.\nAgain, the methods section was clear and set out well. I note the research ethics section. I assume that the semi-structured interviews were mediated rather than 'in-person', although outside of any commentary about the impact of Covid-19 there is little explicit justification for this. It is not stated where the participants were geographically located, although the 'strengths and limitations' section does acknowledge some of this point. I am not sure whether a take-up rate of just over 25% (n=15) is normative in this domain of research.\nData analysis appeared appropriate to the study design, and the specific themes seemed reasonable. Some commentary upon diurnal variation (or time of use) of the CES (morning or evening for example) might have been useful to consider? I also feel that the analysis itself could have been more rigorous insofar as it felt rather descriptive for the most part; But, equally, in keeping with the narrative as a whole.\n\nThe discussion and conclusions are both firmly grounded in the literature and in the findings, and there is valuable acknowledgement of the necessary CES hardware being accessible to all. I also feel that calls for a RCT is also an appropriate conclusion.\nA solid article, well done.\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? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "226772",
"date": "27 Feb 2024",
"name": "Tad T. Brunyé",
"expertise": [
"Reviewer Expertise Neurostimulation"
],
"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 report a qualitative analysis of patient experiences with the Alpha-Stim AID device. Failure to move the science forward: It is unclear whether the current paper helps move the state of CES science forward in any meaningful way. The final sentence of the abstract states that appropriately designed RCTs are required; however, researchers have been saying exactly that about CES for several decades. If this report concludes the very same thing that has plagued the CES literature for the past 50 years, then how is it making a meaningful contribution to theory, mechanism, or research?\nMisrepresentation of cited research: The authors suggest that CES causes \"changes in the brain\" and cite the Nardone (2014) paper. That paper does not experimentally examine CES effects on brain activity, nor does it report on such an effect. In fact, that paper discusses how meta-analyses fail to support the authors' suggestion that CES affects the central nervous system. This is a persistent problem throughout the introduction and conclusion section, with broad and mildly deceptive statements about prior CES research.\nFailure to report competing findings: The authors cite the Ching (2022) paper, but fail to cite the other papers suggesting little to no effects of CES on the symptoms accompanying anxiety disorders. For example, Shekelle's (2018) systematic review failed to find any RCTs with acceptable quality for inclusion. The authors only identified one randomized controlled trial (RCT) examining anxiety without the presence of comorbid disorders (e.g., insomnia, depression), and deemed the study to have serious limitations and overall insufficient quality of evidence. In a meta-analysis, Klawansky (1995) found that while CES appeared to positively affect anxiety symptoms, they also made several cautionary notes: studies tend to be relatively poor quality, including a lack of effective blinding (especially double blinding), and a failure to comprehensively report all analyses, descriptive statistics, and results. They also caution that their result is based on relatively few studies and small sample sizes, there are likely many unpublished studies with equivocal or negative results, and that study teams frequently have potential conflicts of interest. Some more critical findings can be found in Brunye et al (2021), which should be considered. Finally, the results of a more recent meta-analysis examining CES effects on anxiety (Chung, 2023) should be included.\nFailure to acknowledge heterogeneous study methods: The authors discuss the Barclay and Barclay study as a single example of the Alpha-Stim AID influencing anxiety. However, that study did not use the AID device, it used the Alpha-Stim 100 device. This is an issue throughout the manuscript, which generally does not disclose or discuss the heterogeneous devices and parameters (i.e., frequency, intensity, duration, electrode sites) applied across cited studies.\n\nComparison to tDCS: Towards the end of the introduction, the authors discuss qualitative tDCS research examining user views and tolerance of treatment. However, there is no comparison to CES, hypotheses regarding what will be found with CES, or justification for why it is important to examine such data.\nJustification and disclosure of methods: Why was 6 weeks of treatment chosen, at this frequency, daily duration, and intensity? How many participants were asked if they would like to participate? What were the primary and secondary diagnoses of all participants? Who diagnosed them? How were the 15 of the 57 participants chosen for an interview? What prescription medications were the participants taking during the study? How can the researchers verify that the participants used the device as instructed?\nReporting of results: Why are there multiple examples of participant feedback in the positive attributes, but only one example for each negative attribute? Please provide feedback for both participants who reported to identifiable or noticeable change, and noted negative psychological effects. Please provide original source data, perhaps as an appendix, for posterity.\nDiscussion of results: The authors suggest their findings are congruent with research that found \"Alpha-Stim AID significantly reduces anxiety symptoms,\" however many of the cited papers did not examine the AID device, did not report a reduction of anxiety symptoms, or had serious flaws in design or reporting. I also suggest not citing research conducted by individuals with a financial stake in the company (Kirsch), in order to reduce possible bias in your interpretations of extant research and your own results. Please discuss whether the authors believe the present results would extend to other CES devices, other treatment protocols and device parameters, and whether they believe it reflects any changes in clinical symptom frequency or severity. Please also discuss whether they believe the 15 participants who were interviewed are an adequate and reliable representation of the 57 participants and their opinions on the device.\nThere are typos in Figure 1.\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? 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\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-68
|
https://f1000research.com/articles/11-466/v1
|
27 Apr 22
|
{
"type": "Systematic Review",
"title": "Accelerated atherosclerosis in rheumatoid arthritis: a systematic review",
"authors": [
"Rhea Raj",
"Sneha Thomas",
"Vasavi Gorantla",
"Rhea Raj",
"Vasavi Gorantla"
],
"abstract": "Background: Rheumatoid arthritis (RA) is a highly prevalent, chronic inflammatory condition of the synovial joints that affects approximately 1% of the global population. The pathogenesis of RA is predominantly inflammatory in nature, thereby accelerating the co-occurrence of other immunoinflammatory conditions such as atherosclerosis. Apart from traditional cardiovascular risk factors, RA patients possess a multitude of other factors that predispose them to early atherosclerotic disease. The aim of this systematic review is to assess the prevalence of premature atherosclerosis in RA patients and elucidate the role that proinflammatory cytokines, neutrophil extracellular traps, RA-related autoantibodies, and endothelial dysfunction play in the pathophysiology of RA-mediated atherosclerosis. We also discussed novel biomarkers that can be used to predict early atherosclerosis in RA. Methods: This review followed the PRISMA guidelines to select and analyze relevant articles. A literature search for articles was performed on February 25, 2022, through three research databases including PubMed, ProQuest, and ScienceDirect. The query used to identify relevant publications was “Rheumatoid arthritis and atherosclerosis” and the search duration was set from 2011-2022. Relevant articles were selected based on the inclusion and exclusion criteria. Results: Our initial search generated 21,235 articles. We narrowed our search according to the inclusion and exclusion criteria. After assessing eligibility based on the full content of the articles, 73 articles were ultimately chosen for this review. Conclusion: There is a high prevalence of accelerated atherosclerosis among RA patients. We found evidence to explain the role of proinflammatory cytokines, neutrophil extracellular traps, RA-related autoantibodies, and endothelial dysfunction in the pathophysiology RA-mediated atherosclerosis. Therapies targeting either the inflammatory load or traditional CV risk-factors seem to improve vascular outcomes in RA patients. Novel markers of atherosclerosis in RA may be useful in predicting premature atherosclerosis and serve as new targets for therapeutic intervention.",
"keywords": [
"Rheumatoid arthritis",
"atherosclerosis",
"atherogenesis",
"premature",
"pathophysiology",
"inflammation",
"cytokines",
"endothelial dysfunction",
"autoantibodies"
],
"content": "Introduction and background\n\nRheumatoid arthritis (RA) is an autoimmune disorder, often described as a debilitating condition, that severely impairs quality of life by causing extra-articular manifestations.1–3 RA affects approximately 1% of the global population and poses a significant societal and economic burden in terms of cost and disability.4,5 The incidence of comorbidities such as atherosclerosis-related cardiovascular diseases, lung cancer, osteoporosis, and depression are higher among individuals with RA, making it a multisystem disease.6 RA is described as a chronically progressive inflammatory condition that affects the synovial lining of joints in the fingers, wrists, feet, and ankles.1 Since the pathological mechanism that lead to RA is predominantly inflammatory in nature, it facilitates the co-occurrence of other immunoinflammatory conditions such as atherosclerosis.7,8 Atherosclerosis refers to the hardening of an artery due to the buildup of fatty, cholesterol-rich plaque within the intimal lining of the vessel wall.8,9 The pathophysiological link between RA and atherosclerosis has its roots in complex inflammatory pathways that interconnect the two conditions and serve as an explanation for the increased cardiovascular morbidity in RA patients. 10,11 Tumor necrosis factor alpha (TNF-α), is a proinflammatory cytokine that is highly elevated in the synovial fluid of individuals with RA.12,13 TNF-α, along with interleukin-6 (IL-6), promotes the accumulation of oxidized low density lipoprotein (oxLDL) within the vessel wall, which directly contributes to the formation of lipid-laden macrophages, also known as foam cells.13–15 Macrophagic foam cells are considered to be the prototypical cells involved in the development of atherosclerotic plaques.15,16 Interleukin-1 (IL-1) is another cytokine associated with RA that shares its proinflammatory properties with TNF-α as they both upregulate the expression of adhesion molecules on vascular endothelial surfaces, stimulate cytokine production, and induce the expression of proinflammatory genes, all of which favor the initiation of atherogenesis.17–20\n\nThe role of neutrophil extracellular traps (NETs) in the pathogenesis of RA has been increasingly gaining attention.21 NETs are a complex network of granular proteins, nuclear chromatin, and extracellular fibers that eliminate pathogens through the activation of the ROS-mediated suicidal NETosis pathway.21–23 The role of neutrophils in atherogenesis has been historically denied, but recent evidence shows that neutrophils are involved in progressive endothelial damage, recruitment of proinflammatory monocytes, and foam cell formation, thus implicating them in the process of atherosclerosis.24–26 The presence of citrullinated proteins within the synovia of patients with RA has been recognized as a target for anti-citrullinated peptide antibodies (ACPAs).27,28 Citrullinated fibrinogen within atherosclerotic plaques have also shown to be targeted by RA-derived ACPAs, contributing to the development of atherosclerosis in the setting of RA.27,29 It is well known that atherosclerosis is a consequence of progressive endothelial damage and dysfunction.30\n\nThere is ample evidence to support the presence of both micro- and macrovascular endothelial dysfunction in RA which helps to strengthen the pathophysiological link between the two entities.31 Our systematic review will assess the prevalence of premature atherosclerosis in RA patients and elucidate the role that proinflammatory cytokines, neutrophil extracellular traps, RA-related autoantibodies, and endothelial dysfunction play in the pathophysiology of RA-mediated atherosclerosis through analysis of available literature. We will also discuss carotid intima media thickness, flow mediated dilation, lipoprotein-associated phospholipase A2 enzyme activity, osteocalcin and osteoprotegerin levels as markers of predicting early atherosclerosis in RA patients.\n\n\nMethods\n\nThis review strictly follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines as this is a widely accepted and validated methodology for choosing relevant publications to be included in systematic reviews.32 A literature search for articles was performed on February 25, 2022, through three research databases: PubMed, ProQuest, and ScienceDirect. The query used to identify relevant publications was “Rheumatoid arthritis and atherosclerosis” and the search duration was set from 2011–2022. We included primary case–control studies, cohort studies, cross-sectional studies, observational studies, comparative studies, and meta-analyses. Once the search was complete, three co-authors worked independently to screen the results and extract data from each article. We acknowledge that despite our maximum efforts, some relevant articles may have been left off accidently. Our initial search generated 21,235 articles. Using manual screening, we narrowed the search according to the inclusion and exclusion criteria and a total of 73 articles were ultimately included in this systematic review (Figure 1).\n\nThe following inclusion criteria were used: research studies conducted on humans and written in English, studies published in or after 2011, studies relevant to our topic of interest (accelerated atherosclerosis in rheumatoid arthritis), and articles that were full text, peer-reviewed, and primary or original research publications.\n\nThe following criteria were used for exclusion: animal studies, articles that were not primary research studies i.e. case reports, reviews or systematic reviews, abstracts, letters to the editor, book chapters, articles published outside of range (2011–2022), and articles not relevant to our review. All duplicates and non-full-text articles were also excluded. This information is visually presented in the PRISMA flow diagram (Figure 1).\n\nData items\n\nThe information collected from each study included the name of the first author, year of publication, study design, study population, study aim, findings, and conclusion.\n\nRisk of bias in selected studies\n\nOnce studies were selected, three co-authors were to grade the risk of bias in individual studies using using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. GRADE evaluates study flaws such as bias risk, indirectness, imprecision, and publication bias. Two reviewers would have used these criteria on a study-by-study basis, with a third reviewer assessing and providing an outcome if there was any inconsistency.\n\n\nResults\n\nOur literature search yielded 21,235 articles: 1,041 from PubMed, 4121 from ScienceDirect, and 16,073 from ProQuest. 16,955 articles were excluded based on the exclusion criteria (animal studies, articles that were not primary research studies i.e. case reports, reviews or systematic reviews, abstracts, letters to the editor, book chapters, articles published outside of range, and articles not relevant to our review). All duplicates and non-full-text articles were also excluded. This resulted in 4,280 articles to be checked for eligibility. 73 articles were relevant and included in this review. Ultimately, there were 37 prospective studies, 10 case-control studies, eight cross-sectional studies, five comparative studies, three observational studies, three prospective observational studies, three meta-analyses, three retrospective studies, and one cohort analysis included in this review. The study characteristics are tabulated in Table 1.\n\n\nDiscussion\n\nThe pathophysiology of accelerated atherosclerosis in RA is due to a complex interplay between various proinflammatory mediators. TNF-α is an inflammatory cytokine that is highly elevated in the synovial fluid of individuals with RA and is involved in mediating premature atherogenesis by complex signaling pathways involving the p38 mitogen-activated protein kinase (MAPK) and the transcription factor nuclear factor-κB (NF-κB).11,106 As described earlier, TNF-α acts synergistically with IL-6 to form lipid-laden macrophages (foam cells), which are prototypic in the development of atherosclerotic plaques.13–16 The mechanistic pathway that contributes to this process involves the upregulation of the human scavenger receptor-A (SR-A) and lectin-like oxidized LDL receptor-1 (LOX1) on macrophages.15 Anti-TNF-α therapy has become a mainstay for treatment of RA.106,107 In a prospective study by Végh et al., anti-TNF-α therapy was shown to stabilize vascular-related outcomes in RA patients by ameliorating endothelial function.43 Similar findings were also reported by other studies included in this review, where TNF-α inhibition was found to significantly improve vascular function in RA patients.42,45,78\n\nDavies et al. found a positive correlation between RA disease activity and sVCAM-1, and associated it with the role of IL-6 in mediating atherosclerosis in RA.88 They went on to conclude that IL-6 trans-signaling plays an important role in vascular dysfunction in RA and blocking this pathway may be useful for RA patients. IL-1 is considered to be a proatherogenic cytokine as it stimulates SMC proliferation by autocrine induction of the platelet-derived growth factor (PDGF).20,108 SMCs contribute to the initiation of atherosclerosis by producing an extracellular matrix (ECM), precipitating lipid uptake, and inducing foam cell formation to ultimately form a fibrous cap within the vessel wall.109 IL-1 also induces its own gene expression, thus creating a powerful positive feedback loop to maintain a proatherogenic milieu.20 Lo Gullo et al. reported that RA patients had a higher expression of IL-1β and elevated levels of C-reactive protein (CRP) compared with the control group, suggesting a proinflammatory milieu mediated by this cytokine73 Kassem et al. assessed the role of non-traditional risk factors and found that RA patients with carotid atherosclerosis harbored inflammatory markers such as CRP, ESR, IL-6, and VCAM-1.91 Similar findings were reported by Karpouzas et al. and Agca et al. who concluded that inflammation is implicated in the pathophysiology of RA-related vascular complications.54,63 Other studies also found significantly elevated levels of inflammatory biomarkers and pro-inflammatory cytokines in RA patients, further supporting the role of cytokines in premature atherosclerosis in RA.60,80 Individuals with RA have elevated circulating levels of IL-17 as a result of T-helper 17 (Th17) cell activation and differentiation.10,11,110 Although the pathomechanisms that implicate IL-17 as a mediator of atherogenesis in the setting of RA remain unclear, Marder et al. proposed that IL-17 may disrupt normal endothelial function, stimulate myocardial fibrosis, and lower arterial compliance, thus promoting atherosclerosis.86 Yamamoto et al. reported that both traditional CVD risk-factors and inflammatory mediators influence the development of atherosclerosis in RA patients and concluded that the management of RA should involve controlling CVD risk factors and RA disease activity.64 A wealth of data shows that the role of inflammatory cytokines is pivotal when considering the pathomechanisms that explain the increased incidence of premature atherosclerosis in RA.\n\nThe role of NETs in autoimmune disorders is explained by the process of NETosis, which is described as an imbalance between NET formation and NET breakdown.10 In patients with RA, NET formation is thought to be triggered by autoantibodies and immunostimulatory molecules.21 NETs contain citrullinated vimentin (cVim), which is involved in secreting proinflammatory cytokines such as TNF-α and IL-1, thus continually maintaining a state of inflammation in RA.21,111 Even though the role of neutrophils in mediating atherosclerosis has been historically denied, recent evidence shows that neutrophils are involved in progressive endothelial damage, recruitment of proinflammatory monocytes, and foam cell formation.24–26 Researchers have detected the presence of NETs in atherosclerotic plaques of both humans and mice, which may contribute to the pathophysiology of RA-related atherosclerosis.23,112,113 Pérez-Sánchez et al. found that RA patients had enhanced NETosis, which correlated with disease activity and inflammatory and oxidative profiles in these patients. They concluded that NETosis-derived products play a role in mediating atherosclerosis in RA and may be used as a diagnostic tool.44 The lack of primary research studies on this topic area make it difficult to draw definitive conclusions about the role NETosis in RA and atherosclerosis. More research in this particular field would be beneficial in evaluating the diagnostic potential of NETosis-derived products and assessing whether the inhibition of NETs would hold therapeutic value in RA.\n\nCitrullinated proteins within the synovia of patients with RA are a target for anti-citrullinated peptide antibodies (ACPAs).27,28 Sokolove et al. found that citrullinated fibrinogen within atherosclerotic plaques are also targeted by RA-derived ACPAs.28 Clavel et al. found that RA-specific ACPA immune complexes have the potential of inducing macrophage-driven TNF-α secretion via the Fc-gamma receptor IIa (FcγRIIa).114 As detailed earlier, the contribution of TNF-α as an inflammatory mediator of atherosclerosis is remarkable, which provides evidence to support the pathophysiology of RA autoantibody-derived atherosclerosis. RA-derived autoantibodies like ACPAs were found in the serum of patients with RA and were considered an independent risk factor for the development of subclinical and clinical atherosclerosis.51 Nowak et al. found that the presence of anti-CCP antibodies were associated with greater cIMT values, as also confirmed by Vázquez-Del Mercado et al.48,75 Wahab et al. also found higher levels of anti-CCP antibodies in RA patients compared to controls and suggested its use as a useful indicator of subclinical atherosclerosis.92 A number of studies included in this review found similar results concerning RA-derived autoantibodies and atherosclerosis.51,55,84,85,87 An interesting phenomenon was reported by Jacobsen et al., who found polymorphic variations in the mannose-binding lectin gene (MBL) were associated with high scores of RA disease activity, C-reactive protein-based DAS28, and physical disability in anti-CCP-positive RA patients.115 MBL, a serum protein, plays an instrumental role in regulating innate immunity by binding to repeating sugar motifs to activate the complement system via MBL-associated serum proteases. 116 Barbara et al. found that RA patients had a significantly lower MBL serum concentration in relation to controls and found no statistically significant association between MBL and disease activity, ESR, autoantibodies, or IMT.105 A cross-sectional study found that both high and low levels of MBL in RA patients were associated with an increased common carotid artery intima-media thickness (cc-IMT), indicating a quadratic U-shaped relation between serum MBL and ccIMT.117 More studies would be valuable to assess whether MBL truly plays a role in mediating atherosclerosis in RA patients.\n\nAtherosclerosis is a consequence of progressive endothelial damage and dysfunction.30 The endothelium, as an organ, functions as an intimate vascular barrier that is involved with maintaining vascular tone, blood hemostasis, leukocyte migration, and antigen presentation, among other physiological processes.118,119 Endothelial dysfunction is heavily involved in the pathogenesis of atherosclerosis by inducing cell adhesion molecules, facilitating leukocyte emigration, promoting cytokine production, platelet activation, and SMC proliferation120 A number of studies have found elevated serum levels of asymmetric dimethylarginine (ADMA) in RA patients.121–124 ADMA is a potent inhibitor of endothelial nitric oxide synthase (eNOS), an enzyme responsible for the synthesis of vasoprotective NO125 NO serves as a cardioprotective molecule due to its vasodilatory properties and its ability to inhibit platelet aggregation, suppress adhesion molecules, maintain endothelial barrier integrity, and regulate SMC proliferation.126\n\nDi Franco et al. found that RA patients had elevated levels of ADMA and proposed its use as a biomarker of vascular endothelial dysfunction, as also concluded by Dimitroulas et al. and Chandrasekharan et al.50,77,83 Endothelial progenitor cells (EPCs) have also been implicated in RA-related atherogenesis.10 An inverse relationship between circulating EPCs and endothelial function has been established by numerous studies.127–129 When considering RA, a reduction in EPCs has been reported, possibly due to C-reactive protein-mediated apoptosis of EPCs130 Rodríguez-Carrio et al. reported long-standing RA was correlated with a reduction in EPCs and concluded that EPC imbalance is associated with endothelial dysfunction and subsequent CVD in RA.47 Similar findings were also reported by other studies included in this review.53,57 Progressive endothelial dysfunction along with a reduction in EPCs in RA results in the creation of a proatherogenic environment, thus facilitating atherosclerosis and CVD in affected individuals.\n\nCarotid intima media thickness (cIMT) has popularly been used as a marker for subclinical atherosclerosis. In our review, a number of studies utilized cIMT to assess the prevalence of subclinical atherosclerosis in RA. In a cross-sectional study by Hannawi et al., patients with RA had significantly higher cIMT values and a higher carotid plaque burden compared to healthy controls.38 Krajnc et al. also found that patients with RA had a higher cIMT compared with controls, suggesting atherosclerotic plaque build-up and increased risk for subsequent CVD.39 A plethora of other studies included in this review reported similar findings and concluded that there is a high prevalence of premature atherosclerosis in patients with RA.33,34,36,40,41,52,56,58–62,65,66,71,81,99,100,104 However, in a cross-sectional study by van Breukelen-van der et al., no significant association was found between RA and cIMT. These conflicting findings were attributed to the patients having low disease activity and well-controlled RA, suggesting therapeutic strategies that target CVD risk factors seem to improve overall cardiovascular risk in RA.89\n\nFlow-mediated dilation (FMD) is a non-invasive method to assess endothelial dysfunction and has been used as a predictor of early atherosclerosis. Verma et al. found that RA patients had lower FMD and higher cIMT compared to controls, consistent with endothelial dysfunction and accelerated atherosclerosis in patients with RA.37 Adawi et al. also acknowledged the high prevalence of accelerated atherosclerosis in RA patients and proposed the clinical use of FMD as a measure of endothelial function to predict subsequent atherosclerosis.49 Two other studies also reported similar findings regarding endothelial dysfunction in RA patients and the usefulness of FMD as an early marker of atherosclerosis.76,93\n\nCoronary calcium score (CS) utilizes computed tomography to detect the presence of vascular calcification. In a prospective study by Liu et al., the CS was found to be significantly increased in the coronary artery, carotid artery, and aorta of RA patients.68 In another prospective study, coronary artery calcification (CAC) was detected in 46% of RA patients.69 Other studies also reported similar findings.72,90 In a prospective study by Wahlin et al., patients with RA who had CAC were found to have increased values of DAS28 and ESR, implying that inflammation plays a role in mediating RA-induced CAC.79 Contrastingly, Chung et al. found no statistical significance in the incidence of CAC in RA patients compared to controls and concluded that traditional risk-factors for CVD, rather than inflammatory markers are responsible for CAC and atherosclerosis in RA.74 This study also reported that once RA patients developed CAC, the rate of progression was found to be similar to the progression seen in control participants. This study acknowledges that their results were not concordant with their primary hypothesis, and one explanation offered was that the study focused on subclinical atherosclerosis, and RA patients with prior events, who may have contributed to a greater progression of CAC had been excluded, resulting in differential bias. Overall, there is abundant evidence to conclude that premature atherosclerosis in RA is highly prevalent, and that both traditional CVD risk-factors and inflammatory mediators play a role in mediating this process.\n\nPostprandial hyperlipidemia (PPHL) has been shown to be an independent predictor of CVD.131 Mena-Vázquez et al. found that PPHL in RA patients was significantly associated with subclinical atherosclerosis, TNF-α, and high-sensitivity C-reactive protein, suggesting that PPHL in RA is associated with inflammation and subclinical atherosclerosis.95 Other studies have also found that cIMT is associated with postprandial ApoB48 and total ApoB, providing evidence that atherogenic chylomicron remnants contribute to atherosclerosis in RA.103,132\n\nBiomarkers associated with bone turnover such as osteoprotegerin (OPG) have been associated with CAC, carotid plaque, and IMT.133–135 Wahlin et al. examined the role of bone turnover markers in mediating atherosclerosis in RA and found that Osteocalcin (OCN) and OPG were significantly associated with IMT after 11 years, especially in patients with joint erosions. However, there was no significant association between collagen markers of ongoing bone turnover and IMT, suggesting that bone turnover and atherosclerosis may have different pathogenic mechanisms in the setting of RA.96 Beyazal et al. also found higher OPG levels in RA patients than controls and concluded that OPG may be a useful marker to assess CV risk in RA patients.97 More studies investigating this topic area may be beneficial to clarify whether bone turnover truly plays a role in premature atherosclerosis in RA.\n\nOther novel markers found to be associated with accelerated atherosclerosis in RA patients were von Willebrand factor (vWF),101 cellular communication network factor 1 (CCN1),98 human endothelial cell-specific molecule-1 (endocan),70 PCSK9/LDLR system,94 and oxLDL.67,82 Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a biomarker used to assess vascular inflammation.136 Södergren et al. found that Lp-PLA2 is associated with both subclinical atherosclerosis and disease severity in RA patients,102 however, Bes et al. found no significant difference between Lp-PLA2 enzyme in RA patients and healthy controls, possibly because RA patients were undergoing treatment and had low disease activity scores.35 Similarly, there are other novel biomarkers being investigated in their role in developing accelerated atherosclerosis in the setting of RA. More studies in this topic area may be beneficial to predict premature atherosclerosis in RA and identify new therapeutic targets.\n\nDue to the rigorous inclusion and exclusion criteria, studies that may contain supportive evidence according to their results were not included because their aim was not in line with our search criteria. Moreover, some studies did not explicitly state information regarding the study setting and type of study. Based on the current literature and evidence, there are various pathophysiological processes involved in accelerating atherosclerosis in RA which made it difficult to draw definitive conclusions on whether inflammation or traditional cardiovascular risk-factors work together or independently to contribute to these findings.\n\n\nConclusion\n\nIn conclusion, abundant evidence exists to support a high prevalence of accelerated atherosclerosis among RA patients. Since cardiovascular morbidity and mortality in RA is strikingly high, it is important to understand the mechanisms that initiate and govern atherosclerosis in RA so tailored therapeutic regimens can be developed to reduce the CV burden that RA patients carry. We found evidence to support the role of proinflammatory cytokines, neutrophil extracellular traps, RA-related autoantibodies, and endothelial dysfunction in the pathophysiology of RA-mediated atherosclerosis. Proinflammatory cytokines such as IL-6 and TNF-α are involved in the formation of atherogenic foam cells. RA-derived autoantibodies are involved in exacerbating the inflammatory potential of macrophages and endothelial dysfunction is involved in disrupting the integrity of the vascular barrier which create a proatherogenic milieu and favour subsequent atherosclerotic disease. The question of whether inflammation and traditional CV risk factors work synergistically to produce atherosclerosis in RA or if one is more significant than the other remains. Nevertheless, therapies targeting both the inflammatory load or traditional CV risk-factors seem to improve vascular outcomes in RA patients. Lastly, novel markers of atherosclerosis in RA may be useful in predicting early atherosclerosis and serve as new targets for pharmacological intervention.\n\n\nData availability\n\nNo data are associated with this article.\n\n\nReporting guidelines\n\nRaj, Rhea; Gorantla, Vasavi; Thomas, Sneha (2022): Accelerated atherosclerosis in rheumatoid arthritis: a systematic review. figshare. Dataset. https://doi.org/10.6084/m9.figshare.19618947.v1\n\n\nEthical statement\n\nNot applicable. No patient data or animal studies were used in this review.\n\n\nConsent from patients\n\nIn this review, no patient information was used. Consent is not applicable.",
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PubMed Abstract | Publisher Full Text\n\nPérez-Sánchez C, Ruiz-Limón P, Aguirre MA, et al.: Diagnostic potential of NETosis-derived products for disease activity, atherosclerosis and therapeutic effectiveness in Rheumatoid Arthritis patients. J. Autoimmun. 2017 Aug; 82: 31–40. PubMed Abstract | Publisher Full Text\n\nAnghel D, Sîrbu CA, Hoinoiu EM, et al.: Influence of anti-TNF therapy and homocysteine level on carotid intima-media thickness in rheumatoid arthritis patients. Exp. Ther. Med. 2022 Jan; 23(1): 59. PubMed Abstract | Publisher Full Text\n\nMajka DS, Vu TT, Pope RM, et al.: Association of Rheumatoid Factors With Subclinical and Clinical Atherosclerosis in African American Women: The Multiethnic Study of Atherosclerosis. Arthritis Care Res (Hoboken). 2017 Feb; 69(2): 166–174. PubMed Abstract | Publisher Full Text\n\nRodríguez-Carrio J, de Paz B , López P, et al.: IFNα serum levels are associated with endothelial progenitor cells imbalance and disease features in rheumatoid arthritis patients. PLoS One. 2014 Jan 21; 9(1): e86069. PubMed Abstract | Publisher Full Text\n\nNowak B, Madej M, Łuczak A, et al.: Disease Activity, Oxidized-LDL Fraction and Anti-Oxidized LDL Antibodies Influence Cardiovascular Risk in Rheumatoid Arthritis. Adv. Clin. Exp. Med. 2016 Jan-Feb; 25(1): 43–50. Publisher Full Text\n\nAdawi M, Watad A, Bragazzi NL, et al.: Endothelial function in rheumatoid arthritis. QJM. 2018 Apr 1; 111(4): 243–247. Publisher Full Text\n\nDimitroulas T, Hodson J, Sandoo A, et al.: Endothelial injury in rheumatoid arthritis: a crosstalk between dimethylarginines and systemic inflammation. Arthritis Res. Ther. 2017 Feb 10; 19(1): 32. PubMed Abstract | Publisher Full Text\n\nSpinelli FR, Pecani A, Ciciarello F, et al.: Association between antibodies to carbamylated proteins and subclinical atherosclerosis in rheumatoid arthritis patients. BMC Musculoskelet. Disord. 2017 May 25; 18(1): 214. PubMed Abstract | Publisher Full Text\n\nGonzález-Juanatey C, Llorca J, González-Gay MA: Correlation between endothelial function and carotid atherosclerosis in rheumatoid arthritis patients with long-standing disease. Arthritis Res. Ther. 2011 Jun 22; 13(3): R101. PubMed Abstract | Publisher Full Text\n\nRodríguez-Carrio J, Alperi-López M, López P, et al.: Red cell distribution width is associated with endothelial progenitor cell depletion and vascular-related mediators in rheumatoid arthritis. Atherosclerosis. 2015 May; 240(1): 131–136. Publisher Full Text\n\nKarpouzas GA, Ormseth SR, Hernandez E, et al.: Impact of Cumulative Inflammation, Cardiac Risk Factors, and Medication Exposure on Coronary Atherosclerosis Progression in Rheumatoid Arthritis. Arthritis Rheumatol. 2020 Mar; 72(3): 400–408. PubMed Abstract | Publisher Full Text\n\nRamírez Huaranga MA, Mínguez Sánchez MD, Díaz Z, et al.: What role does rheumatoid arthritis disease activity have in cardiovascular risk?. Reumatol. Clin. (Engl Ed). 2018 Nov-Dec; 14(6): 339–345. PubMed Abstract | Publisher Full Text\n\nDehghan P, Rajaei A, Moeineddin R, et al.: Prevalence of atherosclerosis in patients with inactive rheumatoid arthritis. Clin. Rheumatol. 2015 Aug; 34(8): 1363–1366. PubMed Abstract | Publisher Full Text\n\nLo A, Mandraffino G, Sardo MA, et al.: Circulating progenitor cells in rheumatoid arthritis: association with inflammation and oxidative stress. Scand. J. Rheumatol. 2014; 43(3): 184–193.\n\nSahari NS, Shaharir SS, Ismail MR, et al.: Subclinical atherosclerosis among rheumatoid arthritis patients without overt cardiovascular risk factors. Mod. Rheumatol. 2014 Nov; 24(6): 920–925. PubMed Abstract | Publisher Full Text\n\ndel Rincón I , Polak JF, O'Leary DH, et al.: Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Ann. Rheum. Dis. 2015 Jun; 74(6): 1118–1123. PubMed Abstract | Publisher Full Text\n\nSödergren A, Karp K, Bengtsson C, et al.: Biomarkers associated with cardiovascular disease in patients with early rheumatoid arthritis. PLoS One. 2019 Aug 5; 14(8): e0220531. Publisher Full Text\n\nSödergren A, Karp K, Bengtsson C, et al.: The Extent of Subclinical Atherosclerosis Is Partially Predicted by the Inflammatory Load: A Prospective Study over 5 Years in Patients with Rheumatoid Arthritis and Matched Controls. J. Rheumatol. 2015 Jun; 42(6): 935–942. PubMed Abstract | Publisher Full Text\n\nMohan A, Sada S, Kumar BS, et al.: Subclinical atherosclerosis in patients with rheumatoid arthritis by utilizing carotid intima-media thickness as a surrogate marker. Indian J. Med. Res. 2014 Sep; 140(3): 379–386. PubMed Abstract\n\nAgca R, Blanken AB, van Sijl AM , et al.: Arterial wall inflammation is increased in rheumatoid arthritis compared with osteoarthritis, as a marker of early atherosclerosis. Rheumatology (Oxford). 2021 Jul 1; 60(7): 3360–3368. PubMed Abstract | Publisher Full Text\n\nYamamoto H, Nakajima T, Kawahara R, et al.: Evaluation of risk factors for atherosclerosis using carotid ultrasonography in Japanese patients with rheumatoid arthritis. Int. J. Rheum. Dis. 2019 Jul; 22(7): 1312–1318. Publisher Full Text\n\nGuin A, Chatterjee Adhikari M, Chakraborty S, et al.: Effects of disease modifying anti-rheumatic drugs on subclinical atherosclerosis and endothelial dysfunction which has been detected in early rheumatoid arthritis: 1-year follow-up study. Semin. Arthritis Rheum. 2013 Aug; 43(1): 48–54. Publisher Full Text\n\nDalbeni A, Giollo A, Tagetti A, et al.: Traditional cardiovascular risk factors or inflammation: Which factors accelerate atherosclerosis in arthritis patients?. Int. J. Cardiol. 2017 Jun 1; 236: 488–492. Publisher Full Text\n\nAjeganova S, de Faire U , Jogestrand T, et al.: Carotid atherosclerosis, disease measures, oxidized low-density lipoproteins, and atheroprotective natural antibodies for cardiovascular disease in early rheumatoid arthritis–an inception cohort study. J. Rheumatol. 2012 Jun; 39(6): 1146–1154. PubMed Abstract | Publisher Full Text\n\nLiu JH, Ng MY, Cheung T, et al.: Ten-year progression of coronary artery, carotid artery, and aortic calcification in patients with rheumatoid arthritis. Clin. Rheumatol. 2017 Apr; 36(4): 807–816. PubMed Abstract | Publisher Full Text\n\nUdachkina HV, Novikova DS, Popkova TV, et al.: Calcification of coronary arteries in early rheumatoid arthritis prior to anti-rheumatic therapy. Rheumatol. Int. 2018 Feb; 38(2): 211–217. PubMed Abstract | Publisher Full Text\n\nTuzcu G, Uslu AU, Tuzcu A, et al.: A novel marker relationship between carotid intima media thickness and disease activity score-28 in patients with rheumatoid arthritis: Human endothelial cell-specific molecule-1. Turk. J. Med. Sci. 2019 Dec 16; 49(6): 1599–1605. PubMed Abstract | Publisher Full Text\n\nFan CY, Zhang ZY, Mei YF, et al.: Impaired brachial artery flow-mediated dilation and increased carotid intima-media thickness in rheumatoid arthritis patients. Chin. Med. J. 2012 Mar; 125(5): 832–837. PubMed Abstract\n\nYiu KH, Wang S, Mok MY, et al.: Relationship between cardiac valvular and arterial calcification in patients with rheumatoid arthritis and systemic lupus erythematosus. J. Rheumatol. 2011 Apr; 38(4): 621–627. PubMed Abstract | Publisher Full Text\n\nLo Gullo A, Mandraffino G, Imbalzano E, et al.: Toll-like receptor 3 and interleukin 1β expression in CD34+ cells from patients with rheumatoid arthritis: association with inflammation and vascular involvement. Clin. Exp. Rheumatol. 2014 Nov-Dec; 32(6): 922–929. PubMed Abstract\n\nChung CP, Giles JT, Kronmal RA, et al.: Progression of coronary artery atherosclerosis in rheumatoid arthritis: comparison with participants from the Multi-Ethnic Study of Atherosclerosis. Arthritis Res. Ther. 2013 Sep 25; 15(5): R134. PubMed Abstract | Publisher Full Text\n\nVázquez-Del Mercado M, Nuñez-Atahualpa L, Figueroa-Sánchez M, et al.: Serum levels of anticyclic citrullinated peptide antibodies, interleukin-6, tumor necrosis factor-α, and C-reactive protein are associated with increased carotid intima-media thickness: a cross-sectional analysis of a cohort of rheumatoid arthritis patients without cardiovascular risk factors. Biomed. Res. Int. 2015; 2015: 342649.\n\nMondal M, Sarkar RN, Chakroborty A, et al.: Atherosclerosis in an Indian cohort of rheumatoid arthritis with low disease activity and its correlation with inflammatory markers. Indian J. Rheumatol. 2011; 6(2): 61–67. Publisher Full Text\n\nDi Franco M, Spinelli FR, Metere A, et al.: Serum levels of asymmetric dimethylarginine and apelin as potential markers of vascular endothelial dysfunction in early rheumatoid arthritis. Mediat. Inflamm. 2012; 2012: 347268.\n\nKerekes G, Soltész P, Szucs G, et al.: Effects of adalimumab treatment on vascular disease associated with early rheumatoid arthritis. Isr. Med. Assoc. J. 2011 Mar; 13(3): 147–152. PubMed Abstract\n\nWahlin B, Meedt T, Jonsson F, et al.: Coronary Artery Calcification Is Related to Inflammation in Rheumatoid Arthritis: A Long-Term Follow-Up Study. Biomed. Res. Int. 2016; 2016: 1261582.\n\nAhmed A, Hollan I, Curran SA, et al.: Brief Report: Proatherogenic Cytokine Microenvironment in the Aortic Adventitia of Patients With Rheumatoid Arthritis. Arthritis Rheumatol. 2016 Jun; 68(6): 1361–1366. Publisher Full Text\n\nIm CH, Kim NR, Kang JW, et al.: Inflammatory burden interacts with conventional cardiovascular risk factors for carotid plaque formation in rheumatoid arthritis. Rheumatology (Oxford). 2015 May; 54(5): 808–815. PubMed Abstract | Publisher Full Text\n\nProfumo E, Di Franco M, Buttari B, et al.: Biomarkers of subclinical atherosclerosis in patients with autoimmune disorders. Mediat. Inflamm. 2012; 2012: 503942.\n\nChandrasekharan UM, Wang Z, Wu Y, et al.: Elevated levels of plasma symmetric dimethylarginine and increased arginase activity as potential indicators of cardiovascular comorbidity in rheumatoid arthritis. Arthritis Res. Ther. 2018 Jun 8; 20(1): 123. PubMed Abstract | Publisher Full Text\n\nOkano T, Inui K, Sugioka Y, et al.: High titer of anti-citrullinated peptide antibody is a risk factor for severe carotid atherosclerotic plaque in patients with rheumatoid arthritis: the TOMORROW study. Int. J. Rheum. Dis. 2017 Aug; 20(8): 949–959. PubMed Abstract | Publisher Full Text\n\nGeraldino-Pardilla L, Giles JT, Sokolove J, et al.: Association of Anti-Citrullinated Peptide Antibodies With Coronary Artery Calcification in Rheumatoid Arthritis. Arthritis Care Res. (Hoboken). 2017 Aug; 69(8): 1276–1281. Publisher Full Text\n\nMarder W, Khalatbari S, Myles JD, et al.: Interleukin 17 as a novel predictor of vascular function in rheumatoid arthritis. Ann. Rheum. Dis. 2011 Sep; 70(9): 1550–1555. PubMed Abstract | Publisher Full Text\n\nBarbarroja N, Pérez-Sanchez C, Ruiz-Limon P, et al.: Anticyclic citrullinated protein antibodies are implicated in the development of cardiovascular disease in rheumatoid arthritis. Arterioscler. Thromb. Vasc. Biol. 2014 Dec; 34(12): 2706–2716. Publisher Full Text\n\nDavies R, Williams J, Sime K, et al.: The role of interleukin-6 transsignalling on cardiovascular dysfunction in inflammatory arthritis. Rheumatology (Oxford). 2021 Jun 18; 60(6): 2852–2861. PubMed Abstract | Publisher Full Text\n\nvan Breukelen-van der Stoep DF, van Zeben D , Klop B, et al.: Association of Cardiovascular Risk Factors with Carotid Intima Media Thickness in Patients with Rheumatoid Arthritis with Low Disease Activity Compared to Controls: A Cross-Sectional Study. PLoS One. 2015 Oct 20; 10(10): e0140844. Publisher Full Text\n\nKarpouzas GA, Malpeso J, Choi TY, et al.: Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease. Ann. Rheum. Dis. 2014 Oct; 73(10): 1797–1804. Publisher Full Text\n\nKassem E, Ghonimy R, Adel M, El-Sharnoby G: Non traditional risk factors of carotid atherosclerosis in rheumatoid arthritis. The Egyptian Rheumatologist. 2011; 33(3): 113–119. Publisher Full Text\n\nWahab MAKA, El Laban A, Hasan AA, et al.: The clinical value of anti-cyclic citrullinated peptide (anti-ccp) antibodies and insulin resistance (IR) in detection of early and subclinical atherosclerosis in rheumatoid arthritis (RA). The Egyptian Heart Journal. 2016; 68(2): 109–116. Publisher Full Text\n\nDi Minno MN, Ambrosino P, Lupoli R, et al.: Clinical assessment of endothelial function in patients with rheumatoid arthritis: A meta-analysis of literature studies. Eur. J. Intern. Med. 2015 Dec; 26(10): 835–842. PubMed Abstract | Publisher Full Text\n\nArida A, Legaki AI, Kravvariti E, et al.: PCSK9/LDLR System and Rheumatoid Arthritis-Related Atherosclerosis. Front. Cardiovasc. Med. 2021 Oct 8; 8: 738764. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMena-Vázquez N, Redondo-Rodríguez R, Rioja J, et al.: Postprandial Hyperlipidemia: Association with Inflammation and Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis. Biomedicines. 2022 Jan 8; 10(1): 133. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWahlin B, Ramnemark A, Rantapää-Dahlqvist S, et al.: Osteoprotegerin and osteocalcin are associated with atherosclerosis in patients with rheumatoid arthritis: a prospective cohort study. Clin. Exp. Rheumatol. 2021 Nov-Dec; 39(6): 1402–1409. Epub 2021 Feb 25. PubMed Abstract\n\nBeyazal MS, Erdoğan T, Devrimsel G, et al.: Relationship of osteoprotegerin to pulse wave velocity and carotid intima-media thickness in rheumatoid arthritis patients. Z. Rheumatol. 2016 Sep; 75(7): 723–8. English. PubMed Abstract | Publisher Full Text\n\nEsaily HA, Serag DM, Rizk MS, et al.: Relationship between cellular communication network factor 1 (CCN1) and carotid atherosclerosis in patients with rheumatoid arthritis. Med. J. Malaysia. 2021 May; 76(3): 311–317. PubMed Abstract\n\nMulumba C, Lebughe P, Mbuyi-Muamba JM, et al.: Prevalence and associated factors of subclinical atherosclerosis in rheumatoid arthritis at the university hospital of Kinshasa. BMC Rheumatol. 2019 Sep 9; 3: 37. PubMed Abstract | Publisher Full Text | Free Full Text\n\nElshereef RR, Darwish A, Ali A, et al.: Asymptomatic atherosclerosis in egyptian rheumatoid arthritis patients and its relation to disease activity. Int. J. Rheumatol. 2015; 2015: 381931. Epub 2015 Feb 8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRistić GG, Subota V, Lepić T, et al.: Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis and Low Cardiovascular Risk: The Role of von Willebrand Factor Activity. PLoS One. 2015 Aug 6; 10(8): e0130462. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSödergren A, Karp K, Bengtsson C, et al.: Is Lipoprotein-Associated Phospholipase A2 a Link between Inflammation and Subclinical Atherosclerosis in Rheumatoid Arthritis?. 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}
|
[
{
"id": "150875",
"date": "30 Sep 2022",
"name": "Srinivasa Rao Sirasanagandla",
"expertise": [
"Reviewer Expertise Natural products",
"osteoporosis",
"cardiovascular research and Bisphenol A associated toxicity and morphological variations."
],
"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\nI reviewed the article titled \"Accelerated atherosclerosis in rheumatoid arthritis: a systematic review.\" The aim of this study is to assess the prevalence of premature atherosclerosis in RA patients and elucidate the role that proinflammatory cytokines, neutrophil extracellular traps, RA-related autoantibodies, and endothelial dysfunction play in the pathophysiology of RA-mediated atherosclerosis.\nThe paper presented is interesting, and overall, it is well written. However, I have the following comments:\nIn the first paragraph of the methods section and in the inclusion criteria, it is mentioned that \"the search duration was set from 2011–2022. However, in the Prisma table/chart, it mentions the years 2012–2022. Authors should clarify and correct the actual years of inclusion.\n\nFor the results section, it would be better to add all studies with similar study designs in sequence. For example, all prospective studies in sequence. This will be clearer to the readers. Add a letter \"n\" in the heading of study design and population column.\n\nIn the discussion, please add a paragraph on current therapies to treat RA. In addition, authors can discuss research gaps and add future recommendations before concluding their findings.\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",
"responses": [
{
"c_id": "8843",
"date": "30 Sep 2022",
"name": "Vasavi Gorantla",
"role": "Author Response",
"response": "Thank you Doctor for your review. We will incorporate all the suggestions made. Regards, Gorantla"
}
]
},
{
"id": "150876",
"date": "10 Oct 2022",
"name": "Syed-Rehan Hussain",
"expertise": [
"Reviewer Expertise My area of research is in immunology and viral infections. With some experience in autoimmune disease and gene therapy. My co-reviewer Dr Israel Cotzomi-Ortega has experience in the role of neutrophils and infections in kidney 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 systematic review by the authors aimed to find a pathophysiological link between early atherosclerosis and rheumatoid arthritis based upon current and previous 10 years of peer reviewed studies. They have three clearly stated objectives i) what is the prevalence of premature atherosclerosis in RA. ii) The role of cellular infiltrates, NETosis and cytokine dysfunction etc. in disease. iii) Early predictive markers for atherosclerosis in RA.\nAlthough it is a fairly interesting review, I have some queries and concerns about the limited number of supporting articles and some conclusions drawn from these studies.\n“High prevalence of atherosclerosis” on page1 is a subjective term please include percentage/quantifiable value in RA patient.\n\nPage 3 what proinflammatory genes are normally upregulated give examples.\n\nGive full names for acronym like “CV”.\n\nThe authors mention in the abstract and conclusion that NETs are playing a role in RA-mediated atherosclerosis. However, they are not supporting this claim by multiple studies. Kindly explain why one study is enough to find the association between NETs formation, RA and atherosclerosis when in the text on page 17 the authors state that the current data is not sufficient to draw a definitive conclusion.\n\nKindly explain why in the introduction osteocalcin (OCN) and osteoprotegerin (OPG) are referred as early biomarkers, however on page 18 they show OCN and OPG association after 11 years of disease progression not at an early stage.\n\nRegarding only 73 publications being selected out of over 21000. It seems to be very stringent as in 2021 alone there may be 35-40 publication that may fall in the area of “Rheumatoid arthritis and atherosclerosis”. Kindly elaborate why some relevant publications we not cited particularly where the claims for NETosis and early markers were made.\n\nThe presence of citrullinated proteins is not only for NETs. Rather it would be interesting to discuss other activities of neutrophil that causes endothelial damage, such as oxidative burst in the context of atherosclerosis.\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? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly",
"responses": []
},
{
"id": "150874",
"date": "10 Oct 2022",
"name": "Praveen Kumar Kodumuri",
"expertise": [
"Reviewer Expertise Neuroscience",
"Cardiology",
"Electrophysiology and Pulmonology"
],
"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\nAuthors have done exhaustive review of various research articles in order bring the possible link/s between augmented atherosclerosis in rheumatoid arthritis. This review article provides the information about mechanisms, risk factors that initiate and hastens the atherosclerosis in rheumatoid arthritis.\nI have following comments/suggestions for the author’s consideration:\nAuthors may provide precise details of “how 73 research articles were considered among 21,235”. This may clear the ambiguity of selection.\n\nIn exclusion criteria, authors may be asked to provide clarity of information. Overall authors may be asked to provide clear information on inclusion and exclusion criteria. Selection criterion lacks clarity.\n\nSome of the abbreviations may be provided with expanded form like TNF, IL, LDL, sVCAM, SMC, ESR and CVD etc.\n\nIn the “Discussion” part, authors have mentioned that “Anti-TNF-α therapy and vascular related outcomes” and this may be avoided as it is out of review article purview (or) authors may provide rationale for mentioning the specific details.\n\n“Conclusion” of the review article is more elaborate, and authors may be asked to provide in concise form.\n\nAuthors are to be commended for their extensive research and careful analysis of various research articles.\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",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-466
|
https://f1000research.com/articles/12-64/v1
|
16 Jan 23
|
{
"type": "Research Article",
"title": "Impact of clinical factors on hospital stay and hospital readmission rate after acute exacerbation of COPD: a retrospective cross-sectional study",
"authors": [
"Prem Shankar Chaurasiya",
"Dinesh Kumar Lamsal",
"Akash Khatri",
"Laxmi Aryal",
"Dinesh Kumar Lamsal",
"Akash Khatri",
"Laxmi Aryal"
],
"abstract": "Background: Chronic obstructive pulmonary disease (COPD) is a condition with high morbidity and cost to health services due to a high number of exacerbations necessitating multiple and prolonged hospitalizations. The length of hospital stays and hospital readmission rate is related to patient age, sex, disease severity, current smoking status, comorbidities, dyspnea grade, carbon dioxide partial pressures, use of mechanical ventilation, previous exacerbation, long-term oxygen therapy, and inpatient diuretics use. The purpose of the study was to identify the differential effects of patient and treatment-related factors on the length of hospital stay and hospital readmission for COPD exacerbation-related admissions. Methods: A hospital-based retrospective cross-sectional study was conducted among 151 patients with acute exacerbation of COPD admitted at Civil Service Hospital, Kathmandu from August 2021 to March 2022. Ethical approval was taken from the Institutional Review Committee, Civil Service Hospital (Reference no. 18/ 2022). A convenience sampling method was followed. Data regarding different clinical factors were collected in a semi-structured questionnaire. The data were entered and analyzed through Microsoft Excel 365 and SPSS version 22.0 using a binary regression model. Results: Comorbidities, current smoking, dyspnea grade mMRC IV, mechanical ventilation, and long-term oxygen therapy were significantly associated with prolonged hospital stays for COPD exacerbation-related admissions. The corresponding odd ratio is (OR 3.4, 95% CI: 1.24–9.29); (OR 21.4, 95% CI: 6.17–74.57); (OR 2.5, 95% CI: 1.20–5.45); (OR 5.6, 95% CI: 1.20–26.35); (OR 2.4, 95% CI: 1.02–5.90), respectively. Conclusions: The effect of clinical factors such as comorbidities status, current smoking habits, higher grade of mMRC dyspnea scale, mechanical ventilation, and long-term oxygen therapy needed to be considered to optimize care for COPD patients needing hospital admissions and hence decrement in hospital costs.",
"keywords": [
"demography",
"diuretics",
"exacerbation",
"frequency",
"neoplasm",
"oxygen",
"prevalence",
"regression"
],
"content": "Introduction\n\nChronic obstructive pulmonary disease (COPD) is now one of the top three causes of death worldwide and 90% of these deaths occur in low- and middle-income countries. More than three million people died of COPD in 2012 accounting for 6% of all deaths globally.1 It is a condition with high morbidity and cost to health services. Hospitalizations due to COPD negatively affect the well-being of patients with an impact on length and quality of life. Patients with COPD undergo frequent exacerbations which are defined as an acute worsening of respiratory symptoms (increased dyspnea, increased sputum purulence and volume, together with increased cough and wheeze) that results in additional therapy.1 The length of hospital stay for an acute exacerbation of COPD is related to several factors; these include age, disease severity, the presence of comorbidities, dyspnea perception, respiratory rate, and the need for mechanical ventilation or an intensive care unit. Other variables, such as admissions at the weekend and social factors, have also been considered relevant.2 Similarly, hospital readmission after discharge of a COPD patient is affected by many factors. The commonest risk factors for all-cause readmissions within 30 and 90 days are comorbidities, previous exacerbations, hospitalizations, and increased length of stay during the initial admission.3 Gender differences also play a role in the hospital readmission rate.4 Understanding these influences, we can suggest strategies targeting culprit factors so that hospital stays, and readmission rates can be minimized. Thus, the economic burden on society and the psychological effect on the patient can be avoided. Our study aimed to identify the differential effects of patient-related factors and treatment factors on the length of hospital stay and hospital readmission rate for exacerbation of COPD-related admissions.\n\n\nMethods\n\nThe Institutional Review Committee (IRC), Civil Service Hospital of Nepal provided ethical clearance on 14th August 2022 with reference no 18/2022 after submitting the proposal letter beforehand.\n\nThis hospital-based retrospective cross-sectional study was conducted among patients with acute exacerbation of COPD admitted at Civil Service Hospital, Kathmandu, which is an autonomous government health institution under the Ministry of General Administration. It is one of the tertiary care referral centers in the country. It is 132 bedded hospital with many specialist services. The hospital serves the population of Kathmandu valley including many referral cases from outside the valley. It belongs to Bagmati Pradesh which has the highest burden of COPD cases-annual health report Nepal 2077/78.5 The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were strictly followed during the study.6\n\nThe study participants included COPD patients admitted related to exacerbation from August 2021 to March 2022. The prevalence of chronic obstructive pulmonary disease was reported to be 11.7% in 2019.7 A total of 151 samples were calculated considering an infinite population proportion of COPD patient prevalence in Nepal (11.7%); p=0.11; q=0.89; alpha 5% level of significance; with the allowable error of (E)=5.\n\nThe detailed elaboration is as follows:\n\nWhere,\n\nn = required minimum sample size\n\nz = 1.96 at alpha 5% level of significance\n\np = prevalence = 0.11; q (compliment of prevalence) = 0.89\n\nE = allowable error, 5%\n\nOur study began when our study protocol was approved by the Institutional Review Committee (IRC), Civil Service Hospital of Nepal. Hospital records were used to select cases via convenience sampling where researchers collected samples randomly and on a convenient basis. All patients admitted for acute exacerbation of COPD to Civil Service Hospital were included in the study. However, patients with a documented history of concomitant chronic respiratory diseases (e.g., asthma, cystic fibrosis, or interstitial lung disease), those with community-acquired pneumonia or heart failure, and those with incomplete and ambiguous data were excluded from the study. A prolonged hospital stay is defined as a patient admitted for more than 7 days due to COPD-related exacerbation. The duration was calculated by subtracting the date of discharge from the date of admission. For this study, comorbid conditions were defined as patients having ischemic heart disease, congestive heart disease, diabetes, chronic kidney disease, uncontrolled HTN, hypothyroidism, and neoplasm. Before data collection a proper orientation with all coauthors was performed. Data regarding participants’ name, address, age at the time of admission, sex (self-reported); hospital readmission within the first 30 days; duration of hospital stay (fewer than 7 days or prolonged); comorbidities if any; smoking status (nonsmoker/ex-smoker/current smoker); the patient’s dyspnea according to the modified MRC dyspnea grade (mMRC); the requirement of mechanical ventilation in complicated cases; any episodes of previous COPD exacerbation-related admissions; whether the patient was on regular domiciliary oxygen therapy or not and the requirement of the diuretic use in the hospital were carefully recorded in a semi-structured questionnaire. The co guide monitored every aspects of study during data collection and analysis process.\n\nThe data were entered into Microsoft Excel 365 and then analyzed using Statistical Packages for Social Sciences (SPSS), IBM SPSS® v22. Descriptive statistics such as frequency, percentage, mean, and standard deviations were used to express the statistics as applicable. We described the categorical data as frequency and proportions and continuous data as mean ± standard deviation (SD). The binary logistic regression was used to identify the association of COPD exacerbation-related hospital stays and hospital readmission rate with the background characteristics of patients and treatment-related factors. For binary logistic regression analysis, odds ratios (OR) and 95% Confidence Interval (CI) were calculated, and significance was established.\n\n\nResults\n\nA total of 151 participants admitted with acute exacerbation of COPD, were enrolled for the study which met the inclusion criteria. Table 1 shows the age of participants ranged from 46 to 94 years with a mean age of 73.54±11.01. Out of 151 participants, 50 (33.10%) belonged to the 70–79 years age group followed by 48 (31.8%) in the 80–89 years age group; 34 (22.5%) in the 60–69 years age group. The least accounted for the age group 40–49 years, which was only 4 (2.6%). Our study revealed sex distribution of female preponderance (94, 62.3%) with a sex ratio of 1:1.64.\n\nThe data in Table 2 demonstrates, only a few of the admitted patients (34, 22.5%) had a history of hospital admission related to exacerbation during the last 30 days.\n\nThe average hospital stay was 8.3±3.1 days with a range of 1–16 (15 days) (7.78–8.82) at 95% CI). While a proportion of hospital stays of fewer than seven days was found in 49% (74) of patients with acute exacerbation of COPD, 51% (77) were admitted for more than 7 days before discharge Table 3.\n\nTable 4 reveals that the comorbidities were found in 110 (72.8%) participants. Most participants were previous smokers (97 (64.2%)), and 41 (27.2%) were current smokers. However, 13 (8.6%) patients had no history of smoking. During the time of admission, 81 patients had grade III category on mMRC dyspnea scale while the remaining had grade IV (46.4%,70). The hospital record section revealed that 40 (26.5%) people altogether underwent mechanical ventilation with intubation during treatment. Previous exacerbation and admission were found in 114 (75.5%) patients. Similarly, only a few patients (40, 26.5%) with COPD exacerbation were on long-term domiciliary oxygen therapy. The physician required inpatient administration of diuretics among 71 (47.0%) patients.\n\na Comorbidities include ischemic heart disease, Congestive heart disease, diabetes, chronic kidney disease, uncontrolled HTN, Hypothyroidism, neoplasm.\n\nAccording to Table 5 the clinical factors associated with prolonged hospital stays (>7 days) during acute exacerbation of COPD patients, were analyzed using the binary logistic regression model. Comorbidities were found significantly associated (more than four times) with prolonged hospital stays in COPD (OR 4.4, 95% CI: 1.32–15.09). The smoking status also has a great impact on prolonged hospital stays. Current smoking was associated 41-times more with prolonged hospital stay (OR 41.59, 95% CI: 7.13–242.63).\n\nAs per Table 6, the age group 80–89 years, 70–79 years, and 60–69 years were found to have a most of the admission rate of 12 out of 34 (35.3%), nine out of 34 (26.4%), eight out of 34 (23.5%), respectively, within the last month of admission. Similarly, female participants (n=23); hospital stay more than seven days (n=25), the presence of comorbidities (n=25), current smoker (n=15)/ex-smoker (n=16); MMRC grade IV (n=22), no requirement of mechanical ventilation (n=21), participant without long term oxygen therapy (n=18) and use of diuretics (n=18) represented the maximal proportion of patients. However, mechanical ventilation (OR 48.77, 95% CI: 9.08–261.86) and long-term oxygen therapy (OR 5.37, 95% CI: 1.75–16.49) was concluded to be associated significantly with high hospital admission.\n\n\nDiscussion\n\nCOPD is common in chronic smokers. Our study showed the average age of participants admitted with COPD exacerbation was 73.54 years with the predominant 70 to 79 years age group. A retrospective study showed the mean age at COPD diagnosis was 68.1 years in the year 2000 while it was 66.7 years in 2009.8 Another retrospective study conducted in Sweden demonstrated the median age at COPD diagnosis being 74 years (range=34–95).9 Moreover, this study showed female patients had a high percentage of COPD exacerbation whereas a similar study done in Sweden found similar findings. The study concluded, COPD was more prevalent among women (53.8%) and women with COPD experienced more exacerbations with respect to men (6.66 versus 4.66).10 The average hospital stay duration during COPD exacerbation was 8.3±3.1 days. However, the average duration was high in a retrospective study performed in the Macao population (12.28±9.23) days.11\n\nFurthermore, the duration of hospital stay was almost equally distributed among the less than 7 days and more than seven days categories in our study. The current results are very similar to a study conducted (84, 51% prolonged stay >7 days) in Sismanogleio General Hospital, Greece.12\n\nThe study revealed that the age group 80–89 years represented the highest proportion of patients with prolonged hospital stays. But the former study showed the highest population of patients with prolonged stay belonged to age 72.3–79.0 years.12 Female patients with COPD were found to have stayed hospital prolonged (61%) before discharge. The conclusions drawn were the same in another study led by Hatice et al. who concluded that female patients are more prone to have severe exacerbations, a higher number of hospitalizations, and prolonged lengths of stay for hospitalization.13 Another factor found significantly (four times) associated with prolonged hospital stay was comorbidities. A hospital-based study in the USA confirmed that having at least one comorbidity was associated with a 13% greater length of stay (IRR=1.13, 95% CI 1.11–1.15).14 Study findings are further supported by evidence from another cross-sectional study done in tertiary care centers in 2013. It explains a significant association between mean hospitalizations and the presence of comorbidities (p<0.05).15 Our retrospective study demonstrated a significant association between COPD exacerbation-related prolonged hospital stay and current smoking habit (49%) as compared to nonsmokers and ex-smokers. On the other hand, a cohort study in the USA concluded that in comparison to current smokers, ex-smokers had a significantly reduced risk of COPD exacerbation after adjusting for age, comorbidities, markers of COPD severity, and socio-economic status.16 A Nepali cross-sectional retrospective study in a teaching hospital showed a number of comorbidities (p=0.01), dyspnea grade at presentation (p<0.001), eosinophil percentage (p=0.017), use of inhalational medications (p=0.007) and the use of mechanical ventilation (p<0.001) had a significant association with length of hospital stay.17 Furthermore, the previous exacerbations have a high propensity (80%) to cause longer hospital stays. But another study demonstrated patients with ≥1 previous acute exacerbation of COPD requiring hospitalization, the prolonged hospital stay was seen in 38% of patients as compared to 28% of participants who had a normal stay (p=0.029).18 The proportion in our study accounts for twice higher.\n\nThe proportion of patients who had readmission within 30 days constituted 22.5% in this current study which is higher than a retrospective study done in Beijing that revealed the proportion as 15.8%19 but very similar to a study done in Korea that showed the readmission percentage was 26.4%.20 Our observational study found the age group 80–89 years had the highest proportion of readmission rate (35%). The results are supported by a systematic review and meta-analysis that describes older patients with COPD typically had a greater likelihood of being readmitted.21 The likely reason may be the effect of ageing on residual lung function. This study demonstrates the higher readmission rate among females. On the contrary, the male participants were found of the highest proportion of COPD readmission.22 Similarly, the presence of one or more comorbidities, previous prolonged hospital stays, and long-term oxygen therapy stood as predominant findings for higher readmission in our study. The findings are similar to a prospective study that elaborates the commonest risk factors for all-cause readmissions within 30 and 90 days were comorbidities, previous exacerbations, hospitalizations, and increased length of stay during the initial admission.3 Another study done in South Korea showed that higher re-admission rates were associated with male sex, admission to district hospitals, medical aid recipients, and a longer hospital stay which further supports the evidence.22 Another Chinese study found Education level, smoking status, coronary heart disease, hospitalization times of acute exacerbation of COPD in the past one-year, long-term home oxygen therapy, regular medication, nutritional status, and seasonal factors were the influencing factors for readmission.23 Previous use of mechanical ventilation was associated significantly with a higher rate of readmission.\n\nThe sample was taken from the study population admitted at Civil Service Hospital. Therefore, its findings cannot be generalized to other hospitals/places. As a result, a population-based investigation is required to uncover the true effect of clinical factors on hospital stay during exacerbation of COPD.\n\n\nConclusion\n\nAlthough there is a multitude of factors including many confounding factors affecting the duration of hospital stays, our study was only able to correlate with confidence with comorbidities status, current smoking habits, higher grade of mMRC dyspnea scale, mechanical ventilation, and long-term oxygen therapy. The physician may consider these facts to minimize the risk factors to decrease the duration of hospital stay and hence decrement in hospital costs. Understanding these influences will help optimize care for COPD patients needing hospital admissions.",
"appendix": "Data availability\n\nFigshare: Impact of Clinical Factors on Hospital Stay and Hospital Readmission Rate After Acute Exacerbation Of COPD: A Retrospective Cross-Sectional Study, https://doi.org/10.6084/m9.figshare.21304992. 24\n\nThis project contains the following underlying data:\n\n• Data COPD SPSS (raw data for the 151 individuals included in final analysis)\n\nFigshare: Questionnaire COPD, https://doi.org/10.6084/m9.figshare.21304599. 25\n\nThe project contains the following extended data:\n\n• Questionnaire COPD.pdf (tool used for data collection)\n\nFigshare: STROBE checklist for ‘Impact of Clinical Factors on Hospital Stay and Hospital Readmission Rate After Acute Exacerbation Of COPD: A Retrospective Cross-Sectional Study, https://doi.org/10.6084/m9.figshare.21304953. 6\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 would like to thank the hospital record section at the Civil Service Hospital for their coordination and support.\n\n\nReferences\n\nGlobal Initiative for Chronic Obstructive Lung Disease Global Initiative for Chronic Obstructive Lung Disease POCKET GUIDE TO COPD DIAGNOSIS, MANAGEMENT, AND PREVENTION A Guide for Health Care Professionals.2020.Reference Source\n\nCrisafulli E, Ielpo A, Barbeta E, et al.: Clinical variables predicting the risk of a hospital stay for longer than 7 days in patients with severe acute exacerbations of chronic obstructive pulmonary disease: A prospective study. Respir. Res. 2018 Dec 27; 19(1): 261. PubMed Abstract | Publisher Full Text\n\nAlqahtani JS, Aldabayan YS, Aldhahir AM, et al.: Predictors of 30-and 90-Day COPD Exacerbation Readmission: A Prospective Cohort Study. Int. J. Chron. Obstruct. Pulmon. Dis. 2021; 16: 2769–2781. PubMed Abstract | Publisher Full Text\n\nOrozco-Beltrán D, Arriero-Marin JM, Carratalá-Munuera C, et al.: Trends in hospital admissions for chronic obstructive pulmonary disease in men and women in Spain, 1998 to 2018. J. Clin. Med. 2021 Apr 1; 10(7). PubMed Abstract | Publisher Full Text\n\nAnnual Report.\n\nSTROBE-checklist-v4-cross-sectional.pdf.[cited 2022 Oct 10]. Publisher Full Text\n\nDhimal M, Karki KB, Sharma SK, et al.: Prevalence of Selected Chronic Non-Communicable Diseases in Nepal. J. Nepal Health Res. Counc. 2019 Nov 14 [cited 2022 Jul 15]; 17(3): 394–401. Publisher Full Text Reference Source\n\nJames GD, Donaldson GC, Wedzicha JA, et al.: Trends in management and outcomes of COPD patients in primary care, 2000–2009: a retrospective cohort study. NPJ Prim. Care Respir. Med. 2014 24:1. 2014 Jul 3 [cited 2022 Oct 7]; 24(1): 1–7.Reference Source\n\nSundblad BM, Jansson SA, Nyström L, et al.: Chronic Obstructive Pulmonary Disease (COPD) During the Two Last Years of Life – A Retrospective Study of Decedents. PLoS One. 2013 Dec 19 [cited 2022 Oct 7]; 8(12): e84110. PubMed Abstract | Publisher Full Text\n\nLisspers K, Larsson K, Janson C, et al.: Gender differences among Swedish COPD patients: results from the ARCTIC, a real-world retrospective cohort study. NPJ Prim Care. Respir. Med. 2019 Dec 1; 29(1).\n\nLi M, Cheng K, Ku K, et al.: Factors Influencing the Length of Hospital Stay Among Patients with Chronic Obstructive Pulmonary Disease (COPD) in Macao Population: A Retrospective Study of Inpatient Health Record. Int. J. Chron. Obstruct. Pulmon. Dis. 2021 Jun 9 [cited 2022 Oct 7]; 16: 1677–1685. PubMed Abstract | Publisher Full Text Reference Source\n\nDiamantea F, Kostikas K, Bartziokas K, et al.: Prediction of Hospitalization Stay in COPD Exacerbations: The AECOPD-F Score. Respir. Care. 2014 Nov 1 [cited 2022 Jul 14]; 59(11): 1679–1686. PubMed Abstract | Publisher Full Text Reference Source\n\nKilic H, Kokturk N, Cakır M: International Journal of COPD Dovepress Do females behave differently in COPD exacerbation? Int. J. COPD. 2015; 10: 823–830. PubMed Abstract | Publisher Full Text\n\nInabnit LS, Blanchette C, Ruban C: Comorbidities and length of stay in chronic obstructive pulmonary disease patients.2018 Jul 4 [cited 2022 Oct 7]; 15(4): 355–360. Publisher Full Text\n\nSridhara VSHK, Acharya V: Comorbidities of Chronic Obstructive Pulmonary Disease and Their Affect on Hospitalization of Patients in a Tertiary Care Hospital.2021 Jan 2 [cited 2022 Oct 7]; 11(1): 120–123. Publisher Full Text\n\nAu DH, Bryson CL, Chien JW, et al.: The Effects of Smoking Cessation on the Risk of Chronic Obstructive Pulmonary Disease Exacerbations. J. Gen. Intern. Med. 2009; 24(4): 457–463. PubMed Abstract | Publisher Full Text\n\nPokharel P, Lamichhane P, Pant P, et al.: Factors affecting length of hospital stay in chronic obstructive pulmonary disease patients in a tertiary hospital of Nepal: A retrospective cross-sectional study. Ann. Med. Surg. 2022 Aug 1 [cited 2022 Oct 8]; 80: 104246. PubMed Abstract | Publisher Full Text\n\nCrisafulli E, Ielpo A, Barbeta E, et al.: Clinical variables predicting the risk of a hospital stay for longer than 7 days in patients with severe acute exacerbations of chronic obstructive pulmonary disease: a prospective study. Respir. Res. 2018 Dec 27 [cited 2022 Oct 8]; 19(1): 261. PubMed Abstract | Publisher Full Text\n\nLi J, Liang L, Cao S, et al.: Secular trend and risk factors of 30-day COPD-related readmission in Beijing, China. Sci. Rep. 12: 16589. 123AD. PubMed Abstract | Publisher Full Text\n\nJo YS, Rhee CK, Kim KJ, et al.: Risk factors for early readmission after acute exacerbation of chronic obstructive pulmonary disease. Ther. Adv. Respir. Dis. 2020 Oct 18 [cited 2022 Oct 10]; 14: 175346662096168. PubMed Abstract | Publisher Full Text\n\nAlqahtani JS, Njoku CM, Bereznicki B, et al.: Risk factors for all-cause hospital readmission following exacerbation of COPD: A systematic review and meta-analysis. Eur. Respir. Rev. 2020; 29: 190116–190166. Publisher Full Text\n\nWan Kim T, Sil Choi E, Jin Kim W, et al.: The Association with COPD Readmission Rate and Access to Medical Institutions in Elderly Patients. COPD. 2021; 16: 1599–1606. PubMed Abstract | Publisher Full Text\n\nZhang R, Lu H, Chang Y, et al.: Prediction of 30-day risk of acute exacerbation of readmission in elderly patients with COPD based on support vector machine model. BMC Pulm. Med. 2022 Dec 1 [cited 2022 Oct 10]; 22(1): 210–292. PubMed Abstract | Publisher Full Text\n\nData COPD SPSS.sav:[cited 2022 Oct 10]. Publisher Full Text\n\nQuestionnare COPD.pdf:[cited 2022 Oct 10]. Publisher Full Text"
}
|
[
{
"id": "176223",
"date": "30 Jun 2023",
"name": "Dhan Bahadur Shrestha",
"expertise": [
"Reviewer Expertise NCDs",
"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\nI had an interesting read of the manuscript by Chaurasiya et al. Research in the LMIC part of world is scarce and I applaud to the efforts put forth by authors to understand the readmission of COPD, one of the common chronic NCDs in Nepal.\nI have some comments to improve the quality of work.\nAuthors can review and proofread to correct some language-related errors to make it better\n\nFor methods and analytical part: Authors are encouraged to review and follow the recommendations in the \"Guidelines for reporting statistics for clinical research in urology\" (Assel et al., 20191) for guidance on the proper analysis, reporting, and interpretation of clinical research. Use means and standard deviations (SDs) for normally distributed data, and medians and ranges or interquartile ranges (IQRs) for data that are not normally distributed.\n\nThank you for the opportunity to review this work!\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?\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/12-64
|
https://f1000research.com/articles/12-62/v1
|
16 Jan 23
|
{
"type": "Research Article",
"title": "Second-line drug resistance markers as proxy indicators of time to sputum culture conversion among second-line drug resistant tuberculosis patients tested in Uganda: A cross-sectional study",
"authors": [
"Dennis Mujuni",
"Willy Ssengooba",
"Ivan Ibanda",
"Joel Solomon Kabugo",
"Dianah Linda Kasemire",
"Elizabeth Nampewo",
"Andrew Nsawotebba",
"Jody E Phelan",
"Didas Tugumisirize",
"Beatrice Orena",
"Henry Byabajungu",
"Nathan Ntenkaire",
"Diana Nadunga",
"Julius Tumwine",
"Kenneth Musisi",
"Moses Joloba",
"Seungmo Kim",
"Ikwap Kokas",
"William Olaho Mukani",
"Joseph Kungu",
"Mathias Afayoa",
"Willy Ssengooba",
"Ivan Ibanda",
"Joel Solomon Kabugo",
"Dianah Linda Kasemire",
"Elizabeth Nampewo",
"Andrew Nsawotebba",
"Jody E Phelan",
"Didas Tugumisirize",
"Beatrice Orena",
"Henry Byabajungu",
"Nathan Ntenkaire",
"Diana Nadunga",
"Julius Tumwine",
"Kenneth Musisi",
"Moses Joloba",
"Seungmo Kim",
"Ikwap Kokas",
"William Olaho Mukani",
"Joseph Kungu",
"Mathias Afayoa"
],
"abstract": "Background Increased tuberculosis disease burden arises as a result of low treatment success rates stemming from the emergence of second-line drug resistance. We aimed at determining the usefulness of second-line drug (SLD) resistance markers as proxy indicators of time to sputum culture conversion; a renowned predictor of Tuberculosis treatment outcome, among SLD-resistant tuberculosis (TB) patients tested at the Uganda National TB Reference Laboratory (NTRL). Methods A cross-sectional study was conducted on 72 bacteriologically confirmed SLD resistant TB patients with datasets including culture conversion time and second line probe assay mutation profiles between 01/06/2017 and 31/12/2019. The data were then imported into STATA v15 for descriptive statistical analysis, Univariate cox proportional hazard model analysis and Kaplan-Meier survival curves at a 5% level of significance; p-value ≤0.05. Results Results indicate the median time was achieved at 3 (0–12) months across the studied patients. The rrs G1484T mutation associated with conferring drug resistance to injectable agents was observed to have the shortest median conversion time of 1.5 months, longest by the gryB E540D at 5 months. A single mutation in the gryA gene locus showed higher converted proportions 70.8% (58.9–81.0) than those that had two 8.3% (3.1–17.3) or three 2.7% (0.3–10.0) mutations. Conclusions The studied second-line drug resistance markers had no statistically significant association with the time to sputum culture conversion, although increased drug resistance levels reduced the converted proportions and stressed the need to utilize molecular diagnostics data and other crucial variables to better comprehend proxy indicators of SLD resistant tuberculosis management.",
"keywords": [
"Drug-resistant tuberculosis",
"Line Probe Assay",
"Mycobacterium tuberculosis",
"Sputum culture conversion",
"Second-line Drug Resistance"
],
"content": "Introduction\n\nDrug-resistant tuberculosis continues to present a global public health challenge, with 78% of the new cases of rifampicin-resistant TB estimated to have multi-drug resistance.1 Increasing drug resistance has previously been associated with poor treatment outcomes in a logical stepwise manner.2 The latest treatment outcome data show success rates that persistently leave a lot to be desired1,3–5 with national treatment success rates consistently in the range of 50–75%.6 Rigouts et al. (2016) noted that increased drug resistance is associated with decreased patient survival and ‘high-level’ gyrA mutations in particular significantly predict poor treatment outcomes, with a 2.6 hazard ratio.7 Patient mortality has also been linked to certain gyrA and rrs resistance mutations known to confer high-level resistance to second-line anti-TB drugs.8\n\nAchieving sustained bacteriological conversion of a patient’s sputum status from positive to negative is a renown predictor of treatment outcome, and is widely used to assess response to treatment not only for drug-susceptible but also drug-resistant TB.5 Culture is known to be a more sensitive test for bacteriological confirmation of TB than direct microscopy of sputum and other biological specimens. In addition to this, it facilitates phenotypic drug susceptibility testing (DST) with sputum culture monitoring.9 Time to sputum culture conversion (tSCC) is defined as the number of days from the beginning of tuberculosis treatment to the first of two consecutive negative sputum culture results that were at least 30 days apart.10\n\nStrong evidence from various TB treatment prognosis studies has indicated that failure of smear and/or culture conversion in the second month of TB treatment is not only a predictor of treatment failure but also an indicator of patient infectiousness, given culture viability of the organisms.11,12 Culture conversion has been widely investigated, with reported inconsistent findings.13,14 Although less intensive efforts have focused on investigating the variables and risk factors associated with time to sputum culture conversion among multi-drug resistant tuberculosis patients in Sub-Saharan Africa,15 a median time of 61.2 days has been reported in the East African region and nutritional support has been cited as a possible route for improving TB treatment outcomes among multi-drug resistant tuberculosis (MDR-TB) patients in Eastern Africa13 and India.16 A study conducted on 100 participants in Uganda established that 45% of them had converted by the second month, with combined Löwenstein-Jensen and Mycobacteria growth indicator tube (MGIT) culture methods throughout the 6-months for treatment monitoring.17 The authors attributed delayed culture conversion among their counterparts to genetic polymorphisms and method of TB culture being solid or liquid.17\n\nA study by Kim and other investigators showed that the pattern of resistance to anti-TB drugs affects culture conversion rates in the early phase of treatment, and ultimately, the time to culture conversion. The investigators deduced that the effect of the drug resistance pattern on conversion of sputum culture is most evident at eight weeks, and less evident at four and 12 weeks of treatment.18 A related study conducted in 2016 by Zheng et al. also further indicated that the presence of a pncA gene mutation, which confers drug resistance to pyrazinamide,19–21 remained and significantly decreased both the rate of culture conversion at eight weeks and treatment success. Additional drug resistance to fluoroquinolones was also found to significantly reduce the likelihood of treatment success among MDR-TB patients in China.22 Recent findings in China show that genetic drivers of drug resistance, in combination with phenotypic drug-resistant tests, could be helpful indicators for predicting MDR-TB treatment outcome.23\n\nThe National TB and Leprosy Program in Uganda has taken steps through the National TB Reference Laboratory to ensure sophisticated documentation of patient sputum cultures following phenotypic and/or genotypic drug susceptibility testing.24 A study in Uganda by Atwine et al. (2017), established that the tSCC is influenced by the culture method used for monitoring mycobacterial response to anti-TB treatment. The investigators further deliberated that more clarification is needed on the role of genetic polymorphisms in the time to sputum culture conversion.17\n\nThe Uganda National TB Reference Laboratory (NTRL) employs similar methods (solid and liquid culture) for monitoring the treatment prognosis of MDR-TB patients whose samples are transported there for specialized testing.25 Despite proper electronic documentation of monthly culture status for TB treatment prognosis of these MDR-TB patients, there is no accountability for the frequently observed outliers of timely sputum culture conversion among those with SLD resistance, and intervention comes much later after undesirable events are encountered. Our study aimed at determining the usefulness of second-line drug resistance markers as proxy indicators of time to sputum culture conversion among selected MDR-TB patients at the Uganda National Tuberculosis Reference Laboratory.\n\n\nMethods\n\nThis was a cross-sectional study conducted on secondary data of SLD resistant tuberculosis patients bacteriologically confirmed between the months of 01/06/2017 and 31/12/2019. The study was done at the Uganda National Tuberculosis Reference Laboratory, Butabika, Kampala, Uganda.\n\nA total number of 72 SLD resistant tuberculosis samples bacteriologically confirmed and interpreted with second-line line probe assay (LPA) mutation profiles between the months of 01/06/2017 and 31/12/2019 were enrolled in the study. The SLD resistant samples selected were previously detected using second-line LPA and cross-confirmed using Mycobacteria growth indicator tube (MGIT) second-line DST kit. Sample entries with complete SLD mutation profiles and culture data were included in the study. All samples with missing data were excluded from the study.\n\nThis study was composed of dependent, and independent variables. The independent variables included the TB gene mutations, clinical and demographic factors namely, age, gender, patient category, nationality, patient history, second-line drug resistance status, time to sputum culture conversion. The dependent variables included fluoroquinolone (FQ) resistance or injectable agent resistance status [high-level resistance, low-level resistance, mutation characterization, number of mutations per strain (single mutations, two mutations, three mutations)].\n\nThese study variables were measured using descriptive, univariate cox proportional hazard model analyses with the use of the Kaplan-Meier survival curves.as a means of checking whether the variables are related; with the level of significance set at 5%, where a p-value of ≤0.05 was considered statistically significant. Hazard ratios were computed to measure the relationship between the dependent variables found to have strong or weak correlation with the independent variables (time to sputum culture conversion), further described in the statistical analysis section of this paper.\n\nExcept for enrolling SLD resistant participants, all procedures were performed according to standard procedures as described from the manufacturer26,27 with further details as follows; all samples were previously transported to NTRL using the Uganda National TB specimen transport system while maintaining a cold chain. Prior to sample processing, samples were checked upon receipt to ensure they met the minimal sample acceptance criteria N-Acetyl-L-Cysteine-Sodium hydroxide (NALC-NaOH; final concentration of 1.5% NaOH) was used to prepare the samples. The samples were then inoculated onto MGIT and Lowenstein Jensen (LJ) medium. The first and SLDs' MGIT DSTs were carried out in accordance with standard operating procedure.28 The GenoLyse® kit was used to extract DNA for second line LPA DST in the biosafety level (BSL) 3; the Genotype MTBDRsl V2.0 assay (direct) on the processed sediments or (indirect) on the corresponding positive cultures of the eligible participants; and the results were interpreted in accordance with standard procedures26,27 (Figure 1).\n\nAll work involving the manipulation of live cultures, including those from eligible drug resistant samples that initially returned indeterminate results for second line drugs was performed in a fully functional BSL 3 laboratory to ensure safety to personnel and the environment. All waste generated during the laboratory related activities was managed according to the internal safety procedures at the laboratory setting.\n\nAll quality control procedures for the culture media preparation, sample processing, culture, SL-DST, LPA (GenoType® MTBDRsl) and data analysis were conducted according to the NTRL internal quality control/quality assurance procedures which are briefly described as follows; Acceptable internal quality control (IQC) findings were evaluated for the reviewed samples during each run. On the MGIT960 System, comparability testing was carried out using the second line DST kit (Becton Dickinson, Franklin Lakes, New Jersey). LPA testing was also carried out on well-characterized proficiency testing strains from the Supranational Reference Laboratory, Antwerp, Belgium, which were supplied periodically as part of the test's External Quality Assurance requirement. There were records of LOT-to-LOT testing to determine performance for the test reagents and consumables used to test clinical samples. Following the initial evaluation carried out by other independent staff in accordance with the necessary (ISO 15189:2012) international standards,29 a qualified reviewer additionally examined the mutation interpretations after retrieving the data taken into consideration during the study period for medical and testing laboratories. The integrity of the LPA bands was sustained by affixing cello-tape to the strips and placing them against the worksheet, which was then preserved within a sheet protector. With the exception of 10 strips, all of the bands were thus visible to the naked eye.\n\nIn this study, the NTRL laboratory information systems (LIS) was used to extract data for the MDR-TB patients notified from the TB specimen referral system/network, after which the second line drug susceptibility and sputum culture data from baseline to fifth successive culture were exported in Microsoft Excel file 2016 format. Samples were previously received along with the patient’s forms with demographic information like age, sex, referring diagnostic unit, history of treatment among others. Samples had their information accessioned into the NTRL-LIS upon reception at the NTRL, their request forms were scanned and saved on access-controlled backup folders. Hard copies were also kept in box files. Samples were then processed for mycobacterial culture on Löwenstein-Jensen (LJ) media and drug susceptibility testing. Cultures were previously read daily for the first week and biweekly thereafter for up to two months and any growth was confirmed by its acid fastness. M. tuberculosis complex species identification was done based on colony characteristics, positivity for MPT64 antigen as well as time-to-growth on LJ media. When no growth occurred after four weeks, the sample was said to have undergone conversion to negative and the time taken for the sample to convert was noted in the TB culture register. The time to sputum culture conversion was determined and computed based on the definition by the World Health Organization,30 where the first two consecutive negative sputum culture results were recorded, with a distinct 30-day separation between them. The second line drug resistance mutations data obtained from the GenoType® MTBDRsl screening was then added to the already collected metadata for the corresponding SLD resistant TB patients.\n\nThe TB patients whose drug resistance status was previously analyzed following the national diagnostic algorithm31 were re-evaluated using their respective second-line line probe assay DNA strips according to the standard procedures from the manufacturer.27 This was followed by the addition of resistance marker data which were manually curated respectively in a protected Microsoft Excel 2016 sheet [Research Resource Identifiers (RRIDs) RRID:SCR 016137]. This sheet contained the patient datasets with corresponding monthly culture conversion time prior to cleaning to standardize mutation curations and subsequently import these results into STATA v15 (RRID:SCR_012763) for analysis. The analysis included descriptive, Univariate cox proportional hazard model analyses with the use of the Kaplan-Meier survival curves. The level of significance was set at 5% and therefore a p-value ≤0.05 was considered statistically significant. The data were presented in the form of summary statistic tables and figures.\n\nThe Kaplan-Meier analysis was used for computing the median survival estimates over time in spite of all the non-uniformity in days of sputum sample referrals of the study participants during the course of routine monthly sputum culture. The estimates of the median time to sputum culture conversion across different SLD resistance markers were computed using Kaplan Meier survival curves. The Kaplan Meier survival curves were assessed using Univariate cox proportional hazard model analyses and STATA v15 to determine and compare the distribution of time to sputum culture conversion across the studied second-line drug resistance markers over the whole follow up period per patient. For each time interval, survival probability was calculated as the number of subjects surviving divided by the number of subjects at risk. This yielded the cumulative proportions indicated in the Kaplan-Meier survival estimate curves for the enrolled patients. The hazard ratios were then computed to measure the relationship between the drug resistance markers and time to sputum culture conversion.\n\n\nResults\n\nOverall, a total of 20,508 sample entries of new and previously treated patients were screened for eligibility, largely consisting of patients in the MDR-TB follow up 14,880/20,508 (72.5%) patient category (Figure 1). Of the eligible participants, a total of 709 had a final interpretable result of rifampicin and/or isoniazid. Among these was a total of 72 SLD resistant TB patients identified as SLD-resistant using the second-line LPA (GenoType® MTBDRsl), for whom we provide an account. Of these, 68/72 (94.4%) had resistance to any of the SLD whereas 4/72 had independent eis C14T low-level Kanamycin-resistance conferring mutations. Additionally, 42/72 (58.3%) and 12/72 (16.7%) were classified with resistance to fluoroquinolones only and injectable agents (IA) only, respectively. Among the patients with SLD resistance, 54/72 (75%) were either FQ/IA resistant, while 14/72 (19.4%) were resistant to both FQ and IA while 4/72 (5.6%) had low-level resistance to Kanamycin.\n\nThe samples and data used in this study were mainly from males (80.6%) and almost half of the sample cultures analyzed had been obtained from Ugandan patients (59.7%). The age was a median (interquartile ranges, IQR) of 29 (0–12) years and time to sputum culture conversion of 3 (0–12) months respectively. The proportion of sputum culture conversion was found to be 79.2 % (95% CI: 68.0–87.2) after 18 months of follow up. The distribution of the cultures was as follows that converted between the Ugandan 54.4% 95% CI [27.6, 29.4] and Non-Ugandan patient samples 45.6% 95% CI [27.5, 29.5]. Majority of the cultures that converted had been isolated from males 82.5% 95% CI [27.8, 29.2], see Table 1.\n\nTable 1 above shows the results from studying the variables; sex, age, nationality, patient category, and reason for request with the frequencies of sputum culture conversion. The median time to conversion for all the studied socio-demographic is three months. The p-values for all the studied socio-demographic factors are greater than the statistical significance of 0.05, which implies that none of the studied socio-demographic factors were found to have a statistically significant effect on the time to sputum culture conversion for this studied batch of patients.\n\nOut of the 57 sputum cultures that converted, 63%, 86%, 93% and 95% of the converted cultures had converted within 3, 6, 9 and 12 months, respectively (Figure 2).\n\nIn the above figure, the horizontal axis represents the month at which conversion takes place while the vertical represents the cumulative proportion of cultures converting. The median time was achieved at three months across the studied patients (seen when an extrapolation is done at 0.5 from the vertical axis).\n\nThe 102 resistance-conferring mutations found among the SLD resistant TB patients previously described by Mujuni et al. (2022) are depicted below in Figure 3.\n\nThe highest frequency (70) of fluoroquinolone drug resistance conferring mutations was noted in the gryA locus and least (01) in the gryB E540D locus. The highest frequency (25) of second-line drug resistance conferring mutations was noted in the gryA A90V locus and least (01) in the gryB locus. Predominant mutations (26) conferring high-level resistance to moxifloxacin were found to frequently occur in the gryA D94G locus, and closely trailed by gryA D94N/Y locus (12). The gryA D94N/Y, gryA D94G and gryA D94H mutations, all associated with high-level resistance to moxifloxacin were more frequently observed among MDR-TB treatment follow-up patients 18 (54.55 95% CI: 36.4—72.0) as compared to other patient categories. The highest frequency (20) of resistance to injectable agents was observed in both rrs gene A1401G mutation among the patients. Only one mutation was detected in the gryB E540D locus among them.\n\nEven though none of the mutations had a statistically significant hazard ratio, the presence of gryA A90V, gryA D94N/Y, and rrs G1484T mutations showed increased chances of the sputum cultures converting at hazard ratios of 1.37 (95% CI: 0.78–2.40), 1.17 (95% CI: 0.57–2.40), and 1.15 (95% CI: 0.36–3.71), respectively (Table 2).\n\nThe rrs G1484T mutation associated with conferring drug resistance to injectable agents was observed to have the shortest median conversion time of 1.5 months, closely trailed by the gryA A90V with 2.5 months. The gryA D94H among the mutations associated with high-level resistance to moxifloxacin was found to have a median conversion time of five months. The hazard ratios across all the evaluated predictors were either >1.0 or <1.0 indicating that survival was better in one of the groups (one with and one without the predictor of interest), much as the p-values do not show a statistical significance to confidently rely on to make such a call. The presence of one or more mutations in the gryA gene locus also did not have any statistical significance on the median conversion time, although a single mutation in this locus showed higher converted proportions (70.8%) than those that had two (8.3%) or three (2.7%) mutations. Even though none of the mutations had a statistically significant hazard ratio, the presence of rrs G1484T, gryA A90V, and gryA D94N/Y mutations showed increased chances of the sputum cultures converting at 1.5, 2.5 and 3 months respectively.\n\n\nDiscussion\n\nThe response to treatment among SLD resistant tuberculosis patients is known to vary in endemic and non-endemic countries. As we have recently demonstrated,32 routinely employed molecular TB diagnostics generate data, making it opportune to be networked for programmatic decision-making, with later reviews to address important research issues on areas of disease control.33 This study was undertaken to gain insight on the usefulness of second-line drug resistance markers conversion as a proxy measure of the likelihood for early or delayed sputum culture conversion among SLD resistant tuberculosis patients.\n\nA total of 57 (79.17%) of MDR-TB patients achieved un-reversed sputum conversion with median duration of conversion of three months, with the presence of rrs G1484T, gryA A90V, and gryA D94N/Y mutations increasing the chances of timely sputum culture conversion. The data indicate that after three months while on treatment, there was a slower rate of culture conversion, with some relapses, given the slow rate of cumulative proportions of cultures conversion dragging up to month 18 of treatment for the last isolate in this study. The observed three months median time to conversion is similar to that observed in a study conducted in Latvia34 despite the marginal difference from that (two months) reported by Brust et al., for one conducted in South Africa.35 This median and overall time to sputum culture conversion is shorter than that observed in a study conducted by Arax and Elizabeth which showed conversion time of 5.8 (0.5–17) months,36 and another study done by Qazi F et al., in Pakistan that showed a median time of conversion of seven months,37 respectively. The median time was however longer than the one observed in a study done by Raunak Parikh et al., which showed conversion at 1.5 months.38 The cited differences in conversion time could be due to the different treatment regimens used in the different countries and also the differences in living conditions of patients, which possibly caused them to react differently towards the administered treatment regimens.\n\nIn this study, the variables such as sex, age, nationality, patient category, reason for request with the frequencies of sputum culture conversion were all not found to have a statistically significant effect on the time to sputum culture conversion for this studied batch of patients. Studies done by Arax and Elizabeth also showed that age and previous treatment were not associated with conversion time much as male sex emerged as a significant risk factor.36 Other studies done in India however show that patients who had a past history of tuberculosis disease, had significantly delayed sputum culture conversion/non-conversion.38\n\nThe relatively high frequency of fluoroquinolone drug resistance conferring mutations noted in the gyrA locus in this study is in agreement with literature revealing that second-line drug resistance conferring mutations have mostly been found to arise in the gyrA gene locus.39–41 The highest frequency of mutations conferring drug resistance to injectable agents being observed in the rrs gene A1401G among our study population is also in agreement with literature pointing to this as the most common molecular mechanism of drug resistance to the injectable agents; kanamycin and amikacin.42 Another interesting finding is one in which only one mutation (E540D) was detected in the gyrB locus among these patients, as similarly noted in a study by Almeida and other researchers, where rare occurrence of mutations in this gene locus was observed despite performing MTB genome sequencing.43\n\nThe observed high proportion of mutations in the gyrA gene loci known to confer high level drug resistance to moxifloxacin, a pivotal second line anti-TB drug, underlines the need to actively study in-host emergence of drug resistance to second-line drugs. The presence of a single mutation in this gene locus showed higher converted proportions (70.8%) than those that had two (8.3%) or three (2.7%) mutations, most commonly indicative of increased levels of drug resistance. This is somewhat in agreement with previously published findings by Rigouts et al. (2016) that point to the association between increased drug resistance and decreased patient survival. In that study, it was deduced that ‘high-level’ gyrA mutations significantly predict poor treatment outcomes in particular, with a 2.6 hazard ratio.7 The presence of rrs G1484T, gyrA A90V, and gyrA D94N/Y mutations showed increased chances of the sputum cultures converting at 1.5, 2.5 and 3 months, respectively. Despite the respective statistical insignificance in this study, the observed culture conversion time of 2.5-5 months for the mutations occurring in the gyrA gene locus as a quinolone resistance determining region (QRDR) also stresses the need to embrace a patient centered approach for tuberculosis treatment and management. This is due to the fact that these specific mutations of public health concern were found among patients from the MDR-follow up patient category. This could be more of a non-adherence indicator during the course of treatment and less of disease transmissions, stressing the need for deeper methods for treatment monitoring.\n\nThe fact that patients in this study had a sputum culture conversion rate within the same range as patients in other studies and the East African region13 is encouraging. It could probably be as a result of the robust tuberculosis diagnostic system that allows for earlier identification of second line drug resistant patients, timely tuberculosis specimen referral, with strengthened directly observed therapy. This time to sputum culture conversion may further be improved by improving nutritional status of the TB patients under management,13 since a recent study revealed that under nutrition among MDR-TB patients was a factor affecting TB treatment success across the 16 MDR-TB treatment sites in Uganda44 and elsewhere.16\n\nThis study had a few limitations, for instance, this study could not ascertain if the peculiar delays to achieve culture conversion for some patients were due to reinfections or in-host pathogen evolution. Additionally, the sample size was predetermined, and the information on pyrazinamide, treatment plans, and HIV status was either inconsistently or never recorded in the laboratory database, making it difficult to ascertain their influence on the variations in sputum culture conversion times. As a matter of fact, smoking has been reported to have a negative effect on tSCC in studies conducted elsewhere.45,46 However, its effect and association on the tSCC among study participants in this study was not determined as the data on this variable was not available.\n\nIt is essential that the NTRL begin consistently capturing important variables in the LIS as critical predictors alongside drug resistance markers in TB prognostic event monitoring and analysis. These variables include treatment regimens provided, smoking, HIV and nutritional status among others. We suggest that a bigger sample size that includes more drug resistance markers be used in studying the usefulness of SLD resistance conferring mutations on response to TB treatment among this group of drug resistant tuberculosis patients. This can then facilitate in-silico modeling for better patient management, with a focus on actively translating this knowledge into real time solutions for patient care. Laboratories and disease control programs in resource-constrained areas may be able to use laboratory data to model M. tuberculosis drug resistance markers and other variables in real time to better comprehend their utility as proxy indicators in SLD resistant tuberculosis treatment and management.\n\nIn conclusion, we report a three-month median time to sputum conversion among the enrolled SLD resistant tuberculosis patients, which may be categorized as delayed, but marginally acceptable. The association between the studied second-line drug resistance markers and the time to sputum culture conversion was not statistically significant, although increased levels of drug resistance to second-line drugs were found to reduce the converted proportions.\n\nThis project was presented to the Uganda NTRL Research Committee for ethics approval, and the research committee waived the need since this study was based on secondary data of bacteriologically confirmed SLD resistant tuberculosis patients, thereby granting permission to proceed and conduct the study. The Uganda NTRL research committee, directed by the laboratory manager, granted authorization to access the data and conduct the study, after which the lead author signed a confidentiality agreement and filed it with the data manager in accordance with relevant norms and regulations. All the data collected for the study were fully anonymized and no patient names were used throughout the data collection and analysis phase.\n\nThe Uganda National Guidelines for Research involving humans as research participants - (July-2014.page 28) requires that sample collection follows acceptable standard procedures and that any person who collects identifiable human materials shall ensure that appropriate informed consent has been obtained from the sample sources, including consent for storage for possible uses in future.\n\nIn our case, the secondary data of bacteriologically confirmed SLD resistant TB patients’ data used in this operational research study were initially collected for routine care between 01/06/2017 and 31/12/2019 in efforts to detect and control the spread of tuberculosis. As a result, patient consent could not be obtained for isolates whose results had already been reported in accordance with the set Ministry of Health and World Health Organization reporting mechanisms and recommendations. Consent (informed consent) to provide a sample does not need to be obtained from the patient whose samples are going to be used in their care and management, according to the current authorized version of the NTRL Clinicians Handbook (Version 4.0, February-2019, Page 7 of 20) issued under the Uganda Ministry of Health.\n\nAdditionally, it further states that the patient who voluntarily moves to the laboratory to provide a sample has already consented. As a result, according to the aforementioned national regulations, the need for informed consent is deemed unnecessary according to national regulations and was no longer required.",
"appendix": "Data availability\n\nThe datasets used and/or analyzed during the current study are available from the https://doi.org/10.5281/zenodo.7495497. 47\n\nThe project contains the following underlying data https://doi.org/10.5281/zenodo.7495497 47 :\n\n- [Usefulness of SL DR Mutations and tSCC Dataset June 2017-December 2019.csv] (raw CSV data).\n\n- [README_SLD Proxy indicators of sputum culture conversion in Uganda.md] (README.md).\n\nFigshare: [Figure 1: Flow chart for sample processing and enrolment into the study]\n\nFigshare: [Figure 2: Kaplan-Meier survival estimate for culture conversion]\n\nFigshare: [Figure 3: Distribution of genetic mutations among second-line drug resistant tuberculosis patients]\n\nThis project contains the following extended data under https://doi.org/10.5281/zenodo.7495497 47 :\n\n- Supplementary Table 1.\n\n- Supplementary Table 2.\n\n- Supplementary Figure 1.\n\n- Supplementary Figure 2.\n\n- Supplementary Figure 3.\n\nSTROBE checklist for ‘Second-line drug resistance markers as proxy indicators of time to sputum culture conversion among second-line drug resistant tuberculosis patients tested in Uganda: A cross-sectional study’. https://doi.org/10.5281/zenodo.7495497. 47\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication) under https://doi.org/10.5061/dryad.0zpc86724. 48\n\n\nAcknowledgements\n\nThe laboratory manager and data manager at the Uganda National Tuberculosis Reference Laboratory are highly acknowledged for their general support for this piece of work. With their permission, the Laboratory staff who helped generate the data used in this study are hereby specifically acknowledged for their technical support of this effort. The financial support to run all the diagnostic activities that contributed to the generation of the data used in the study was part of the routine funding from the Regional Global Fund through the East, Central and Southern Africa (ECSA) Health Community Project to the Supra-National Reference Laboratory of Uganda to support Tuberculosis (TB) diagnostic implementation and quality management systems in the laboratories performing TB testing. The Africa Center of Excellence in Materials, Product Development and Nanotechnology (MAPRONANO ACE), backed by the World Bank project fund, provided DM with research scholarship funding to acquire some of the items used in the secondary analysis to complete this work. ECSA and MAPRONANO ACE had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nWS is a NURTURE fellow under NIH grant D43TW010132, a postdoctoral fellow under MUII+, Uganda Medical Informatics Centre (UMIC) Bioinformatics endeavour and under the European & Developing Countries Clinical Trials Partnership (EDCTP) grant TMA2018CDF-2351. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\n\nReferences\n\nWorld Health Organisation: Global TB Report 2019.[cited 3 Feb 2021].Reference Source\n\nCegielski JP, Kurbatova E, Walt MVD, et al.: Multidrug-Resistant Tuberculosis Treatment Outcomes in Relation to Treatment and Initial Versus Acquired Second-Line Drug Resistance. Clin. Infect. Dis. 2016; 62: civ910–civ430. 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Dis. 2022; ciac915. PubMed Abstract | Publisher Full Text\n\nAtwine D, Orikiriza P, Taremwa I, et al.: Predictors of delayed culture conversion among Ugandan patients. BMC Infect. Dis. 2017; 17: 298–299. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKim J, Kwak N, Youn H, et al.: International Journal of Infectious Diseases Effect of drug resistance on negative conversion of sputum culture in patients with pulmonary tuberculosis. Int. J. Infect. Dis. 2016; 42: 64–68. PubMed Abstract | Publisher Full Text\n\nNaluyange R, Mboowa G, Komakech K, et al.: High prevalence of phenotypic pyrazinamide resistance and its association with pncA gene mutations in Mycobacterium tuberculosis isolates from Uganda. PLoS One. 2020; 15: e0232543–e0232548. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSodja E, Koren S, Toplak N, et al.: Next-generation sequencing to characterize pyrazinamide resistance in Mycobacterium tuberculosis isolates from two Balkan countries. J. Glob. Antimicrob. Resist. 2021; 29: 507–512. S2213-7165(21)00254-X. PubMed Abstract | Publisher Full Text\n\nRahman A, Ferdous S, Ahmed S, et al.: Pyrazinamide Susceptibility and pncA Mutation Profiles of Mycobacterium tuberculosis among Multidrug-Resistant Tuberculosis Patients in Bangladesh. Antimicrob. Agents Chemother. 2017; 61: 1–12.\n\nZheng X, Ning Z, Drobniewski F, et al.: pncA mutations are associated with slower sputum conversion during standard treatment of multidrug-resistant tuberculosis. Int. J. Antimicrob. Agents. 2017; 49: 183–188. PubMed Abstract | Publisher Full Text\n\nChe Y, Yang T, Lin L, et al.: Comparative Utility of Genetic Determinants of Drug Resistance and Phenotypic Drug Susceptibility Profiling in Predicting Clinical Outcomes in Patients With Multidrug-Resistant Mycobacterium tuberculosis. Front. Public Health. 2021; 9: 9. Publisher Full Text\n\nJoloba M, Mwangi C, Alexander H, et al.: Strengthening the Tuberculosis Specimen Referral Network in Uganda: The Role of Public-Private Partnerships.2016; 213: 41–46. Publisher Full Text\n\nNTRL: National TB Reference Laboratory.2020 [cited 21 Sep 2022].Reference Source\n\nGenoLyse®|Manual isolation of bacterial DNA from patient samples:[cited 20 Nov 2021].Reference Source\n\nGlobal Laboratory Initiative: Global Laboratory Initiative Line probe assays for drug- resistant tuberculosis detection.2008. [cited 2 Nov 2021].Reference Source\n\nSiddiqi SH, Rüsch-Gerdes S: For BACTEC MGIT 960 TB system.Nov 2006 [cited 3 Nov 2021].Reference Source\n\nInternational Standards Organisation: ISO - ISO 15189:2012 - Medical laboratories — Requirements for quality and competence. 3rd Edition.[cited 3 Feb 2021].Reference Source\n\nWorld Health Organization: Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis (2014). World Health Organization;2014.Reference Source\n\nNational Tuberculosis and Leprosy Control Programme Tuberculosis Specimen Referral System Clinician Handbook RD 001 February 2019.2019.\n\nMujuni D, Kasemire DL, Ibanda I, et al.: Molecular characterisation of second-line drug resistance among drug resistant tuberculosis patients tested in Uganda: a two and a half-year’s review. BMC Infect. Dis. 2022; 22: 363. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTaaffe J, Croda J, Moultrie H, et al.: Advancing TB research using digitized programmatic data. Int. J. Tuberc. Lung Dis. 2021; 25: 890–895. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHoltz TH, Sternberg M, Kammerer S, et al.: Time to Sputum Culture Conversion in Multidrug-Resistant Tuberculosis: Predictors and Relationship to Treatment Outcome. Ann. Intern. Med. 2006; 144: 650–659. PubMed Abstract | Publisher Full Text\n\nBrust JCM, Lygizos M, Chaiyachati K, et al.: Culture conversion among HIV co-infected multidrug-resistant tuberculosis patients in Tugela ferry, South Africa. PLoS One. 2011; 6. Publisher Full Text\n\nHovhannesyan A, Breeze E: Time to sputum conversion in multidrug-resistant tuberculosis patients in Armenia: retrospective cohort study Tango Rapperswil. Glob. J. Med. Public Health. 2012; 2021.\n\nQazi F, Khan U, Khowaja S, et al.: Predictors of delayed culture conversion in patients treated for multidrug-resistant tuberculosis in Pakistan. Int. J. Tuberc. Lung Dis. 2011; 15: 1556–1560. PubMed Abstract | Publisher Full Text | Free Full Text\n\nParikh R, Nataraj G, Kanade S, et al.: Time to sputum conversion in smear positive pulmonary TB patients on category I DOTS and factors delaying it. J. Assoc. Physicians India. 2012; 60: 22–26. PubMed Abstract\n\nGeorghiou SB, Seifert M, Catanzaro D, et al.: Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape. Antimicrob. Agents Chemother. 2016; 60: 3994–4004. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKateete DP, Kamulegeya R, Kigozi E, et al.: Frequency and patterns of second-line resistance conferring mutations among MDR-TB isolates resistant to a second-line drug from eSwatini, Somalia and Uganda (2014 – 2016).2019; 1–9.\n\nZhao X, Xu C, Domagala J, et al.: DNA topoisomerase targets of the fluoroquinolones: A strategy for avoiding bacterial resistance. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13991–13996. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJugheli L, Bzekalava N, de Rijk P , et al.: High level of cross-resistance between kanamycin, amikacin, and capreomycin among Mycobacterium tuberculosis isolates from Georgia and a close relation with mutations in the rrs gene. Antimicrob. Agents Chemother. 2009; 53: 5064–5068. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlmeida Da Silva PEA, Palomino JC: Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs. J. Antimicrob. Chemother. 2011; 66: 1417–1430. PubMed Abstract | Publisher Full Text\n\nBaluku JB, Namiiro S, Nabwana M, et al.: Undernutrition and Treatment Success in Drug-Resistant Tuberculosis in Uganda. IDrugs. 2021; 14: 3673–3681. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCailleaux-Cezar M, Loredo C, Silva JRL e, et al.: Impact of smoking on sputum culture conversion and pulmonary tuberculosis treatment outcomes in Brazil: a retrospective cohort study. J. Bras. Pneumol. 2018; 44: 99–105. PubMed Abstract | Publisher Full Text | Free Full Text\n\nReimann M, Schaub D, Kalsdorf B, et al.: Cigarette smoking and culture conversion in patients with susceptible and M/XDR-TB. Int. J. Tuberc. Lung Dis. 2019; 23: 93–98. Publisher Full Text\n\nMujuni D, Ibanda I, Kabugo JS, et al.: SLD Proxy indicators of sputum culture conversion in Uganda.2022 [cited 30 Dec 2022]. Publisher Full Text\n\nMujuni D, Ibanda I, Kabugo JS, et al.: SLD Proxy indicators of sputum culture conversion in Uganda. Dryad. 2022; 15501 bytes. Publisher Full Text"
}
|
[
{
"id": "197227",
"date": "01 Sep 2023",
"name": "Hyungjin Eoh",
"expertise": [
"Reviewer Expertise Microbiology"
],
"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 entitled “SLD resistance markers as proxy indicators of time to sputum culture conversion among SLD resistant tuberculosis patients tested in Uganda: A cross-sectional study” collected 72 SLD samples and sought to identify the functionally meaningful SLD genetic mutations that can be associated with tSCC and treatment outcome. Overall, the study is interesting, but it failed to discover SLD genetic mutation markers that are statistically meaningful to link the tSSC and treatment outcome. Nevertheless, the approaches and clinical data used in this study have a potential interest.\nGene name 'gyr' was continually used wrong – gry à gyr.\n\nIntroduction: The last paragraph is too complicated to understand what the authors want to say. Please revise it.\n\nStudy population: the characteristics of 72 SDL samples (MGIT result, LPA assay, DST result, and so on) should be listed in the text or a table.\n\nStudy variables should be described in the text or a text.\n\nIn Figure 1 and table 1, the authors described the 72 final sample drug resistant profiles and socio-demographic factors without information about the drug resistant profile and demographic factors of each bacillus. Please provide the info of each sample. Also, the authors didn’t examine the role of socio-demographic factors in determining rSCC duration or treatment outcome.\n\nFig. 2: Provide the further info if one sample harbors multiple mutations and how these multiple mutations are functionally associated with delayed conversion time.\n\nAlthough mutations at gyrA or rrs gene are functionally related to rSCC and treatment outcome, the authors failed to see the statistically significant outcome. This should be discussed in the discussion section by using other gene examples or exemplifying some samples with multiple mutations.\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": "324769",
"date": "09 Nov 2024",
"name": "Bayode Romeo Adegbite",
"expertise": [
"Reviewer Expertise Infectious diseases and epidemiology with focus on public health microbiology",
"tuberculosis",
"sepsis and AMR"
],
"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\nDennis Mujuni et all reported data on the performance of drug resistance markers as proxy indicators of time to sputum culture conversion among second-line drug-resistant tuberculosis patients tested in Uganda This is a good research question\n\nMethod: The last paragraph in variable section can be moved to the statistical section The study design could not be cross-sectional as you followed up with the participant, please review this -Was this a retrospective analysis? -The data was collected in 2019, why is it published now? -The sample size is a big limitation -Some cofounder effects such as treatment adherence were not investigated, this is a big bias to take into consideration and it makes the data not strong. I would suggest to author design a good prospective study to investigate this interesting research question\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? 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 source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-62
|
https://f1000research.com/articles/12-60/v1
|
16 Jan 23
|
{
"type": "Research Article",
"title": "Application of Fuzzy Deep Neural Networks for Covid 19 diagnosis through chest Radiographs",
"authors": [
"Priyanka Yadlapalli",
"Bhavana D",
"Bhavana D"
],
"abstract": "Background: The increasing number of COVID-19 patients around the world and the limited number of detection kits pose a challenge in determining the presence of the disease. Imaging modalities such as X-rays are commonly used because they are readily available and cost-effective. Deep learning has proved to be an excellent tool because of the abundance of online medical images in various medical modalities, such as X-Ray, computerized tomography (CT) Scan, and magnetic resonance imaging (MRI). A large number of medical research projects have been proposed and launched since early 2020 due to the overwhelming use of deep learning techniques in medical imaging. Methods: We have used fuzzy logic and deep learning to determine if chest X-ray images belong to people who have pneumonia related to COVID-19 and people who have interstitial pneumonias that aren't related to COVID-19. Results: In comparison to the current literature, the proposed transfer learning approach is more successful. It is possible to classify covid, viral, and bacterial pneumonia or a healthy patient using ResNet 18 Architecture's four-class classifiers. The proposed method achieved a 97% classification accuracy, 96% precision, and 98% recall in the case of COVID-19 detection using chest X-ray images, which demonstrates the importance of deep learning in medical image diagnosis. Furthermore, the results demonstrate that the proposed technique has the maximum sensitivity rate, with 97.1% ratio. Finally, with a 97.47% F1-score rate, the proposed strategy yields the highest value when compared to the others. Conclusions: DeepLearning techniques and fuzzy features resulted in an improved classification ability, with an accuracy rate of up to 97.7% using ResNet 18, which is a better value when compared to the remaining techniques. Classification of COVID-19 scans and other pneumonia cases have been done successfully by demonstrating the potential for applying such deep learning techniques in the near future.",
"keywords": [
"Corona virus pandemic",
"Fuzzy logic",
"Deep learning",
"Residual Networks",
"Neural network"
],
"content": "Introduction\n\nCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since May 28 2020, across the globe many people have lost their lives due to COVID-19.1,2 The majority of patients who had been affected from COVID-19 have been diagnosed with flu like symptoms, and quite a small number of patients developed chronic infections like pneumonia and acute respiratory distress syndrome (ARDS).3 No treatment will be effective until patients have been properly screened for COVID-19. Reverse transcription polymerase chain reaction (RT PCR), is considered as the golden standard screening method for identifying SARS-CoV-2, having a success rate of around 30-60% only.4\n\nOver the last decade, medical image analysis has undergone a paradigm shift, owing largely to the phenomenal success of deep learning methods that achieve excellent performance on a variety of tasks. Medical image analysis has developed into a large and active field of research in recent decades as a result of its significant clinical impact and remaining challenges. Conventional radiography has several advantages over other imaging modalities, including a short examination time, high spatial resolution, and low image cost.5 In medicine, conventional radiography is one of the most ineffective imaging modalities, due to its wide range of applications for different body parts and diseases. Hence, chest X-rays through computer-aided diagnostic systems have been in great demand for the detection of COVID-19 pneumonia.6\n\nFuzzy logic is an effective technique for tackling uncertainty and imprecision. In addition to providing accurate data, uncertainty intervals allow for double control of the detection process, reducing false negatives and positives and improving COVID-19 patient detection.7 A fuzzy model based medical diagnosis system relies on expert knowledge, observation, and experience.8\n\nDue to the increase in the number of cases, COVID-19 viruses have evolved and infected humans, making them more widely spread. COVID-19 has been diagnosed using a variety of artificial intelligence (AI) technologies and radiographic image databases in recent years. COVID-19-related lung computerized tomography (CT) images are publicly available for deep learning research.\n\n\nLiterature survey\n\nTable 1 summarises the various methods developed for automated detection of infected cases. Chest X-ray images are trained using different deep learning techniques. These techniques have gained popularity in recent years9,16 due to their low computational time and high accuracy efficiency.\n\nTo summarise, deep learning is favored for the reasons listed below:\n\na) Effective use of unstructured data.\n\nb) Reduced computational time.\n\nc) Ability to deliver accurate results.\n\nDeep learning has many advantages. For the purposes of comparing the accuracy of their performance in detecting COVID-19 cases, the researchers used a variety of training models including Inception V3, ResNet 50, ResNetV2, MobileNet, VGG19, and others (Table 1).\n\nIeracitano et al.9 proposed a fuzzy enhanced deep learning approach for the detection of COVID-19 with an accuracy of 81%.\n\nUsing ResNetV2 architecture, Alqudah has achieved 98% accuracy.10 Using the VGG19 architecture, Apostolopoulos and Bessiana12 classified virus cases with pneumonia and normal cases with a 97.8% success rate. SqueezeNet Architecture was developed by Togacar et al13 classified COVID-19 with normal cases, resulting in an accuracy percentage of 99.27%. To classify COVID-19 as pneumonia, Ozturk et al.14 used Dark CovidNet and achieved an accuracy rate of 87.9%.14 By using the COVID-NET Training Model and classifying COVID-19 into the Normal and Pneumonia categories, Linda Wang et al.15 has achieved an accuracy of 93.3%.\n\nFrom the above mentioned methods, we can deduce that the highest accuracy that was obtained was around 96.84%. In order to increase the accuracy levels of the above areas, four different transfer learning techniques have been adopted for this study and their performances has been analysed. CNN-based transfer-learning method provides greater accuracy for detection and classification. Radiographic findings, on the other hand, have so far been ineffective in determining the underlying cause of pneumonia.17 Machine learning can be used to diagnose pneumonia by analyzing a radiograph which is shown in Figure 1, and it can also be used to distinguish viral and bacterial pneumonia more accurately [31]. The objective of the study is to evaluate the performance of various deep learning architectures and to classify and detect the chest radiographs for detection of Covid 19 along with other pneumonial diseases which is depicted in Figure 2.\n\nThe analysis in this study was done using chest radiograph images from two different sources.11,18 To compile an archive of COVID-19 images, Cohen JP used images which are freely available online.11 The images on this site are constantly being updated by researchers from all over the world. In the database, more than 350 X-ray images have been classified as COVID-19. By selecting 397 frontal chest X-ray images from Kaggle,18 we can avoid the problem of data imbalance as the data we are selecting is random. Table 2 shows the specifics of the data set.\n\nFigure 3 shows the data distribution has been graphically represented using four different classes. Chest X-rays of healthy people, patients with bacterial pneumonia, viral pneumonia, and patients with COVID-19 are depicted in Figure 4.\n\nThe significant contribution of the proposed research is:\n\n• Limited and imbalanced data sets are made available to the general public.\n\n• For this reason, we used multi-operation data augmentation to balance the COVID-19 and normal classes.\n\n• VGG-16, AlexNet, SqueezeNet and ResNet 18 are the four most effective pre-trained deep CNN models that have been thoroughly compared.\n\n• In the end, we have found the best model for designing a more efficient CNN-based solution for the early detection of COVID-19 infection.\n\nThe rest of the article is organised as follows. Literature Survey section contains various methods describing current research on COVID-19 virus detection methods using machine learning. It also describes the samples used to validate various CNN models. The ‘Methods in testing’ section discusses the proposed methodology for accurately detecting COVID-19 virus in chest X-ray frames. The ‘Results’ section is where various classification schemes are described and compared to the proposed method. The last section focuses on the conclusion and areas for future research.\n\n\nMethods in testing\n\nThe three stages of the proposed methodology are\n\na) Preprocessing of images.\n\nb) Augmentation of data.\n\nc) Training of a deep learning CNN.\n\nFigure 5 depicts the feature extraction and classification stages of convolution neural networks.\n\nAll the changes made to the raw data prior to feeding it to the machine learning or deep learning algorithm are referred to as preprocessing. The resized images are preprocessed in order to increase the efficiency and accuracy of the deep learning models by using ImageNet database.19 It is a freely accessible data set for computer vision which includes millions of images and thousands of image classes. Transfer learning refers to the training of the network on a new dataset based on an earlier trained network on an ImageNet index.\n\nThe augmented data helps deep learning algorithms to improve their classification accuracy. The results of deep learning techniques can be improved by enhancing existing data rather than collecting new data, because the amount of input data can be increased by improving images of existing data. It also helps to avoid the over fitting problem when training a machine model using Google Colab.\n\nRotation, translation, scaling, and horizontal flipping of the training set are used to address the issue of data scarcity. There are several techniques that can be applied to each image in training.\n\nThe image can be rotated in either a clockwise or counterclockwise direction using Google Colab, at an angle ranging from 0 to 15 degrees. The image's proportions are lost when it is rotated. The final image size may also be affected by finer angle rotations.\n\nImage scaling\n\nImages can be scaled in two ways: outwards and inwards. Image size increases when the image is scaled outward, while image size decreases when the image is scaled inward. Samples between 90 and 110% of the image's frame size can be taken at random.\n\nTranslation\n\nImage translation by -10% to 10% on the horizontal (X) and vertical (Y) axis. In this method, the entities can be identified anywhere in the image.\n\nHorizontal flip\n\nThe image is flipped horizontally from left to right in this operation. 0.5% of the time, the image is flipped horizontally.\n\nGaussian blur\n\nUsing a Gaussian filter with a kernel size of 5x5, one can blur or smooth images by removing high frequency components. Training data includes the blurred images obtained from the Gaussian filter.\n\nFuzzy logic (FL) can transfer an input space to an output space and is one approach for complex systems.5 The results of the study can aid in patient diagnosis and community self-identification, making it simpler for everyone to deal with Covid-19. Fuzzy algorithms tend to be robust and reasoning processes tend to be simple, FL was chosen as the soft computing approach for implementing the proposed COVID-19 diagnosis system. This means that FL uses less computing power and takes less time to develop than more traditional methods. FL is adaptable and is simple to incorporate into machine learning techniques, which makes it an especially useful characteristic for real-time systems like online diagnostic apps.20\n\nAn enormous amount of data and a long period of training are necessary. For many deep learning models, the most fundamental presupposition is that both testing and training data should be collected from the same distribution.21 Due to its prohibitive costs and data labelling requirements, it cannot be used in practical applications. In CNN, the transfer learning technique is used for training the datasets. The ImageNet database contains a transfer learning network that has been pre-trained, which is used in this study to train on the dataset. The derivative of the activation function is used to build the neural network and leads to the vanishing gradient problem. This problem is alleviated by using this transfer learning method. Transfer learning is depicted in Figure 6, where a large dataset like ImageNet can be used to train a model for a smaller dataset application.\n\nTransfer learning has the advantage of already learning basic features like recognizing shapes and edges in an image. The main advantage of the pre-trained model is that it learns basic features from the images in its database22,23 As a further benefit, only the network's final layers need to be trained, which reduces the amount of computation time. In addition to Dense networks, Squeeze Net, VGG, Inception, and Residual Networks, CNN already has a variety of architectures. When it comes to accuracy, computational time, and various other challenges, residual networks have surpassed the rest. Residual networks have proved the best when compared to other learning techniques as they solve the degradation problem by using skip connections to connect shallow to deep layers.24\n\nConvolution layer has been divided into the following further layers:\n\na) Adaptive ConcatPool2D layer\n\nb) Flattened Layer\n\nc) Blocks of rectified Linear Unit (ReLu)\n\nd) Dropout layer\n\ne) Linear layer\n\nf) Batch Norm1D\n\nIn the final linear layer block, we would get exactly the same quantity of outputs as equal to the same quantity of classes in the dataset, which is very important. Pareto's 80/20 rule dictates that 70% of the preprocessed Chest X-ray images are used for training; 20% of the images are used for network testing; and the remaining 10% of the preprocessed images are used for validation. Classification accuracy is improved by using variable learning rates that do not have fixed values. In the Fast Ai library, the learning rate (LR) find function can be used to find the best method for training a network model's learning rate.\n\nThe VGG architecture comprises of numerous convolutional layers activated by ReLU (rectified linear unit), with a kernel size of 3x3.25 The VGG models VGG-11, VGG-16, and VGG-19 are three versions of the VGG model that are structurally similar. They are made up of three fully connected layers, followed by subsequent convolution and pooling layers. The sole difference between them is the number of convolution layers (11, 16, or 19), as indicated by their titles.\n\nAlexNet nearly uses 650k neurons and 60 million parameters thus classifying more than 1000 classes. One Softmax layer, three pooling layers, two FLCs, and five convolutional layers (CLs) comprise this network.26 A 227x227 three AlexNet input image must have 96 kernels sized at 11 x11x 3 which is given as the input to the second Convolutional Layer, so that it can produce four number of pixels.\n\nIn addition to ImageNet, SqueezeNet is a CNN trained on this database. In comparison, SqueezeNet has 50 times fewer parameters than AlexNet, which was trained on over 1 million images during its development.27 Both the expand and squeeze layers are included in this network's structure. Extend layer contains a mix of 1x1 filters and 3x3 convolution filters, which feed into this layer. The suggested fire module, which consists of two sections, the squeeze portion and the expand part, is at the heart of SqueezeNet. A 1x1 convolutional kernel and a 1x1 convolutional layer make up the squeeze component. 1x1 and 3x3 convolutional kernels and convolutional layers, respectively, make up the expand component. The 1x1 and 3x3 feature maps are concatenated in the expanded layer. A comparison of SqueezeNet and AlexNet's accuracy on the ImageNet dataset reveals that they are about equal.\n\nShowkat et al.28 has proposed ResNet which is one of the various deep learning models. As the shallower models are very much prone to copy learning parameters and setting the additional layers for identity mapping which in fact is the basic principle behind ResNet. As a result of which the deeper networks have found to be more difficult to optimize Residual models are built to fit into the residual mapping F(x) rather than the underlying desired mapping\n\nH(x) in order to improve deeper models. By superimposing two 3x3 convolutional layers the ResNet architecture can be constructed.\n\nResNet incorporates the original input into the output feature map after it has been passed through one or more convolutional layers. Here, we'll take a closer look at Figure 7. The result is referred to as Relu, and it is either the first data or the data from the block before it. As long as the output and input sizes don't match, a constrained 1x1 convolution is used to reproject the filters, and a stride value of 2 is used to reduce the output size by half as much as possible through pooling.\n\nIn order to establish a distinction between Covid-19 and other viral pneumonias, ResNet18 has more layered blocks. With ResNet18, you can train on over 11 million different variables. The ResNet18 model distinguishes between normal cases in addition to COVID-19 cases with bacterial and viral pneumonia. As seen in Figure 8, a lot of factors are required to generalise for the various virus classifications.\n\nFor the identification of COVID-19 CT images, ResNet is a commonly used and preferred deep learning network. The accuracy of the model prediction decreases as the depth of the network goes beyond a specific number in ResNet and other DL networks,29 therefore the model depth must be carefully adjusted. This difficulty was overcome by transferring features from lower layers to higher layers and creating an identity mapping between the network's higher and lower layers. The block use multiplier is the primary difference between ResNet-18 and ResNet-34.\n\nThe learning rate is a critical factor for deep neural networks when it comes to the process of learning. By using equation.1, the formula outputs the most recent weights at the end of each epoch.\n\nj –It's the number of epochs that have been run.\n\nj(ϴ) – loss function\n\nα - learning rate\n\nθj+1 updated new weight\n\n∂Jϴ∂ϴi gradient weight of θj\n\nIn some cases, choosing the optimal learning rate can be difficult. Converging of weights too quickly results in sub-optimal weight loss and an unstable training process when the rate of learning is high. When the network-based model is constantly tweaked with different learning rates, the process requires manual intervention. Having a low learning rate slows down the training process and causes the network to be delayed. This study describes an experiment where the optimal learning rate may be started by cyclically changing the learner's speed in line with their boundaries. Remaining networks are trained using X-ray images of patient’s lungs with bacterial and viral infections and healthy lungs to distinguish between them.\n\nAlthough models of deep learning are regarded as black box techniques, most researchers and practitioners are unable to understand where the network is drawing its input data activation from, or how the network has reached its final destination; this is the reality in practice. For this purpose, a debugging technique called Grad-CAM (Gradient-Weighted Class Activation Mapping) algorithm,30 which is a visual class activation map is commonly used in deep neural networks. To further aid in the study and understanding of deep learning models, Grad-CAM provides an evaluation method. In the final convolutional layer, Grad-CAM uses the inclinations of any objective idea to generate an image-based coarse limitation map that highlights the image's most critical regions for predicting the idea. If a chest radiograph assessment is required, the network can approve the location using Grad-CAM. The slope of the data flowing into the network's final convolutional layer is examined by Graduate CAM. This tool generates a heat map based on a particular class label.\n\nConvolutional networks look for specific features in an image, which are represented by a heat map in the experimental analysis section. Visualization in Figure 9 shows the areas of an image where COVID-19 is believed to be presented.\n\nThe VGG 16, Alex Net, SqueezeNet, and ResNet 18 models were trained and assessed on a Tesla K80 GPU (graphics processing unit) with a memory capacity of approximately 12GB offered by the Google Colab.\n\nClassifier performance on test data is frequently evaluated using the confusion matrix. In this table, you'll find all of the test data's actual and expected instances of the classes that are represented. F1-score, specificity and sensitivity, precision and classification accuracy can all be calculated using it. To calculate these parameters from the confusion matrix, a few terms need to be specified, such as\n\n1. True Positive for correctly predicting the positive class (TP).\n\n2. To accurately predict the negative class, use (b) True Negative (TN).\n\n3. True Negative (TN) if the positive class is estimated incorrectly.\n\n4. Negative class prediction error causes a False Positive (FP).\n\nClassification problems can be summarized in a confusion matrix, which includes both the predicted and the actual labels. In addition to reporting on the errors, the classifier provides information on the types of errors it has made. Fig 10 shows a diagram of the confusion matrix.\n\nFigure 10 shows the confusion matrix, with true positive and true negative values, as well as false positive and false negative values. Due to an uneven distribution of images in the test set, with different image instances for each of the testing classes. We can use an AUC (Area Under the Curve) score for binary classification and a weighted F1 score for four-class classification to evaluate the model. Four -class classification requires that precision (P) and recall (R) for each class be calculated independently and averaged to calculate the F1 score. To evaluate models on the imbalance dataset, the F1 score is a weighted harmonic mean of P and R. The values listed can be calculated using the following equations:\n\nAccuracy:\n\nAccuracy is defined as the ratio of correct predictions (COVID-19 cases) from the overall number of cases for each type of case is mathematically conveyed as:\n\nTP = No. Correct Positive Case Predictions.\n\nTN = No. of correct negative case predictions.\n\nFP = Percentage of positive cases correctly predicted.\n\nFN = No. of in correct predictions of negative cases.\n\nPrecision:\n\nThe percentage of positive cases that were correctly predicted. A lower false positive rate is directly related to greater precision\n\nRecall:\n\nThe percentage of correctly predicted positive class observations that actually occurred is nothing but recall.\n\nSpecificity:\n\nThe percentage of predicted negative events that actually occurred is called specificity.\n\nF- Measure:\n\nThe F-measure is calculated when there are a large number of true negative observations in the class distribution. As a result, it finds a good balance between the two.\n\nEquations 2-6 gives us accuracy, recall, specificity and F-measure formulas are used for calculating the performance evaluation of various deep learning techniques.\n\n\nResults\n\nTable 3 shows the Comparison of different deep learning techniques for the four different types of viruses. When multiple models from the figure are compared, deeper networks outperform shallower networks. When it comes to accuracy, recall and specificity, we can conclude that ResNet18's design is far superior to other architectures as it is highlighted in green in Table 3. It is possible to develop prototypes that can automatically classify results into four categories (COVID-19, viral, bacterial pneumonia and normal cases) using the proposed method, which has the highest accuracy values among recent studies, according to our knowledge.\n\n\nConclusion\n\nThe detection of COVID-19, bacterial, and viral pneumonias, as well as healthy cases, was performed in this work utilising deep learning models. Because it is critical to detect COVID-19 that spreads swiftly and globally, artificial intelligence approaches are utilised to do so precisely and promptly. By comparing model visualisation across a large number of samples as well as accuracy scores, we demonstrated the importance of Grad-CAM heatmaps are used as the major model validation metric. The deep learning models employed in the proposed approach (“VGG16, Alex Net, Squeeze Net, and ResNet 18“) have less parameters than the other deep learning models which resulted in increasing speed and performance. Experiments indicated that combining chest X-ray and fuzzy features increases the classification ability, with an accuracy rate of up to 97.7% using ResNet 18, which is a higher value when compared to the other methodologies. The suggested model makes use of the end-to-end learning scheme, which is one of the major advantages of CNN models. In the future, deep learning-based analysis can be performed on images of other organs impacted by the virus, in accordance with the views of COVID-19 experts. Additionally, we can investigate using a bigger chest X-ray dataset to evaluate our suggested model in the near future. Our research is not focused on building a perfect detection system; rather, it is focused on developing cost-effective approaches to tackle this disease.",
"appendix": "Data availability\n\nKaggle: COVID-19 Detection X-Ray Dataset, https://doi.org/10.34740/kaggle/dsv/3122958. 31\n\nThe dataset is organized into 3 folders (train, test, val) and contains subfolders for each image category (Pneumonia/Normal). There are 5,863 X-Ray images (JPEG) and 2 categories (Pneumonia/Normal).\n\nData are available under the terms of the Creative Commons Attribution-Sharealike 4.0 International (CC BY-SA 4.0).\n\n\nReferences\n\nRahmani AM, Mirmahaleh SYH: Coronavirus disease (COVID-19) prevention and treatment methods and effective parameters: A systematic literature review. Sustain. Cities Soc. 2021; 64: 102568. Publisher Full Text\n\nJain G, Mittal D, Thakur D, et al.: A deep learning approach to detect Covid-19 coronavirus with X-Ray images. Biocybernetics and biomedical engineering. 2020; 40(4): 1391–1405. PubMed Abstract | Publisher Full Text\n\nShoeibi A, Khodatars M, Alizadehsani R, et al.: Automated detection and forecasting of covid-19 using deep learning techniques: A review. arXiv preprint arXiv:2007.10785. 2020.\n\nSaygılı A: A new approach for computer-aided detection of coronavirus (COVID-19) from CT and X-ray images using machine learning methods. Appl. Soft Comput. 2021 Jul 1; 105: 107323. PubMed Abstract | Publisher Full Text\n\nSakib S, Tazrin T, Fouda MM, et al.: DL-CRC: deep learning-based chest radiograph classification for COVID-19 detection: a novel approach. Ieee Access. 2020 Sep 18; 8: 171575–171589. PubMed Abstract | Publisher Full Text\n\nIsmael AM, Şengür A: Deep learning approaches for COVID-19 detection based on chest X-ray images. Expert Syst. Appl. 2021 Feb 1; 164: 114054. PubMed Abstract | Publisher Full Text\n\nHu Q, Gois FN, Costa R, et al.: Explainable artificial intelligence-based edge fuzzy images for COVID-19 detection and identification. Appl. Soft Comput. 2022 Jul 1; 123: 108966. PubMed Abstract | Publisher Full Text\n\nChoudhury SH, Aurin AJ, Mitaly TA, et al.: Predicting the possibility of COVID-19 infection using fuzzy logic system. International Journal of Intelligent Information and Database Systems. 2021; 14(3): 239–256. Publisher Full Text\n\nIeracitano, et al.: A Fuzzy-enhanced Deep Learning Approach for Early Detection of Covid-19 Pneumonia from Portable Chest X-Ray Images. Neurocomputing. 2022; 481: 202–215. PubMed Abstract | Publisher Full Text\n\nAlqudah AM, Qazan S, Alqudah A: Automated systems for detection of COVID-19 using chest X-ray images and lightweight convolutional neural networks.2020.\n\nCohen JP, Morrison P, Dao L: COVID-19 image data collection. arXiv preprint arXiv:2003.11597. 2020.\n\nApostolopoulos ID, Bessiana T: Covid-19: Automatic detection from X-Ray images utilizing Transfer Learning with Convolutional Neural Networks. arXiv e-prints. 2020 March 01. arXiv preprint arXiv:2003.11617. 2020.\n\nToğaçar M, Ergen B, Cömert Z: COVID-19 detection using deep learning models to exploit Social Mimic Optimization and structured chest X-ray images using fuzzy color and stacking approaches. Comput. Biol. Med. 2020; 121: 103805. Publisher Full Text\n\nOzturk T, Talo M, Yildirim EA, et al.: Automated detection of COVID-19 cases using deep neural networks with X-ray images. Comput. Biol. Med. 2020; 121: 103792. PubMed Abstract | Publisher Full Text\n\nWang L, Lin ZQ, Wong A: Covid-net: A tailored deep convolutional neural network design for detection of covid-19 cases from chest x-ray images. Sci. Rep. 2020 Nov 11; 10(1): 1–2.\n\nSmith LN: Cyclical learning rates for training neural networks. 2017 IEEE winter conference on applications of computer vision (WACV). IEEE;2017, March; (pp. 464–472).\n\nGilanie G, Bajwa UI, Waraich MM, et al.: Coronavirus (COVID-19) detection from chest radiology images using convolutional neural networks. Biomedical Signal Processing and Control. 2021 Apr 1; 66: 102490. PubMed Abstract | Publisher Full Text\n\nGitHub:COVID-19. [dataset].Retrieved March 10, 2020.Reference Source\n\nAkçay S, Kundegorski ME, Devereux M, et al.: Transfer learning using convolutional neural networks for object classification within X-ray baggage security imagery. 2016 IEEE International Conference on Image Processing (ICIP). IEEE;2016, September; (pp. 1057–1061).\n\nSalehi S, Abedi A, Balakrishnan S, et al.: Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients. AJR Am. J. Roentgenol. 2020; 215(1): 87–93. PubMed Abstract | Publisher Full Text\n\nMinaee S, Kafieh R, Sonka M, et al.: Deep-COVID: Predicting COVID-19 from chest X-ray images using deep transfer learning. Med. Image Anal. 2020; 65: 101794. PubMed Abstract | Publisher Full Text\n\nYang H, Mei S, Song K, et al.: Transfer-learning-based online Mura defect classification. IEEE Trans. Semicond. Manuf. 2017; 31(1): 116–123. Publisher Full Text\n\nPanwar H, Gupta PK, Siddiqui MK, et al.: Application of deep learning for fast detection of COVID-19 in X-Rays using nCOVnet. Chaos, Solitons Fractals. 2020; 138: 109944. PubMed Abstract | Publisher Full Text\n\nIsmael SA, Mohammed A, Hefny H: An enhanced deep learning approach for brain cancer MRI images classification using residual networks. Artif. Intell. Med. 2020 Jan 1; 102: 101779. PubMed Abstract | Publisher Full Text\n\nBelaid ON, Loudini M: Classification of brain tumor by combination of pre-trained vgg16 cnn. Journal of Information Technology Management. 2020; 12(2): 13–25.\n\nHeidari A, Erfanian H: Online COVID-19 Infection Diagnoses via Chest X-Ray Images using Alexnet Deep Learning Model. International Journal of Web Research. 2022 Jun 1; 5(1): 50–55.\n\nSyed Nizamudeen Ahmed J, Mohamed Sathik M, Nallaperumal K, et al.:Automated Diagnosis of COVID-19 Using Squeeze Net Architecture Based on Deep Learning. InEmergent Converging Technologies and Biomedical Systems. Singapore:Springer;2022; (pp. 651–662).\n\nShowkat S, Qureshi S: Efficacy of Transfer Learning-based ResNet models in Chest X-ray image classification for detecting COVID-19 Pneumonia. Chemom. Intell. Lab. Syst. 2022 May 15; 224: 104534. PubMed Abstract | Publisher Full Text\n\nAlom MZ, Yakopcic C, Nasrin M, et al.: Breast cancer classification from histopathological images with inception recurrent residual convolutional neural network. J. Digit. Imaging. 2019; 32(4): 605–617. PubMed Abstract | Publisher Full Text\n\nSelvaraju RR, Cogswell M, Das A, et al.: Grad-cam: Visual explanations from deep networks via gradient-based localization. Proceedings of the IEEE international conference on computer vision. 2017; (pp. 618–626).\n\nTahir AM, Chowdhury MEH, Qiblawey Y, et al.: COVID-QU-Ex Dataset . [Data set]. Kaggle.2022. Publisher Full Text"
}
|
[
{
"id": "204714",
"date": "13 Oct 2023",
"name": "Kogilavani Shanmugavadivel",
"expertise": [
"Reviewer Expertise Machine learning",
"Natural language Processing"
],
"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\nThe article proposes a novel approach that combines fuzzy logic with deep learning, specifically employing ResNet-18 architecture, to diagnose COVID-19 and distinguish it from other types of pneumonia and healthy cases through chest X-ray images. The introduction emphasizes the scarcity of COVID-19 detection kits and the potential of deep learning in medical imaging. The methodology section highlights the integration of fuzzy logic within the deep neural network and the use of a carefully selected dataset. The results demonstrate a high classification accuracy of 97% for COVID-19 detection, outperforming existing literature. The study concludes by affirming the effectiveness of the proposed approach and underscores the potential of employing deep learning techniques for accurate classification of COVID-19 and other pneumonia cases, suggesting promising applications in the near future.\nReview Comments\nThe introduction could benefit from a clear statement of the research objectives and hypotheses to provide readers with a more focused understanding of the study's purpose.\n\nConsider including a brief overview of the limitations and challenges associated with using chest X-ray images for COVID-19 diagnosis to provide a well-rounded context for the study.\n\nProvide a thorough explanation of the dataset used, including its size, diversity, and any potential biases, to ensure transparency and replicability of the study.\n\nElaborate on the selection criteria for chest X-ray images to establish the rationale for including specific images in the dataset.\n\nClarify the rationale for choosing ResNet-18 architecture and why it was deemed suitable for the proposed classification task.\n\nDiscuss any pre-processing techniques applied to the chest X-ray images and justify their necessity for improving the model's performance.\n\nInclude comparisons with other deep learning models or traditional machine learning approaches to showcase the superiority of the proposed fuzzy deep neural network.\n\nProvide more details on the fuzzy logic integration within the deep learning model and how it enhances the classification accuracy.\n\nIncorporate visualizations of the fuzzy logic components and how they influence the network's decision-making process for improved comprehension.\n\nDiscuss potential challenges or limitations of the fuzzy logic integration, such as computational complexity or interpretability, and propose ways to mitigate them.\n\nClarify the evaluation metrics used (e.g., accuracy, precision, recall) and why they were chosen to assess the model's performance.\n\nSuggest future directions for research, such as exploring the interpretability of the fuzzy logic components in the context of COVID-19 diagnosis.\n\nConsider discussing the computational resources required to implement the proposed approach, which can be crucial for practical application and scalability.\n\nHighlight any ethical considerations related to the use of medical imaging data and deep learning in healthcare, emphasizing the importance of patient privacy and data security.\n\nProvide a brief discussion on the potential impact of the proposed approach on clinical practice and patient outcomes.\n\nEnsure proper citation and acknowledgment of previous research in the field, especially regarding existing approaches to COVID-19 detection using medical imaging.\n\nReview the manuscript for grammatical errors and clarity to enhance readability and comprehension.\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": "204708",
"date": "24 Nov 2023",
"name": "Ervin Gubin Moung",
"expertise": [
"Reviewer Expertise machine learning",
"deep learning",
"object detection",
"artificial intelligence."
],
"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 paper provides an overview of the methodology, but details like specific model architectures and configurations are not fully presented in the paper.\n\nSpecifics about Random's seed values or the context of randomness aren't detailed in the paper. Kindly provide this information for reproducibility purpose.\n\nSpecific hyperparameters and model configurations were not found in the paper. Kindly tabulate all these information for reproducibility purpose.\n\nExplicit information and settings about the preprocessing step is not mentioned in this paper. Kindly tabulate this information for reproducibility purpose.\n\nThe paper does mention splitting the data into training (70%), testing (20%), and validation (10%) sets, but specifics about each set or potential overlaps are not provided. Provide the \"seed\" information for random shuffling (if applied).\n\nA comparison of this paper's performance against existing literature on the same topic is missing. Kindly add a table that compares and discusses the key metrics, methodologies, and results from both this study and relevant works in the field. This will provide readers with a clearer context and understanding of the research's significance and advancements.\n\nThe abstract and conclusion of the paper don’t clearly state what makes this research special. Please make sure to highlight the main contributions of your work in these sections. Additionally, it would be helpful to talk about any limitations of your study and suggest ideas for what might be researched next.\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? No\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "183249",
"date": "19 Sep 2024",
"name": "Chiagoziem Chima Ukwuoma",
"expertise": [
"Reviewer Expertise Deep learning",
"Medical Imaging",
"Attention Mechanism",
"Object Segmentation",
"Detection and Classification"
],
"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 manuscript, the authors proposed an Application of Fuzzy Deep Neural Networks for Covid-19 diagnosis through chest Radiographs, First, Covid-19 is generally known and more than half a million article are already published demonstrating the various strategies researchers proposed to tackle the disease. Second, The structure of this manuscript is somehow vague and lacks academic presentation standard. Third, what is/are the aims of the authors? Fourth, this submission can be put in as a conference paper if arranged well other than a journal article.\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? 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": []
},
{
"id": "160391",
"date": "28 Sep 2024",
"name": "Yasin kaya",
"expertise": [
"Reviewer Expertise Computer 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 work proposes a Fuzzy Deep Neural Networks application for Covid 19 diagnosis using chest x-rays. The topic is one of the hottest topics for last 3 years. A lot of works has been done considering this topic. Thus, the authors should clearly explain the following questions.\n\nThe aim of the study, the gap in the literature, the main focus of the study, challenges of the previous works must be clearly given in the introduction section. The novelty of the study is not explicit.\n\nThe literature survey must be extended using recent works. Especially, deep learning and transfer learning works that use X-ray images.\n\nThe training parameters of the study must be indicated clearly. How did the authors define the hyperparameters of the system?\n\nA table should be given to compare the results of recent works with the results of the proposed method.\n\nIn the discussion section, the merits and demerits of the algorithm must be given.\n\nThe conclusion section should be expanded. The future scope of the study must be given.\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? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-60
|
https://f1000research.com/articles/12-59/v1
|
16 Jan 23
|
{
"type": "Systematic Review",
"title": "Suicide and attempted suicide by insulin: A systematic review",
"authors": [
"Majd A. Assad",
"Fatimah A. Alawami",
"Raihanah S. Al Khatem",
"Zahra Y. Al Daif",
"Zainb A. Alrumaih",
"Ritesh G. Menezes",
"Majd A. Assad",
"Raihanah S. Al Khatem",
"Zahra Y. Al Daif",
"Zainb A. Alrumaih",
"Ritesh G. Menezes"
],
"abstract": "Background: Intentional insulin overdose either in people with diabetes or without can be used to attempt suicide. Massive insulin administration may result in coma and unexplained hypoglycemia. In this study, we aim at reviewing the demographic data of suicidal cases, the relation of psychiatric illness to dying by suicide and attempting suicide using insulin, route of insulin administration and outcome, post-mortem findings in suicide by insulin and collaborative evidence, initial presentation, blood glucose level and complications in attempting suicide cases. Methods: PubMed, Web of Science, and Scopus databases were searched on October 4, 2021, using a comprehensive strategy review. The following search terms were applied: (Insulin) AND (toxicity OR overdose OR toxicology OR poisoning OR intoxication) AND (Suicide OR attempted suicide OR Self-harm OR Self harm). The search strategy was set based on PRISMA guideline; 11 papers were eligible for inclusion and additional 23 studies were added from the citation search. All English articles related to suicide and attempted suicide using insulin were included and no specific timeline or filter was used. Any non-English article and accidental or homicidal cases were excluded from the review. Results: The analysis included 179 victims, aged between 13 to 76 years with male predominance and people with diabetes, especially T1DM, having higher prevalence, with subcutaneous injection being the most common route of administration. In addition, psychiatric illnesses and multiple suicide attempts were identified in many cases besides the use of insulin in a combination with other medications. Conclusions: Dying by suicide using insulin is uncommon, however, as diabetes mellitus prevalence increases worldwide, it is expected that intentional insulin overdose will also increase. Furthermore, psychiatric illnesses and easy access to insulin are important factors that should be put into consideration.",
"keywords": [
"suicide",
"attempted suicide",
"insulin",
"overdose",
"self-poisoning"
],
"content": "Introduction\n\nSuicide is considered one of the increasing public health problems. According to the World Health Organization (WHO), more than 700,000 people die by suicide each year. Even more, it is considered the fourth leading cause of death among adolescents aged 15 to 19 years. In 2019, when suicidal cases were analyzed based on the socioeconomic status of different countries, 77% of the total reported suicide cases were among low and middle-income countries. Besides, ingestion of pesticides, hanging, and firearms were the most commonly reported methods.1\n\nThe incidence of suicide is believed to be the highest among adolescents and increases more among those experiencing stressors of abuse, conflicts, and bullying. Moreover, even though women tend to have more suicidal attempts, the incidence of men dying by suicide is higher due to their tendency to choose more lethal methods and higher lethality acts, which explains why women are more likely to survive each attempt.2,3 Regarding the methods of suicide, hanging is the most common method used among women, while firearms are most commonly used by men, with hanging being the most fatal method among both.2,3 Concerning the profession, a higher risk of suicide is found to be among physicians, particularly those who are female.4\n\nInsulin is a polypeptide hormone that is secreted by β cells of the pancreas and regulated by glucose level in the blood, some amino acids, autonomic mediators, and other hormones. Artificial insulin is an exogenous insulin given to all patients with T1DM, and some patients with T2DM. Insulin can be divided into rapid-acting (lispro, lispro-aabc, glulisine, aspart, and faster aspart), short-acting (regular insulin), intermediate-acting (neutral protamine hagedorn (NPH)), long-acting (glargine, detemir, and degludec), and premixed insulin.5,6 Subcutaneous injection is the most commonly used route of administration of insulin, which can be delivered via various methods, including, vials, syringes, insulin pens, and insulin pumps.7 Since there is no safe medication, artificial insulin carries its side effects, and hypoglycemia is the most common one.6\n\nFew cases of insulin overdose are reported every year, which can be accidental or intentional for the purpose of dying by suicide. Surprisingly, these reported cases include not only individuals with diabetes of both types but also those who do not have diabetes. People with massive insulin overdose might develop neurological complications, such as hypoglycemic coma, which can be reversible or result in death.8,9\n\nAlthough there are no clear studies stating that diabetes mellitus is a known risk factor for suicide, it is found that individuals with T1DM have 11 times higher risk of attempting suicide than people who do not have diabetes. Moreover, other studies conclude that suicidal ideation in people with diabetes mellitus was associated with these individuals not taking their medication.10\n\nAs insulin can be used as a method to attempt suicide, we aim in this paper to analyze research published on attempting or dying by suicide with insulin. The review focuses on six dimensions, which are the demographic data of suicidal cases, the relation of psychiatric illness to dying by and attempting suicide using insulin, route of insulin administration and outcome, post-mortem findings in suicide by insulin and collaborative evidence, initial presentation, blood glucose level and complications in attempting suicide cases.\n\n\nMethods\n\nArticles concerning suicide and attempted suicide by insulin were identified by searching Scopus (RRID:SCR_022559), PubMed (RRID:SCR_004846), and Web of Science (RRID:SCR_022706) databases. The search was done on October 4, 2021, and the following search terms were applied: (Insulin) AND (toxicity OR overdose OR toxicology OR poisoning OR intoxication) AND (suicide OR attempted suicide OR self-harm OR self harm). The search strategy was set based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline 2020.11 The study was not registered in the International Prospective Register of Systematic Reviews (PROSPERO).\n\nInclusion criteria were set to include all English articles that focused on cases of suicide and suicide attempts using insulin with or without any other medication and no restrictions were used regarding the timeline and study design. Studies that reported homicides and cases of accidental (unintentional) overdoses using insulin and non-English articles were excluded from this review.\n\nThe search was done manually by two independent reviewers (MAA, FAA). In the preliminary search in PubMed, Web of Science, and Scopus, 216, 193, and 16 records were identified, respectively. Titles and abstracts of all records were evaluated for relevance. This was followed by a full-text assessment to ensure the eligibility of the records to be included in the review (Figure 1). Other reviewers (RSA, ZYA, ZAA, RGM) were consulted regarding any search issue, if present. Automation tools were not used in the selection process and data collection process.\n\n\nResults\n\nThe literature search identified a total of 425 records from PubMed (n = 216), Web of Science (n = 193), and Scopus (n = 16). After removing 196 duplicate records, an initial screening of 229 records was done and led to the exclusion of 187 articles. Further, a full-text review excluded 31 articles due to the following reasons: non-English articles (n = 29) (Derobert L et al.,12 Domart A et al.,13 Lenhardt A,14 Richter R,15 Szabo Z et al.,16 Chlud K,17 Sachsse B,18 Bourgeois M et al.,19 Vincent V et al.,20 Creutzfeldt W et al.,21 Euler-Rolle J et al.,22 Stofer A et al.,23 Tourniaire J et al.,24 Holldorf L et al.,25 Marigo S et al.,26 Bourgeois M,27 Stefan J,28 Zilker T et al.,29 Schneider V et al.,30 Hambrecht M et al.,31 Logemann E et al.,32 von Albert H et al.,33 Szponar J et al.,34 Wehner F et al.,35 Nikolić S et al.,36 Klimaszyk D et al.,37 Uesugi K,38 Chen L et al.,39 Tong F et al.,40 and articles that could not be retrieved (n = 2) (Lionte C et al.,41 Arbouche N et al.42). From the primary search of the databases 11 records met the inclusion criteria. Also, an additional 23 records were identified by screening the references of the included studies from the primary search. Eventually, a total of 34 articles met the inclusion criteria and were considered in the present review.8,9,43–73 A PRISMA flow chart for the literature search is shown in Figure 1.\n\nThe analyzed studies were published in a time period between 1934 and 2020. Most studies were case reports (n = 22), while few were case series (n = 3), retrospective cohort (n = 2), prospective study (n = 1), hospital based (n = 2), population based (n = 1), case-control (n = 1), case conference (n = 1) and cross-sectional (n = 1) studies. A summary of the important results is presented in Table 1.\n\n\n\n1. 20\n\n2. 47\n\n3. 22\n\n4. 53\n\n\n\n1. Female\n\n2. Female\n\n3. Male\n\n4. Female\n\n\n\n1. Insulin (ultralente)\n\n2. Insulin (NPH) and Diazepam\n\n3. Insulin (NPH), Alcohol and Barbiturate\n\n4. Insulin (semilente) and Nitrazepam\n\n\n\n- Insulin alone (12)\n\n- Mixtures of Insulins (8)\n\n\n\n1. 13\n\n2. 16\n\n\n\n1. Dysthymic disorder and parent-child problem- substance use disorder\n\n2. Major depression and borderline personality disorder\n\n\n\n1. Insulin (regular)\n\n2. Insulin (regular)\n\n\n\n1. 150\n\n2. 600\n\n\n\n1. 48\n\n2. 36\n\n3. 24\n\n4. 44\n\n\n\n1. Male\n\n2. Female\n\n3. Male\n\n4. Male\n\n\n\n1. NMb\n\n2. NMb\n\n3. Depression\n\n4. Depression and substance use (Alcohol)\n\n\n\n1. Insulin (NPH)\n\n2. Insulin\n\n3. Insulin\n\n4. Insulin (Novolin) and Diphenhydramine\n\n\n\n1. 100\n\n2. NMb\n\n3. NMb\n\n4. 100\n\na United States of America.\n\nb Not mentioned.\n\nc Subcutaneous.\n\nd Type 1 Diabetes Mellitus.\n\ne United Kingdom.\n\nf Type 2 Diabetes Mellitus.\n\n* The exact number of men and women. However, the article stated that the female percentage was significantly higher among those individuals.\n\n** Among the 20 cases, only 15 individuals were with known age and sex, in the remaining five patients age and sex were not mentioned.\n\nThe analysis included 179 people (Table 1). The age of these individuals ranged from 13 to 76 years. A total of 51 of them were men and 43 were women, while the rest were unknown (n = 85). Regarding work status, only 21 of the people mentioned their occupations, 16 of them were healthcare providers (physicians, nurses, anesthetists, pharmacists, and paramedics). Other occupations included students (n = 2), teacher (n = 1), and unemployed (n = 3).\n\nThe cases that were included in the various articles were reported from multiple countries, including: Austria (n = 56), France (n = 33), United Kingdom (n = 25), Germany (n =13), United States (n = 11), Switzerland (n = 2), Belgium (n = 1), South China (n = 1), Finland (n = 8), India (n = 1), Israel (n = 1), Scotland (n = 1), Australia (n = 1), Turkey (n = 1), and the only Arabic country was Tunisia (n = 1).\n\nConcerning the diabetes mellitus status, the majority of the people had been diagnosed with diabetes (n = 130). Moreover, 35 did not have diabetes, seven were relatives of an individual with diabetes and for seven their diabetic status was not mentioned. In regard to type of diabetes mellitus, T1DM (n = 102) showed greater prevalence than T2DM (n = 21).\n\nIn regard to psychiatric status, 67 of the individuals had a mental illness and 58 showed behavioral disturbances (Table 1). The highest prevalence of mental illnesses included depressive disorders (n = 29), followed by alcohol use disorder (n = 11), and other substance use (n = 5), including clonazepam and cannabis (n = 1), tobacco and cocaine (n = 1), while the rest of the substances were not mentioned. Other psychiatric illnesses included anxiety and panic disorders (n = 3), obsessive compulsive disorder (n = 2), borderline personality disorder (n = 3), manic-depressive disorder (n = 1), dysthymic disorder (n = 1), eating disorder (n = 1), and dementia (n = 1). Previous suicidal attempts were also reported among individuals who had a psychiatric illness (n = 12).\n\nDifferent routes of insulin administration were reported (Table 1), with the majority of cases (n = 68) using the subcutaneous route. Notably, oral administration of insulin was reported in one case in which an individual had a suicide attempt via ingesting a large amount of insulin vials. In 46 cases the route of administration was an injection and it was not mentioned in 64 of the cases.\n\nInsulin injections in combination with other medications were reported in 28 of the cases. The most common medication reported was benzodiazepines (n = 23). Other medications were antidepressants (n = 3), anxiolytics (n = 2), morphine (n = 1), dihydromorphinone (n = 1), non-steroidal anti-inflammatory drugs (NSAIDs) (n = 1), antihistamine (n = 1), beta blockers (n = 1), barbiturate (n = 1), and cardiovascular system drugs (n = 1).\n\nOut of all individuals who were included in the study (n = 179) the majority (n = 141) attempted suicide, while only a few (n = 38) were suicide cases.\n\nHistory and circumstances, including the scene of the act and suicidal notes, were mentioned in 22 out of 38 cases. In 14/22, needles and empty insulin vials were found at the scene. In one case, missing drugs from the individual’s cabinet were found, including a vial of Novolin 70/30, a syringe, and 12 capsules of 25 mg diphenhydramine. In addition, there were four individuals who left a suicide note at the scene, three out of them were written notes, and there was one case where verbal suicidal intent was mentioned.\n\nThe external examination of 19 of the cases showed evidence of injection sites in multiple sites of the body including gluteal region, antecubital fossa, umbilicus, and thighs. Some of these injections were new, and some were old ones. In one case, external examination showed evidence of vomitus at the corner of the mouth, fingernail cyanosis and petechiae.\n\nFurthermore, autopsy was performed in 38 cases, gross findings of the pancreas, lung, brain and heart were reported. Pancreas findings included fibrosis and autolysis. Brain findings included hypoglycemic brain damage with cortical laminar necrosis, cerebral and mid-brain infarcts, and cerebral edema. Lung findings included an evidence of aspiration of gastric contents that was extending into intra-pulmonary compartment with acute congestion of the lung, whereas heart findings included the presence of epicardial petechiae. The rest of microscopic autopsy findings and toxicological analysis of the provided cases are summarized in Table 2.\n\n\n\n- Known to carry a suicide note in his pocket\n\n\n\n- Insulin bottled and a syringe found\n\n\n\n- Verbal note several weeks earlier, \"If I ever kill myself, it will be with insulin.\"\n\n\n\n- Missing drugs from her cabinet included: a vial of Novolin 70/30, a syringe, and 12 capsules of 25 mg diphenhydramine\n\n\n\n- Alcohol: 0.121%\n\n- Metabolites of marijuana\n\n\n\n- Insulin: 31 μU/ml\n\n- Glucose: 26 mg/dl.\n\n\n\n- Insulin: 840 μU/ml\n\n- C peptide: 0.5 ng/ml\n\n- Diphenhydramine, alcohol: not detected\n\n\n\n- Normal\n\n\n\n- Fibrosis\n\n\n\n- Three empty disposable syringes and an empty ampoule of insulin\n\n\n\n- He left a suicide note\n\na Cerebrospinal fluid.\n\nIn 141 cases of attempted suicide, the clinical findings, initial glucose level, and complications are summarized in Table 3. The initial presentation in those who attempted suicide by insulin varies from asymptomatic to loss of consciousness and coma. Furthermore, in all individuals, where the initial blood glucose level was measured, the blood glucose levels were ranging from 2 to 234 mg/dl. Finally, complications were only found in nine cases in the form of significant neurological sequelae related to insulin intoxication, such as cognitive damage and recurrent hypoglycemic coma.\n\n\n\n• Slightly unconscious and weak\n\n• Flushed face, dilated neck vein and forceful carotid pulse\n\n• Slight tachycardia, cold body bathed in perspiration\n\n• Fine in all extremities\n\n\n\n• Moist, perspired skin\n\n• Deviation of the eye with pin-point pupil\n\n• Flaccid arms and legs\n\na Not mentioned.\n\n* At initial presentation.\n\n** Hypoglycemic symptoms presented and were managed at home.\n\n\nDiscussion\n\nDiabetes and psychiatric illnesses can co-exist and have a significant impact on people’s lives. Studies showed that there is a significant association between diabetes and alcohol use disorder, substance use, mood disorders, anxiety disorders, and psychotic disorders, which puts them at an increased risk of suicide.74,75 This goes in harmony with this systematic review where 67 out of 179 (37.43%) reported cases were diagnosed with mental illnesses. Furthermore, insulin overdose, alongside its congeners, is not an uncommon method of suicide attempts among individuals with diabetes.76 However, publications regarding the incidence of insulin suicide are scarce.10 In the current existing data, those with T1DM showed higher incidence of insulin suicide (n = 102) than in T2DM (n = 21), which represents 63.35% and 13.04%, respectively. This could be explained by two possible reasons. First, T1DM is managed mainly by insulin, which makes it readily accessible to them.76 Second, generally, the incidence of dying by suicide is considered to be higher among newly diagnosed youth with T1DM. The suicidal ideation and attempts are believed to be related to symptomology and initial psychiatric status shortly after being diagnosed.77\n\nAlthough multiple professions are prone to die by suicide, the medical field is considered a high-risk profession. Multiple studies reported a higher incidence of anxiety and depression among physicians. It may be attributed to the stressful work environment and the emotional burden when facing illness, breaking bad news, and death.4,78,79 Up to this point, self-poisoning is the most common method of suicide among healthcare providers.80 In addition to that, the thorough medical knowledge of the rapid lethal insulin-induced hypoglycemia can make the available insulin in hospitals a feasible weapon for suicide.81 This systematic review showed that 9.93% (n = 16) of victims were healthcare providers and, as anticipated, most of them were suffering from mental illnesses.\n\nIn reality, many individuals who are chronically ill, including those with diabetes, attempt suicide using a combination of different prescribed medications.82 A very recent study found that a benzodiazepine overdose can be linked to hypoglycemia.83 Surprisingly, we found that the most common medication used in combination with insulin is a benzodiazepine, which can be explained by the fact that a lower threshold of insulin will be needed to result in death. In addition to benzodiazepines, the consumption of alcohol was also associated with an increased risk of hypoglycemia the day after the intake. This is most likely due to the inhibitory properties of alcohol to hepatic gluconeogenesis.84,85 This systematic review reported eight attempted suicides by individuals with diabetes who were also suffering from alcohol use disorder. This suggests a higher risk for those individuals to develop life-threatening hypoglycemic episodes, even though alcohol was not consumed on the same day of the event.\n\nDespite the fact that hypoglycemia symptoms are usually typical, almost all of them are nonspecific. For this, the only evidence to know that the individual is suffering from hypoglycemia is to measure blood glucose level. Studies have shown that the threshold of developing hypoglycemia symptoms is when plasma glucose level falls below 80 mg/dL, while cognitive dysfunction mainly develops at 45 mg/dL. Moreover, the most commonly reported symptoms were mild, which include a combination of diplopia, diaphoresis, palpitations, and blurred vision. Furthermore, more severe symptoms were also reported in 65% of the cases, which are unconsciousness or amnesia, and generalized convulsions.86 In this systematic review, most of the findings of the reported cases are consistent with the previous studies, excluding a single case who had a glucose level of 25.2 mg/dL without any symptoms except for diaphoresis. For this, it is believed that signs and symptoms of hypoglycemia can vary greatly among people despite the blood glucose level readings.\n\nThe absence of autopsy and histology findings makes the diagnosis of hypoglycemia very challenging.87 Although biochemistry analysis is the only current way to estimate hypoglycemia, post-mortem blood glucose levels have no diagnostic value in determining hypoglycemia. After death, the persisting cells still have the ability to metabolize blood glucose, which results in a rapid variable decrease in blood glucose levels, making the diagnosis of insulin-induced hypoglycemia difficult.88 Thus, in order to estimate ante-mortem glucose levels, according to Traube’s formula, a measurement of post-mortem glucose and lactate in both cerebrospinal fluid (CSF) and vitreous humor, and also hemoglobin A1c should be obtained. All these measurements are combined in a score, where a score of less than 50 is almost diagnostic of hypoglycemia.58 However, some studies suggested that the combined measurements of glucose and lactate in vitreous humor and CSF have no value in estimating blood glucose concentration before death.88 Yet, this cannot be evaluated by this systematic review since no data was reported in this regard. We found that the mean glucose levels in vitreous humor is 22.37, while 5.9 in CSF. These findings were limited to the few studies that had performed the biochemistry analysis in vitreous humor and CSF. Even though post-mortem analysis of insulin is challenging, fortunately, a new promising validated quantitative method has been introduced. It quantifies human insulin and its various analogues in samples obtained from post-mortem blood and tissues (kidney, liver, and skeletal muscles) with an accuracy reaching 70% up to 130%, using liquid chromatography-mass spectrometry with high-resolution mass spectrometry (LC-MS/HRMS) analysis. This method provides quantitative measures of both therapeutic and toxic levels of insulin. It was tested on several forensic cases, and it identified the insulin prescribed to the victims even though many types of insulin were undetermined before death. However, this assay has five steps for sample preparation (tissue sample size reduction, homogenization, extraction, concentration, and immunopurification), which is a very time-consuming process.89,90 Moreover, insulin is considered a large molecular weight substance, which makes it challenging to reach certainty of post-mortem insulin toxicity. For this, routine determination of insulin in post-mortem specimens is not offered frequently.91 This can explain the variation among the cases included in this systematic review where the results of insulin levels were ranging from negative to 1,848.8 mU/ml.\n\nOur review was subject to several limitations. First, evaluation of the accuracy of post-mortem glucose measurements could not be done since the included articles were mainly focusing on the characteristics of victims, interventions, and complications rather than detection of insulin overdose. Second, as post-mortem insulin analysis is a new method, data in case reports were limited in this regard. Thus, it is recommended that further research and assessment of the accuracy and feasibility of postmortem insulin analysis as it is a new promising method to detect insulin in suicide cases.\n\nOur findings regarding the demographic characteristics of suicides by insulin and attempted suicides advocate physicians to do routine psychological assessments among high-risk people, including individuals with diabetes, relatives of those with diabetes and healthcare providers. This will help in improving the preventative measures of suicide and decrease the burden of suicidality in the community. Furthermore, to diagnose patients who died by insulin suicide, post-mortem insulin analysis should be considered.\n\n\nConclusions\n\nInsulin overdose as a method of dying by suicide is not uncommon among those with diabetes, however, it can lead to unfavorable neurological sequelae and death. As the prevalence of diabetes mellitus is increasing worldwide and insulin is one of the medications used in the management, it is expected that self-poisoning with insulin will be also increased in both individuals with diabetes and those without diabetes. It is crucial that physicians suspect insulin self-poisoning as one of the differential diagnoses when an individual, with diabetes or without, presents with a coma or unexplained hypoglycemia especially if it is prolonged or recurrent. Evaluation and early management of psychiatric illnesses especially among those with diabetes, mainly depression, are some of the important measures that may prevent suicidality. In addition, easy access to insulin in those without diabetes in the case of individuals with relatives or friends who have diabetes, or among healthcare providers should be considered. Since post-mortem evaluation of insulin toxicity victims is challenging, attention needs to be given to developing a more accurate approach to establish and confirm the diagnosis of insulin poisoning. At the end, managing an individual who presents with intentional insulin poisoning should include a multidisciplinary team and be treated as a whole, from all aspects rather than managing only the individual’s presentation.",
"appendix": "Data 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 ‘Suicide by insulin: a systematic review’. https://doi.org/10.6084/m9.figshare.21762530. 92\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nSuicide: Online Referencing. 2021. (accessed 17 November 2021).Reference Source\n\nLee S, Dwyer J, Paul E, et al.: Differences by age and sex in adolescent suicide. Aust. N. Z. J. Public Health. 2019; 43: 248–253. Publisher Full Text\n\nBaca-Garcia E: Behavioral Neurobiology of Suicide and Self Harm. Switzerland;2020; pp. 89–115. Publisher Full Text\n\nDutheil F, Aubert C, Pereira B, et al.: Suicide among physicians and health-care workers: A systematic review and meta-analysis. PLoS One. 2019; 14: e0226361. 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PubMed Abstract | Publisher Full Text\n\nSchober E, Wagner G, Berger G, et al.: Prevalence of intentional under- and overdosing of insulin in children and adolescents with type 1 diabetes. Pediatr. Diabetes. 2011; 12: 627–631. PubMed Abstract | Publisher Full Text\n\nLöfman S, Hakko H, Mainio A, et al.: Characteristics of suicide among diabetes patients: a population based study of suicide victims in Northern Finland. J. Psychosom. Res. 2012; 73: 268–271. PubMed Abstract | Publisher Full Text\n\nDoǧan FS, Onur ÖE, Altinok AD, et al.: Insulin glargine overdose. J. Pharmacol. Pharmacother. 2012; 3: 333–335. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPalmiere C, Sabatasso S, Torrent C, et al.: Post-mortem determination of insulin using chemiluminescence enzyme immunoassay: preliminary results. Drug Test. Anal. 2015; 7: 797–803. PubMed Abstract | Publisher Full Text\n\nEssafi F, Aymen MR, Youssef B, et al.: Intentional Overdose with Insulin Glargine in a Non Diabetic Patient. J. Pharmacol. Clin. Toxicol. 2017; 5: 1081.\n\nStein D, Keller S, Ifergan IS, et al.: Extreme Risk-Taking Behaviors in Patients With Eating Disorders. Front. Psych. 2020; 11: 1.\n\nBalhara YP: Diabetes and psychiatric disorders. Indian J. Endocrinol. Metab. 2011; 15: 274–283. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrådvik L: Suicide Risk and Mental Disorders. Int. J. Environ. Res. Public Health. 2018; 15: 2028. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSarkar S, Balhara YP: Diabetes mellitus and suicide. Indian J. Endocrinol. Metab. 2014; 18: 468–474. PubMed Abstract | Publisher Full Text\n\nGoldston DB, Kovacs M, Ho VY, et al.: Suicidal ideation and suicide attempts among youth with insulin-dependent diabetes mellitus. J. Am. Acad. Child Adolesc. Psychiatry. 1994; 33: 240–246. PubMed Abstract | Publisher Full Text\n\nHarvey SB, Epstein RM, Glozier N, et al.: Mental illness and suicide among physicians. Lancet. 2021; 398: 920–930. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGerada C: Doctors and suicide. Br. J. Gen. Pract. 2018; 68: 168–169. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDuarte D, El-Hagrassy MM, Couto TC, et al.: Male and Female Physician Suicidality: A Systematic Review and Meta-analysis. JAMA Psychiat. 2020; 77: 587–597. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBehera C, Swain R, Mridha AR, et al.: Suicide by injecting lispro insulin with an intravenous cannula. Med. Leg. J. 2015; 83: 147–149. PubMed Abstract | Publisher Full Text\n\nGavrielatos G, Komitopoulos N, Kanellos P, et al.: Suicidal attempts by prescription drug overdose in the elderly: a study of 44 cases. Neuropsychiatr. Dis. Treat. 2006; 2: 359–363. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSoroosh D, Zakariaei Z, Azadeh H, et al.: Ocurrence of hypoglycemia in patients with benzodiazepines poisoning: A cross-sectional study. Ann. Med. Surg (Lond). 2021; 69: 102772. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTurner BC, Jenkins E, Kerr D, et al.: The effect of evening alcohol consumption on next-morning glucose control in type 1 diabetes. Diabetes Care. 2001; 24: 1888–1893. PubMed Abstract | Publisher Full Text\n\nKrebs HA, Freedland RA, Hems R, et al.: Inhibition of hepatic gluconeogenesis by ethanol. Biochem. J. 1969; 112: 117–124. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCryer PE. Symptoms of hypoglycemia, thresholds for their occurrence, and hypoglycemia unawareness. Endocrinol. Metab. Clin. N. Am. 1999; 28: 495–500. v-vi. PubMed Abstract | Publisher Full Text\n\nBoulagnon C, Garnotel R, Fornes P, et al.: Post-mortem biochemistry of vitreous humor and glucose metabolism: an update. Clin. Chem. Lab. Med. 2011; 49: 1265–1270. PubMed Abstract | Publisher Full Text\n\nPalmiere C: Postmortem diagnosis of diabetes mellitus and its complications. Croat. Med. J. 2015; 56: 181–193. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBottinelli C, Nicoli R, Bévalot F, et al.: Development and validation of a method for quantification of human insulin and its synthetic analogues in plasma and post-mortem sera by LC-MS/HRMS. Talanta. 2021; 225: 122047. PubMed Abstract | Publisher Full Text\n\nBottinelli C, Bévalot F, Cartiser N, et al.: Detection of insulins in postmortem tissues: an optimized workflow based on immunopurification and LC-MS/HRMS detection. Int. J. Legal Med. 2021; 135: 1813–1822. PubMed Abstract | Publisher Full Text\n\nLabay LM, Bitting CP, Legg KM, et al.: The Determination of Insulin Overdose in Postmortem Investigation. Acad Forensic Pathol. 2016; 6: 174–183. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAssad M, Alawami F, Khatem A, et al.:PRISMA checklist Suicide by insulin a systematic review.docx. [Dataset]. figshare. 2022. Publisher Full Text"
}
|
[
{
"id": "240289",
"date": "13 May 2024",
"name": "Fabio Del Duca",
"expertise": [
"Reviewer Expertise forensic 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 article deal with the insulin overdose as a cause of suicide. Insulin overdose is a relatively common method of suicide, particularly among individuals with diabetes. This is concerning due to the associated neurological complications and risk of death. Authors support that physicians should consider insulin self-poisoning as a potential cause when faced with a coma or unexplained hypoglycemia, especially if recurrent. Preventative measures must be added, including addressing psychiatric conditions, particularly depression, early on, and controlling access to insulin, especially in those without diabetes who may have connections to individuals with the condition. Due to the challenges in post-mortem evaluation, efforts should be directed towards developing more accurate diagnostic approaches for insulin poisoning. Managing intentional insulin poisoning requires a comprehensive, multidisciplinary approach, considering all aspects rather than focusing solely on the individual's immediate presentation.\nThe article is well written for this journal. I advice you to add this paper: [ Ref 1 ] In fact this paper seems to fit into your study, please add.\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",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-59
|
https://f1000research.com/articles/8-1165/v1
|
23 Jul 19
|
{
"type": "Study Protocol",
"title": "Protocol for the electroencephalography guidance of anesthesia to alleviate geriatric syndromes (ENGAGES-Canada) study: A pragmatic, randomized clinical trial",
"authors": [
"Alain Deschamps",
"Tarit Saha",
"Renée El-Gabalawy",
"Eric Jacobsohn",
"Charles Overbeek",
"Jennifer Palermo",
"Sophie Robichaud",
"Andrea Alicia Dumont",
"George Djaiani",
"Jo Carroll",
"Morvarid S. Kavosh",
"Rob Tanzola",
"Eva M. Schmitt",
"Sharon K. Inouye",
"Jordan Oberhaus",
"Angela Mickle",
"Arbi Ben Abdallah",
"Michael S. Avidan",
"Canadian Perioperative Anesthesia Clinical Trials Group",
"Tarit Saha",
"Renée El-Gabalawy",
"Eric Jacobsohn",
"Charles Overbeek",
"Jennifer Palermo",
"Sophie Robichaud",
"Andrea Alicia Dumont",
"George Djaiani",
"Jo Carroll",
"Morvarid S. Kavosh",
"Rob Tanzola",
"Eva M. Schmitt",
"Sharon K. Inouye",
"Jordan Oberhaus",
"Angela Mickle",
"Arbi Ben Abdallah",
"Michael S. Avidan",
"Canadian Perioperative Anesthesia Clinical Trials Group"
],
"abstract": "Background: There is some evidence that electroencephalography guidance of general anesthesia can decrease postoperative delirium after non-cardiac surgery. There is limited evidence in this regard for cardiac surgery. A suppressed electroencephalogram pattern, occurring with deep anesthesia, is associated with increased incidence of postoperative delirium (POD) and death. However, it is not yet clear whether this electroencephalographic pattern reflects an underlying vulnerability associated with increased incidence of delirium and mortality, or whether it is a modifiable risk factor for these adverse outcomes. Methods: The Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES-Canada) is an ongoing pragmatic 1200 patient trial at four Canadian sites. The study compares the effect of two anesthetic management approaches on the incidence of POD after cardiac surgery. One approach is based on current standard anesthetic practice and the other on electroencephalography guidance to reduce POD. In the guided arm, clinicians are encouraged to decrease anesthetic administration, primarily if there is electroencephalogram suppression and secondarily if the EEG index is lower than the manufacturers recommended value (bispectral index (BIS) or WAVcns below 40 or Patient State Index below 25). The aim in the guided group is to administer the minimum concentration of anesthetic considered safe for individual patients. The primary outcome of the study is the incidence of POD, detected using the confusion assessment method or the confusion assessment method for the intensive care unit; coupled with structured delirium chart review. Secondary outcomes include unexpected intraoperative movement, awareness, length of intensive care unit and hospital stay, delirium severity and duration, quality of life, falls, and predictors and outcomes of perioperative distress and dissociation. Discussion: The ENGAGES-Canada trial will help to clarify whether or not using the electroencephalogram to guide anesthetic administration during cardiac surgery decreases the incidence, severity, and duration of POD. Registration: ClinicalTrials.gov (NCT02692300) 26/02/2016",
"keywords": [
"EEG suppression",
"geriatric outcomes",
"postoperative delirium",
"cardiac surgery",
"anesthetic management",
"cardiopulmonary bypass",
"volatile anesthetics",
"perioperative risk factors"
],
"content": "Background\n\nPostoperative delirium (POD) is an acute and typically reversible syndrome, characterized by a fluctuating level of consciousness and disturbances in attention and cognition1. Patients undergoing cardiac surgery are at especially high risk of developing POD2–9. The incidence of POD after cardiac surgery is estimated to be between 20% and 70% depending on the population studied and the methods used to assess delirium2–9. Delirium has been described either as hyperactive or hypoactive, the latter being more difficult to diagnose in the clinical setting than the former1. As one of the most common complications after cardiac surgery in older adults, POD is associated with prolonged length of hospital and intensive care unit (ICU) stay, increased morbidity and mortality, functional and cognitive decline, and is often associated with placement in long-term care facility6,7,10.\n\nSeveral non-modifiable risk factors at the time of surgery are associated with POD including age 60 years and older, preexisting cognitive impairment, psychiatric comorbidities, and low baseline regional cerebral oxygen saturation8,9,11–13. Possible precipitating risk factors specific to cardiac surgery include the type of cardiac surgery, cardiopulmonary bypass time, and the number of blood product transfusions7,9. The identification of potentially modifiable perioperative risk factors, for example relating to the conduct of general anesthesia for cardiac surgery7, could positively impact this major health issue.\n\nWhile the use of processed electroencephalogram (EEG) indices to monitor depth of anesthesia is relatively prevalent in the anesthesiology community, these have mainly been directed towards avoiding patient awareness during surgery14–16. Recent interest has shifted to the potential for intraoperative EEG monitoring to prevent postoperative delirium17,18. The notion is that there might be specific EEG patterns that are strongly associated with POD, and these can be avoided through alterations in anesthetic management. One of these patterns is burst suppression, which is characterized by an isoelectric or suppressed EEG pattern followed by a short burst of high amplitude activity. Burst suppression is considered to be “a strong synchronized outflow of thalamic discharges to a widely unresponsive cortex”19. Burst suppression is not encountered in normal physiological conditions such as sleep, but is associated with coma, induced hypothermia, some forms of epilepsy, cerebral hypoxia, and deep general anesthesia20. Both the occurrence of burst suppression and the cumulative duration of EEG suppression during general anesthesia have been associated with POD, but without clear evidence for causality3,21,22. The risk for burst suppression during general anesthesia might be increased by older age, medical comorbidities, a greater intraoperative dose of benzodiazepines, and, most importantly, increased intraoperative volatile or intravenous anesthetic concentration3,21. The combination of EEG suppression and hypotension has been associated with increased mortality at 90 days post-surgery23. We therefore hypothesized that intraoperative guidance of anesthesia with the aim of avoiding or minimizing EEG suppression could decrease the incidence of POD in cardiac surgery patients. Evidence for this hypothesis is bolstered by recently published meta-analyses of randomized trials, which reported that using a processed EEG monitor to guide anesthetic administration is likely to substantially decrease the incidence of POD7,24,25. While a recent randomized controlled trial using a strategy to avoid EEG suppression in older adults undergoing major surgery was not shown to be effective in decreasing the incidence of POD26, this strategy has not been tested specifically in older cardiac surgery patients, a population with many risk factors and a high incidence of POD.\n\nThe intent of the ENGAGES-Canada study is to determine if EEG-guided anesthesia to reduce anesthetic agent administration, thereby minimizing episodes and durations of EEG suppression, can effectively decrease the incidence of POD and its downstream sequelae in patients undergoing cardiac surgery (Table 1). The approach of minimizing periods of EEG suppression specifically during cardiac anesthesia has not been previously tested in a large clinical trial. Recently published meta-analyses have suggested that EEG guidance of anesthesia decreases the incidence of POD by more than a third25. If this result is reproduced in subsequent rigorous clinical trials, it will have important implications for how anesthesia is administered – especially to older adults. On the other hand, premature implementation based on the existing preliminary evidence might have unintended negative consequences. It is within this context that the ENGAGES trial and ENGAGES-Canada will provide critically clarifying information27,28. The ENGAGES trial addressed the question in unselected older adults undergoing major surgery26. ENGAGES-Canada will address the question specifically in cardiac surgery patients, where the risk of POD is especially high2–9.\n\nAssessment acronyms: EEG – Electroencephalogram; ICU – Intensive Care Unit.\n\nThus, the objective of the ENGAGES-Canada trial is to address whether reducing anesthetic administration based on EEG information during cardiac surgery primarily decreases the incidence of POD, and secondarily decreases the duration and severity of POD. Other relevant measures in the trial will be clinically relevant outcomes determined at the index hospitalization, at approximately 30-day postoperatively, and at approximately 1-year postoperatively.\n\n\nMethods\n\nThe Research Ethics Boards of the Montreal Heart Institute (2017-2164), the University of Manitoba (HS18290), Kingston University (ANAE-298-16), and the University of Toronto (17-5933) all approved the study. The details of the design of the ENGAGES-Canada study are included in this protocol and it contains the complete list of elements from the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) checklist29,30. This study was registered with ClinicalTrials.gov (NCT02692300) on 26 February 2016.\n\nThe ENGAGES-Canada will randomize 1200 patients of 60 years old and older in a clinical trial designed to be pragmatic. The first patient randomized in the trial was enrolled in November 2016. Competent patients who provide informed consent and who are undergoing elective cardiac surgery with cardiopulmonary bypass are eligible to be included in the study. There are no absolute contraindications to EEG monitoring, and the design of the ENGAGES-Canada trial is largely pragmatic. Exclusion criteria include positive preoperative delirium screening. In addition, patients with hearing impairment, and those who are blind, illiterate, or do not speak French or English will be excluded because they will not be able to participate adequately in delirium screening. Finally, patients who have previously had general anesthesia and who have reported experiencing intraoperative awareness will also be excluded31.\n\nParticipants are randomized to either one of two groups: in the guided group, anesthetic administration is guided largely by EEG waveform; in the other group, patients receive current usual anesthetic care for cardiac surgery. Delirium and other assessments take place preoperatively, and delirium is assessed postoperatively from day one to five while the patient is in the hospital. The primary outcome will be the incidence of postoperative delirium. As secondary and other outcomes, we will also examine stress reaction and dissociation at discharge as potential factors associated with delirium and predictors of postoperative psychiatric symptoms. At 30-days and at 1-year, follow-up assessments include the quality of life as related to health, cognitive functioning, and information on psychiatric symptoms and on the incidence of falls – collected via self-report.\n\nAll patients in the study are asked to sign an informed consent (see extended data32). Subjects are recruited through the Pre-Anesthesia Clinics, and baseline questionnaires are given at that time if they agree to participate. Perioperative clinics are staffed with anesthesiologists and nurses specialized in perioperative medicine to evaluate the perioperative risks of each patient. Patients can also be enrolled prior to surgery in hospital wards during the preoperative visit.\n\nBased on data from previous clinical trials including those focused exclusively on cardiac surgery2,8, we expect the study population to be largely balanced based on sex and there is no stratification of randomization by sex. Older and more vulnerable patients are often under-represented in clinical research. The patients enrolled in the trial should constitute a broad representation of older adults undergoing cardiac surgery in Canada.\n\nComputer-generated assignment at the patient level is used for randomization. Patients who are eligible, and have given informed consent, are randomized to either usual care or to the protocol for guided anesthesia according to the EEG. A one to one ratio of randomization of the patients between usual care and the protocol for EEG-guidance is used. Within the research team, members are trained to enroll participants and assign the randomization between the usual care or the protocol for EEG-guidance. Anesthesiologists and their team learn of the group assignment after the patient is brought into the operating room; an opaque, sequentially numbered, sealed envelope is opened to reveal the study group. The randomization sequence is generated by the data analysis center. The anesthesiologist and the team caring for the patient intraoperatively are not blinded to the group assignment. The patients and family members are not aware of the group assignment. The research team members who are in charge of the assessment of delirium postoperatively remain blinded to the group assignment. Chart reviews are conducted by individuals blinded to the group assignment and blinded to the outcome of the postoperative delirium assessments29,30. Predictability of the randomization sequence is minimized by recording in a separate document, unavailable to the members of the research team who enroll participants and assign groups, the details of patients who have already been randomized.\n\nPatients randomized to the EEG-guided group undergo anesthesia based on a pragmatic protocol to guide anesthesia administration according to EEG information. Prior to study participation, anesthesiologists are trained to recognize the typical EEG patterns of the different levels of anesthesia seen during anesthesia with volatile anesthetic agents; from the pattern in awake patients to the pattern typically found during general anesthesia. Practitioners are also encouraged to complete the online training provided on the website www.anesthesiaEEG.com as well as to watch two educational modules on the website www.icetap.org: one on waveforms of EEG and depth of anesthesia, and the other on Clinical decision making in anesthesia using the EEG. For sites using BIS processed electroencephalogram monitors, the proprietary processed BIS value is used in the EEG-guided group for the trial, as well as the raw waveforms of the EEG and all the numerical values seen on the monitor that are non-proprietary. These include the spectral edge frequency and the burst suppression ratio. For sites using a SedLine® monitor, the processed Patient State Index (PSi) in the EEG-guided group is used as well as the raw EEG waveform, spectrograms and suppression ratio. For sites using the NeuroSENSE® monitor, the processed WAVcns in the EEG-guided group is used as well as the raw EEG waveform, spectrograms and suppression ratio. To see clearly the low frequency slow delta waves, the EEG filter is turned off. If there is too much artifact in the EEG signal, practitioners may intermittently turn on the EEG filter to improve the resolution of the EEG trace. The anesthesiologists and their team are advised to inspect the waveform of the EEG to detect when there are periods of EEG suppression. EEG suppression can usually be recognized easily, and this pattern represents the main trigger, according to the protocol, for decreasing anesthetic administration. The low alarm is set at a value of 40 on the BIS monitor and NeuroSENSE® monitor or 25 on the SedLine® monitor. The sounding of this low alarm indicates an increased risk of a burst suppression pattern on the EEG (see PSI 25-50 white paper)33. EEG index values less than manufactures’ recommendations (BIS and WAVcns values less than 40 or a PSi less than 25) indicate a second trigger for decreasing the administration of anesthetic agents. It is important to remember that the protocol of guidance of anesthesia according to the EEG waveform is suggestive and not prescriptive. Clinical judgment can inform deviations from the protocol according to the specific situations encountered. For all patients, regardless of the allocation group, the low volatile alarm (0.3 minimum alveolar concentration or clinician’s discretion) sounds to decrease the risk of intraoperative awareness. In the usual care group, the EEG monitor values are masked from the anesthesia team, except for the signal quality measures, and the data are stored for analysis of epochs of EEG suppression. For sites using the BIS monitors and NeuroSENSE® monitors, anesthesiologists see the signal quality index (SQI) only and for sites using the SedLine® monitor practitioners only see the impedance quality of the electrodes.\n\nMonitoring devices can only influence and change clinical practice if important and useful information can be used by clinicians to make decisions regarding patient treatment during a case. Motivation to make decisions and act upon data from a monitoring device relies on familiarity with the device as well as evidence relating to outcomes. The use of EEG guidance of anesthesia in clinical practice is limited by the fact that electroencephalography is not formally part of the current residency curriculum. It is therefore not surprising that EEG guidance of anesthesia has not been adopted into usual anesthetic care. Focused training sessions have shown that anesthesiologists can readily learn the changes in EEG waveform associated with sedation and general anesthesia34. Clinicians are capable of integrating the information from the EEG waveform when provided with clinical context and of estimating the BIS values associated with specific EEG waveforms34. Arising from the results of this study, an international non-profit initiative focused on EEG education was launched: International Consortium for Electroencephalograph Training of Anesthesia Practitioners.\n\nTeaching the EEG waveform to anesthesiologists at our institutions and emphasizing the role of EEG in the guidance of anesthetic management are crucial ingredients to the success of the ENGAGES-Canada study. EEG derived parameters are captured electronically. This includes both the proprietary values, such as the BIS, WAVcns and PSi values, and non-proprietary values such as the suppression ratio. As a proof of concept, we were able to show in the first 102 patients enrolled to the ENGAGES-Canada trial that there was a reduction in both cumulative EEG suppression time and volatile anesthetic administration in the patients randomized to EEG-guided anesthetic care. Since our fundamental hypothesis for the ENGAGES-Canada study is that, in real-world practice, alterations in the management of anesthesia guided by the EEG waveform can prevent postoperative delirium, a crucial step was to confirm the ability of cardiac anesthesiologists to decrease the duration of EEG suppression by following the EEG-guided protocol.\n\nThe primary outcome is the occurrence of incident delirium on postoperative days 1-5. Secondary outcomes include: length of ICU and hospital stay; duration and severity of delirium POD 1-5; incidence of falls and association between delirium and falls at 30 days and at 1 year; association between delirium and quality of life by PROMIS Global Health; predictors of Post-Traumatic Stress Disorder (PTSD) by PDEQ at 5 days and 30 days postoperatively; and predictors of Post-Traumatic Stress Disorder (PTSD) by PDEQ at 5 days and 30 days postoperatively. Exploratory outcomes include co-variates of delirium, functionality, and cognitive impairment at 30 days and at 1 year postoperatively. Pre-specified exploratory analyses include intraoperative mediating events such as anesthetic concentrations, electroencephalogram suppression time, and hypotension duration. Perioperative adverse events include undesirable intraoperative movement, awareness with recall, complications such as major blood loss and transfusions, stroke, sternal wound infection, sepsis, dialysis, prolonged intubation, and mortality rates at 30-day and at 1-year.\n\n\nData collection\n\nPreoperative assessments are performed in the Pre-Anesthesia Clinic or hospital ward. These include demographic information and medical history, assessment of preoperative quality of life, psychiatric symptoms (i.e., anxiety, depression, alcohol use, trauma history, and posttraumatic stress disorder), objective and subjective cognitive functioning measures35,36, and evaluation of falls’ history. The purpose of the preoperative assessments is to identify cognitive and psychiatric disorders in order to better understand risk factors for postoperative delirium and its sequelae. For example, postoperative delirium has been associated with impaired performance on preoperative cognitive tests37, and postoperative delirium predicts persistent postoperative cognitive decline6. These known risk factors will be included in covariate analysis for the primary outcome and will be used in exploratory analyses. The following measures were selected for the assessment of cognitive and psychiatric symptoms based on their brevity, frequency of use in medical practice, validity for older adults, and lack of copyright restrictions: (1) 8-item AD8 Dementia Screen38, (2) History of Delirium Screen, (3) Short Blessed Test39, (4) 3-item Alcohol Use Disorders Identification Test (AUDIT-C), (5) 1-item surgical anxiety visual analogue scale, (6) Trauma History Screen, (7) Posttraumatic Stress Disorder Checklist (PCL-5; past-month PTSD assessment), (8) 4-item Primary Care PTSD Screen (PC-PTSD; lifetime PTSD assessment), (9) 4-item Patient Health Questionnaire (PHQ-4; anxiety and depressive symptoms), (10) 10-item Patient Reported Outcomes Measurement Information System (PROMIS) Global Health (physical and mental health related quality of life), (11) 4-item PROMIS Applied Cognition-Cognitive Concerns, (12) 4-item PROMIS Applied Cognition-Abilities (see extended data32). Patients will also receive a questionnaire regarding history of falls. Baseline screening, informed consent, delirium assessments (described below), and self-report symptom measures take approximately 30-40 minutes. Research assistants obtain informed consent and administer AD8 Dementia Screen, History of Delirium Screen, Confusion Assessment Method (CAM long form; detailed below), and the Short Blessed Test; the remaining surveys can be completed independently if the patient has the capacity to do so. A script is provided to research assistants to introduce the psychiatric symptom measures (extended data32). If patients request a direct referral for mental health related issues, they are referred to the appropriate clinician by the attending anesthesiologist in the Pre-Anesthesia Clinic.\n\nDelirium and pain are assessed postoperatively in the afternoon/evening while patients are in the hospital. Daily delirium assessments collected specifically for the ENGAGES-Canada study are entered into the Washington University School of Medicine Research Electronic Data Capture (REDCap)40 database. EEG data, including BIS values, WAVcns, PSi values, and duration of EEG burst suppression are collected in both the guided as well as in the usual care group. In the usual care group, anesthesiologists are blinded to EEG data41,42. Perioperative data, including the repeated measures data, are saved for analysis from the intraoperative electronic data capture. As part of the routine data collection, we obtain for each patient a detailed medical history, surgical history, specific risk factors, medications, Blessed Dementia rating scale, screening for sleep apnea, laboratory values, medications during surgery, physiological readings, and parameters from the postoperative recovery period. At the time of discharge, patients will also complete a measure of immediate stress reactions (13-item Peritraumatic Distress Inventory; PDI) and peritraumatic dissociation (10-item Peritraumatic Dissociative Experiences Questionnaire; PDEQ) in the perioperative period, which have been found to be strong predictors of incident psychiatric disorders immediately following the stressful experience. Furthermore, they will complete an adapted 4-item PHQ-4 concerning more general anxiety and depressive symptoms, specifically during the perioperative period. These tests take patients approximately 5 minutes in addition to their CAM long form assessment (10 minutes).\n\nThe primary outcome of the study is the incidence of postoperative delirium. Assessment of postoperative delirium is conducted in patients that can be sufficiently aroused according to a Richmond Agitation and Sedation Score ≥ -3. Assessment of patients for delirium is performed from day one to day 5, once daily, in the afternoon/evening. A diagnosis of delirium for each patient is based on an approach combining a standardized daily assessment with a structured chart review. Members of the research team who are blinded to the treatment arm of the study assess patients for delirium using the Confusion Assessment Method (CAM long form)43, or the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)44,45 for patients who are unable to speak (e.g., have a tracheal tube or tracheostomy). The CAM long form is deemed a viable tool that can be used by non-psychiatrists and by non-mental health professionals for delirium detection43. The CAM long form has subsequently been validated in a number of studies and against a reference standard, with a sensitivity of >94% and a specificity of >89%46. The CAM long form and the CAM-ICU are reliable instruments in good agreement with the DSM-IV criteria for delirium45,47,48. To complete the delirium assessment of patients, a trained clinical researcher blinded to the CAM results and group assignment conducts a structured chart reviews for delirium detection. A positive CAM long form, or CAM-ICU, or chart review delirium detection49,50 is deemed sufficient and necessary to diagnose incident delirium in the ENGAGES-Canada trial. The approach combining a CAM long form interview, or a CAM-ICU, plus a chart review results in an increase in the sensitivity while retaining specificity in detecting incident delirium49,50. In addition, use of a chart review bolsters the pragmatic aspects of this trial, since it obtains information from a readily available source. Determination of delirium severity is based on the CAM-S long form measure or the CAM-ICU-7 Delirium severity instrument51,52.\n\nThe CAM long form assessment that is used in the trial was developed by Dr. Inouye and colleagues43, and includes a brief cognitive battery. All study team members who perform delirium assessments undergo a structured training process. For the initial training, representatives from the research team participated in a full-day training program led by Dr. Inouye, the original creator of the CAM long form53. Those who attended this initial training are overseeing the training of other team members. Trainees must demonstrate competence at both conducting CAM long form and CAM-ICU interviews and in scoring these interviews. To establish their ability to score CAM long form interviews, trainees accompany trained team members to conduct CAM long form interviews. A trained member of the research team conducts each CAM long form interview for patients enrolled in the trial. The trainee observes the interview, but scores the CAM long form independently. The trainee must agree with the trainer on the presence or absence of all 12 cognitive features assessed by the CAM long form on a minimum of two delirious and two non-delirious patients. After meeting the stipulations of training, the newly trained team member will conduct their first interview of a patient enrolled into the trial in the presence of a previously trained team member. Independently of the training, all team members who are participating in CAM long form assessments must view and rate nine videos of standard interviews of actors depicting delirious and non-delirious patients. Research team members must be trained on CAM long form assessments prior to completing any structured delirium chart reviews.\n\nThis structured process is employed to evaluate and confirm the quality of the assessments of delirium. In all cases the assessments of delirium are reviewed within three days by a fellow member of the research team to evaluate internal consistency of scoring and completeness. Once a month, all challenging delirium assessments are discussed in a conference call including investigators from all sites. Whenever there is ongoing disagreement regarding a CAM long form, CAM-ICU or delirium chart review, these are allocated to experts for adjudication (involving ES, SI). Ongoing interrater-reliability assessments of all study staff are planned annually. A random selection of CAM long form, CAM-ICU, and structured chart reviews are sent to experts for quality control purposes.\n\nSelf-report psychiatric and cognitive symptom measures are either mailed to patients 30-days post-surgery with a stamped and addressed return envelope, sent by e-mail, or obtained through a telephone call. The following measures are re-administered: Falls Questionnaire, AUDIT-C, PDEQ, PCL-5, PHQ-4, PROMIS Global Health, PROMIS Applied Cognition-General Concerns, and PROMIS Applied Cognition-Cognitive Abilities. These tests take approximately 15 minutes for patients to complete.\n\nSelf-report psychiatric and cognitive symptom measures are either mailed to patients 1-year post-surgery with a stamped and addressed return envelope, sent by e-mail, or obtained through a telephone call. The following measures are re-administered: Falls Questionnaire, AUDIT-C, PCL-5, PHQ-4, PROMIS Global Health, PROMIS Applied Cognition-General Concerns, and PROMIS Applied Cognition-Cognitive Abilities. Additionally, patients are contacted via phone and receive the Short Blessed Test. These tests take patients approximately 15 minutes to complete by writing. The phone call for the Short Blessed Test lasts approximately 3 minutes.\n\nBased on previous studies in cardiac surgery patients, we conservatively estimated a delirium incidence in the control group of 25%2–9 and based on meta-analyses of randomized trials we estimated a relative reduction in delirium with guidance of anesthesia based on EEG waveform of more than one-third3,7,24. Assuming a two-sided alpha <0.05 and 1200 patients, we estimated >90% power to be able to detect an absolute decrease in the incidence of delirium of 8%27. With a more stringent two-sided alpha <0.005, we estimated >70% power. We anticipate that most patients will be available for primary outcome ascertainment (i.e. incident postoperative delirium assessment). Continuous variables will be presented as mean (SD) or median (interquartile range [IQR]), depending on their distributions. Chi-square or Fisher’s exact tests will be used for comparisons of discrete data. Unpaired Student’s t or Mann–Whitney U tests will be used for comparisons of continuous data, depending on their distributions. Confidence intervals for median differences will be calculated using Hodges-Lehmann estimates, and for differences between proportions we will use Newcombe’s method with continuity correction54. For the primary outcome, the proportion of patients with incident postoperative delirium will be compared between the two study groups. We will conduct three post-hoc sensitivity analyses to assess whether improved clinician fidelity to the guided protocol might alter the primary outcome. Within the guided group 25% of cases will be excluded with the (1) longest cumulative electroencephalogram suppression time; (2) longest cumulative time with BIS, WAVcns <40 or PSi <25; and (3) highest median volatile anesthetic concentrations. To compare time to delirium onset between groups, we will construct Kaplan-Meier curves for each group and conduct a log-rank test. We will perform a covariate adjustment including likely risk factors for delirium (including age, sex, history of depression, history of delirium, AD* Test, Short Blessed Test, comorbidity index, and study center) using two methods: (1) logistic regression and (2) standardized estimator combined with bootstrapped 95% confidence intervals (CIs)55. We will compare delirium incidence between groups, segregated by Charlson Comorbidity Index categories56. Patients will be assessed based on their randomization group in accordance with an intention-to-treat approach. We will also conduct a per protocol sensitivity analysis: when clinicians in the usual care group view EEG data, these patients will be included in the guided group; and where there are technical difficulties in viewing electroencephalogram data in the guided group, these patients will be included in the blinded group. Patients who cannot be assessed for delirium will be excluded from the primary outcome analysis. In two sensitivity analyses, these patients (unless they die during surgery) will either all be assumed to have had incident delirium or not to have had incident delirium. We will compare preoperative characteristics between respondents and alive non-respondents to 30-day postoperative surveys. We will do the same for the 1-year postoperative surveys. Results will be presented with 95% CIs. All significance testing will be two-sided, with P values <0.05 considered as providing suggestive evidence and P values <0.005 as providing more compelling evidence57. The statistical analyses will be performed with SAS, V.9.4 (SAS Institute, Cary, North Carolina) and/or STATA, V.14.2 (StataCorp LP, College Station, Texas).\n\nEstimations of the primary outcome (incidence of delirium) was used for the calculation of the overall sample size of our study. For secondary analyses, it is assumed that 80% (∼1000 patients) of the trial population will have completed the 30-day and 1-year follow-up survey. With a sample size of 1000 patients, it should be possible to detect a difference of 0.5 points (SD of 2.5) in mean score of the Physical Health Score from baseline to 30-day and 1-year follow-up survey between the usual care and guided group with a power of >80% and a 2-sided alpha level of p<0.05. Secondary outcomes and exploratory analyses will be examined in a number of ways; including multivariable regressions.\n\nStrengths. Several important strengths can be ascribed to the ENGAGES-Canada study. The clinical trial is randomized, pragmatic, includes high volume sites, and is conducted in real life settings. The interventions to avoid EEG suppression are easily implemented and the primary outcome, the incidence of delirium, is of tremendous importance to patients, health care systems and society. In relation to the primary outcome (delirium incidence), the CAM instrument has been validated against reference standard DSM-IV and DSM-IV-TR criteria in multiple studies, and has been appraised as one of the two most reliable instruments for detecting delirium in a research context58. The CAM long form has been demonstrated to have excellent psychometric properties for both hypoactive and hyperactive delirium59. Programmatic training, coupled with the highly structured use of the CAM long form (as we are doing in the trial), has demonstrated excellent inter-rater reliability of researchers28,60. In addition, by complementing the CAM long form (or CAM-ICU) with validated chart review50, we are bolstering delirium detection and minimizing missing primary outcome assessments. Since many components of the study are already incorporated into existing processes and infrastructures at participating Canadian sites, its implementation can be efficient. Enrollment is easily achieved within the flow of the clinic. The study is largely conducted by anesthesiologists and is integrated into the course of their clinical workday. Randomization is implemented in the operating room at the point of patient care because the anesthesia protocols do not require any advanced preparation or lead-in time. Enrollment of vulnerable patients 60 years old and older allows us to study a population that is understudied in clinical research. The importance of studying and understanding this targeted population lies in the potential of significant benefits from reducing the incidence of postoperative delirium and its related outcomes. Secondary outcomes such as patient-reported health-related quality of life factors are especially relevant to older patients who remain a largely understudied population. Trial feasibility is enhanced by the participation of investigators from multiple disciplines, who as a group has managed to establish a track record of successful collaboration and the completion of several major clinical trials (Canadian PACT group61–63). Since EEG guidance of anesthesia is straightforward and inexpensive, positive results from the study could provide strong effectiveness evidence, and would facilitate implementation, sustainability and dissemination of the EEG-guided protocol on a national level in Canada, as well as in other countries.\n\nLimitations. Some limitations for the trial should be considered. The EEG-guided protocol can only be effective if anesthesiologists adhere to it. Including patients in a clinical trial aiming at the prevention of the incidence of postoperative delirium and providing patients and family members with educational material on the subject could possibly decrease the incidence of postoperative delirium. Three methods of assessment will be used to diagnose postoperative delirium, a pragmatic structured chart review, the full CAM and the CAM-ICU. The CAM-ICU has a decreased sensitivity compared to the CAM long form. However, the CAM-ICU is broadly used and has been validated for patients who are unable to speak (i.e., with a tracheostomy or a breathing tube in place). Available data from participating centers indicate that the vast majority of patients enrolled in the in the study will be extubated within the first 48 hours. As a result, delirium assessment will usually be obtained with the more specific and sensitive instrument – the CAM long form. Since the 30-day and the 1-year follow-ups for patient are based on self-report outcome measures, a potential limitation is an incomplete follow-up at these periods in time. Consequently, a sensitivity analysis was performed in our power calculations to take into account this possible attrition (80% response rate at 30-day and at 1-year). We plan to improve follow-up by contacting patients first by mail and, if unsuccessful, by e mail or telephone calls. Postoperative delirium could be missed with recurrent assessments because it is well known to be a fluctuating disorder. In our efforts to minimize missed diagnosis of postoperative delirium, we have included a structured chart review. This validated complementary approach has been shown to increase the detection of postoperative delirium49,50.\n\nBenefits. If our hypotheses are confirmed, patients randomized into the group with the EEG-guided anesthesia will have a greater chance of avoiding postoperative delirium and its consequences’ downstream; including decrement in quality of life, falls, and cognitive decline. Evaluation of any potential unanticipated negative effects of EEG-guidance by investigating this range of psychiatric, cognitive, and functioning outcomes will also be possible.\n\nRisks. There are few risks associated with this study. Breach of confidentiality is a rare risk. Psychiatric symptom self-report measures may also cause patients temporary distress, but it may also provide the opportunity for distressed patients to obtain community mental health resources and/or appropriate referral. EEG guidance of anesthesia poses a theoretical risk of intraoperative movement and/or awareness with recall. Nevertheless, previous studies have not found an increased incidence of awareness with randomization of patients to protocols using EEG guidance of anesthesia14,15,64. In our study, intraoperative awareness with recall will be tracked within 48 hours of extubation postoperatively with a modified Brice interview65 (see extended data32). Review of adverse events by a data-safety monitoring committee and the PI, in consultation with the institutional review board, might lead to the recommendation to stop the trial in the event of increased reporting of intraoperative awareness in the EEG-guided group. In the informed consent for this study, patients are made aware of the rare risk of intraoperative awareness with recall. Serious side effects will be reported to the Ethics Committees and to the study’s data safety monitoring board. There is no financial compensation for the participating patients and all expenses related to the study are incurred by the participating research sites.\n\nMembers of the research team will share protected and necessary health information. Confidentiality will be protected by storing charts in locked cabinets located inside locked research offices. Demographic information and electronic data will be password-protected on an electronic database and will be stored on the network drive of the participating sites. Computers accessing this network will also be password-protected. This information will be entered by a designated member of the research team. The documents and data used for evaluation or statistical analyses will only contain coded numbers. Patients are free to decline participation in the study without penalties for the care they receive. Data management and processing will be done by the Division of Biostatistics Informatics Core at Washington University. Washington University is part of a consortium of institutional partners working to provide clinical trial data and management of research through a software toolset and workflow methodology for electronic collection. REDCap (Research Electronic Data Capture) data collection projects rely on a thorough study-specific data dictionary defined in an iterative self-documenting process by all members of the research team with planning assistance from the Division of Biostatistics Informatics Core. A well-planned data collection strategy for individual studies results from an iterative development and testing process. REDCap servers are securely housed in an on-site limited access data center managed by the Division of Biostatistics at Washington University. All web-based information transmission is encrypted. The data is stored on a private network, firewall-protected. Individual user identifiers and passwords are given to all users with restricted access depending on the specific role in the study. REDCap was developed specifically around HIPAA-Security guidelines, and is implemented and maintained according to University guidelines. More than 500 academic and/or non-profit consortium are supported by REDCap on 6 continents and 38,800 research end-users.\n\nAdverse events during the study will be monitored by the research team. If a serious adverse event (SAE) occurs, it will be directly reported to the REB in accordance with REB stipulations. For this pragmatic study, the safety monitoring plan seems appropriate. We conducted three large clinical studies where EEG-guided general anesthesia was given to half of the 28,000 patients studied. From these studies, no adverse events were attributable to EEG-guided anesthesia14,15,64. There is therefore no reason to think that adverse events attributable to EEG-guided anesthesia would occur in the present study. Since this is a low risk trial, the study has an appropriate data and safety-monitoring plan. The Data Safety Monitoring Board (DSMB) provides oversight of the ENGAGES-Canada Clinical Trial. The DSMB will examine data for the safety of the participants and will review the general conduct of the study66. Recommendations will be made by the DSMB regarding the modification, continuation, or termination of the study67. The expertise of the DSMB members will allow examination the cumulative data, protection of the integrity of the clinical experiments to which the patients have consented to participate, and to assure the regulatory bodies and the public that conflicts of interest do not compromise either patient safety or trial integrity68. An annual review of the safety events will be conducted by the DSMB. The DSMB may advise to stop the trial for safety concerns, but not for reasons of efficacy or because of futility66. Implausibly large treatment effects are found in trials that stop early for benefit, especially with small number of events69. Trials that have terminated early show greater effect sizes compared to trials that are continued, independent of existing statistical rules for terminating the trial70.\n\nEarly stoppage of the trial. On average, we can assume that patients in the group with EEG-guided anesthesia will receive, on average, lower concentrations of inhaled anesthetic agents during surgery. Studies using similar strategies have been reported without increased incidents related to intraoperative awareness with recall71,72. Nevertheless, we cannot exclude the possibility that patients receiving lower concentrations of inhaled anesthetic agents could experience a higher incidence of intraoperative awareness. Therefore, it will be necessary to compare the incidence of intraoperative awareness between groups in the trial. We recommend to the DSMB that this occurs at mid-point during the study (600 patients). Results from a one-tailed comparison of the incidences of awareness between the groups showing an increased incidence of awareness in the EEG-guided group (with a p value <0.05) will result in consideration by the DSMB to terminate the study. The severity of the awareness experiences; including reports of pain, paralysis, and distress could be taken into consideration by the DSMB73. Furthermore, other measures of peritraumatic distress and dissociation are administered at discharge, which will further allow for an evaluation of severity of awareness. Besides intraoperative awareness, a lower administration of inhaled anesthetic agents is not hypothesized to result in adverse outcomes that would be clinically important such as death, myocardial infarction, and/or stroke. Other events that could be associated with decreased anesthetic administration include intraoperative patient movement and higher intraoperative blood pressure and/or heart rate. These measures have unclear clinical relevance if not related to more severe adverse events and, as such, should not influence the decision to stop the study early.\n\nIt is recommended that an interim efficacy analysis of EEG guidance should not be performed by the DSMB with respect to the primary outcome of incident delirium. Some data support the hypothesis that EEG-guided anesthesia decreases the incidence of postoperative delirium, but other data do not support this hypothesis7,72,74,75. A higher incidence of postoperative delirium in the EEG-guided group would conflict with the results of current studies. The results of a partially completed trial would therefore be unlikely to provide compelling evidence to influence future clinical practice for anesthesia guided by EEG waveform in this patient population.\n\nAll major changes to the protocol will be decided by the trial steering committee. The committee will communicate these changes to the REB and appropriate parties.\n\nThe final dataset of the trial is the property of the investigative team and shall not be shared without permission from the principal investigator. Dissemination plans include presentations at local, national and international scientific conferences. Every effort will be made to publish results of the ENGAGES-Canada trial in a peer-reviewed journal. Dissemination of results to study participants and their family members will be available upon request. Updates and results of the study will be available to the public at www.clinicaltrials.gov.\n\nCanadian centers participating in the ENGAGES-Canada Trial are encouraged to develop sub-studies related to the trial if approved by their local REBs. No sub-study can be published prior to pre-approval by the ENGAGES-Canada Trial Management Committee.\n\na) Association between delirium and clinically relevant outcomes\n\nThe Engages-Canada trial will explore the associations between outcomes that are clinically relevant such as cognitive decline, falls, functional decline, ICU and hospital length of stay, and mortality; and the severity, incidence, and duration of delirium.\n\nb) Differences between observational and patient-reported pain scores\n\nPatients with postoperative delirium may lack the ability to express verbally the level of pain they are suffering76. Understanding that uncontrolled postoperative pain may be related to delirium emphasizes the importance of the assessment and treatment of postoperative pain. A comparison of behavioral pain assessment and patient reported pain will be made in delirious and non-delirious patients76. These pain scores can also be explored in the context of psychiatric status as high comorbidity rates exist.\n\nc) Patient outcomes and delirium\n\nThe association between cognitive status, falls, and quality of life with postoperative delirium will be evaluated at 30-day and at 1-year post surgery.\n\nd) Anesthesia depth and postoperative outcomes\n\nSecondary measures, that can be related to the difference in anesthesia depth between the two groups of patients, will be evaluated since patients in the EEG-guided group will almost certainly be exposed to lower concentrations of anesthetic agents. We will then be able to compare our results with an ongoing randomized clinical trial looking at the effects of depth of anesthesia on a range of outcomes77, such as cardiac arrest, pulmonary embolus, death, stroke, myocardial infarction, cardiac arrest, surgical site infection, ICU and hospital length of stay, and intraoperative awareness.\n\ne) Post-traumatic stress disorder (PTSD) outcomes\n\nThere is growing interest in understanding PTSD post-operatively given its high prevalence in surgical cohorts78. The current study allows for an incidence investigation, as a history of PTSD is assessed at baseline. This study will allow for a thorough investigation using contemporary DSM-5 PTSD criteria. Incident PTSD at 30-day and at 1-year follow-up will be assessed and several potential mechanisms can be explored including: pre-operative factors, dissociation and distress during the surgical period, delirium, surgical complications, psychiatric and cognitive status, and depth of anesthesia.\n\nf) Decreases in Regional Cerebral Oxygen Saturation and EEG Suppression Patterns\n\nSome of the participating sites measure Regional Cerebral Oxygen Saturation (rSO2) on a regular basis. Several studies have shown an association between significant perioperative decreases in rSO2, cognitive decline, and postoperative complications62,79,80. We therefore intend to explore the relationship between EEG suppression and cerebral desaturations.\n\n\nStudy status\n\nTo date two interim analyses have been performed, one at 240 patients and another at 570 patients. While randomization remains blinded, both analyses confirmed separation of the groups in term of total time in EEG suppression pattern (control group with more suppression) as well as a total incidence of delirium within the range of the predicted value used for the original power analysis.\n\n\nStrengths\n\nThe ENGAGES-Canada study is a multi-center clinical trial, conducted with a pragmatic design to reflect the clinical setting encountered in real-life.\n\nCardiac surgery patients are at high risk for postoperative delirium.\n\nPostoperative delirium is important to patients, healthcare providers, and society.\n\nGuidance of anesthesia by electroencephalography is low-cost and could be broadly accepted.\n\nAs a secondary aim, this study will also include cognitive and psychiatric outcomes 30-days and 1-year after surgery.\n\n\nLimitations\n\nThe protocol-guiding anesthesia with electroencephalography can only be effective if anesthesiologists adhere to it.\n\nDelirium is a disorder that fluctuates in the course of 24 hours. It can be easily missed with scheduled assessments, regardless of the rigor of these assessments.\n\nWhen patients are unable to speak, delirium assessment might be less sensitive.\n\nIncomplete follow-up at 30 days and 1-year postoperatively might limit some of the interpretations.\n\nSelf-reported cognitive and psychiatric symptom measures are less reliable than structured clinical interviews.\n\n\nData availability\n\nNo data is associated with this article.\n\nOpen Science Framework. ‘Protocol for the electroencephalography guidance of anesthesia to alleviate geriatric syndromes (engages-Canada) study: A pragmatic, randomized clinical trial’, https://doi.org/10.17605/OSF.IO/DXY2732\n\nThis project contains the following extended data:\n\nENGAGES-CANADA Protocol Appendix.pdf (PDF file containing all study questionnaires and screening materials)\n\nENGAGES-CANADA Script.pdf (script for research assistants to introduce the psychiatric symptom measures)\n\nENGAGES-CARDIAC Conscent French.pdf (Consent form, French)\n\nENGAGES-CARDIAC Consent English.pdf (Consent form, English)\n\nOpen Science Framework: SPIRIT 2013 checklist for ‘Protocol for the electroencephalography guidance of anesthesia to alleviate geriatric syndromes (engages-Canada) study: A pragmatic, randomized clinical trial’, https://doi.org/10.17605/OSF.IO/DXY2732\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Grant information\n\nFunding for the ENGAGES-Canada trial is through the Canadian Institute of Health Research (CIHR) [159482] and from departmental funding at participating sites. The Dr. Seymour and Rose T. Brown Endowed Chair are providing funding at the Washington University site.\n\nThe funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\n\nAcknowledgements\n\nThe authors would like to acknowledge the help of Lamarche Y, Denault A, Couture P, Courbe A, Rousseau-Saine N, Lebon JS, Cogan J, Chamberland ME, Rochon A, Desjardins G, Ayoub C, Raymond M, Vogler L, Schreiber S, Karkri F, DuMerton D, Chen K, Reike N in supporting the conduct of the study.\n\n\nReferences\n\nInouye SK, Westendorp RG, Saczynski JS: Delirium in elderly people. Lancet. 2014; 383(9920): 911–22. 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JAMA. 2001; 286(21): 2703–10. PubMed Abstract | Publisher Full Text\n\nEly EW, Margolin R, Francis J, et al.: Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001; 29(7): 1370–9. PubMed Abstract | Publisher Full Text\n\nWei LA, Fearing MA, Sternberg EJ, et al.: The Confusion Assessment Method: a systematic review of current usage. J Am Geriatr Soc. 2008; 56(5): 823–30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLuetz A, Heymann A, Radtke FM, et al.: Different assessment tools for intensive care unit delirium: which score to use? Crit Care Med. 2010; 38(2): 409–18. PubMed Abstract | Publisher Full Text\n\nPlaschke K, von Haken R, Scholz M, et al.: Comparison of the confusion assessment method for the intensive care unit (CAM-ICU) with the Intensive Care Delirium Screening Checklist (ICDSC) for delirium in critical care patients gives high agreement rate(s). Intensive Care Med. 2008; 34(3): 431–6. PubMed Abstract | Publisher Full Text\n\nInouye SK, Leo-Summers L, Zhang Y, et al.: A chart-based method for identification of delirium: validation compared with interviewer ratings using the confusion assessment method. J Am Geriatr Soc. 2005; 53(2): 312–8. PubMed Abstract | Publisher Full Text\n\nSaczynski JS, Kosar CM, Xu G, et al.: A tale of two methods: chart and interview methods for identifying delirium. J Am Geriatr Soc. 2014; 62(3): 518–24. PubMed Abstract | Publisher Full Text | Free Full Text\n\nInouye SK, Kosar CM, Tommet D, et al.: The CAM-S: development and validation of a new scoring system for delirium severity in 2 cohorts. Ann Intern Med. 2014; 160(8): 526–33. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhan BA, Perkins AJ, Gao S, et al.: The Confusion Assessment Method for the ICU-7 Delirium Severity Scale: A Novel Delirium Severity Instrument for Use in the ICU. Crit Care Med. 2017; 45(5): 851–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRamaswamy R, Dix EF, Drew JE, et al.: Beyond grand rounds: a comprehensive and sequential intervention to improve identification of delirium. Gerontologist. 2011; 51(1): 122–31. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNewcombe RG: Interval estimation for the difference between independent proportions: comparison of eleven methods. Stat Med. 1998; 17(8): 873–90. PubMed Abstract | Publisher Full Text\n\nSteingrimsson JA, Hanley DF, Rosenblum M: Improving precision by adjusting for prognostic baseline variables in randomized trials with binary outcomes, without regression model assumptions. Contemp Clin Trials. 2017; 54: 18–24. PubMed Abstract | Publisher Full Text\n\nSieber FE, Neufeld KJ, Gottschalk A, et al.: Effect of Depth of Sedation in Older Patients Undergoing Hip Fracture Repair on Postoperative Delirium: The STRIDE Randomized Clinical Trial. JAMA Surg. 2018; 153(11): 987–995. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJohnson VE: Revised standards for statistical evidence. Proc Natl Acad Sci U S A. 2013; 110(48): 19313–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nvan Velthuijsen EL, Zwakhalen SM, Warnier RM, et al.: Psychometric properties and feasibility of instruments for the detection of delirium in older hospitalized patients: a systematic review. Int J Geriatr Psychiatry. 2016; 31(9): 974–89. PubMed Abstract | Publisher Full Text\n\nAdamis D, Sharma N, Whelan PJ, et al.: Delirium scales: A review of current evidence. Aging Ment Health. 2010; 14(5): 543–55. PubMed Abstract | Publisher Full Text\n\nMaybrier HR, Mickle AM, Escallier KE, et al.: Reliability and accuracy of delirium assessments among investigators at multiple international centres. BMJ Open. 2018; 8(11): e023137. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHall R, Beattie S, Cheng D, et al.: Can we develop a Canadian Perioperative Anesthesiology Clinical Trials group? Can J Anaesth. 2010; 57(12): 1051–7. PubMed Abstract | Publisher Full Text\n\nDeschamps A, Hall R, Grocott H, et al.: Cerebral Oximetry Monitoring to Maintain Normal Cerebral Oxygen Saturation during High-risk Cardiac Surgery: A Randomized Controlled Feasibility Trial. Anesthesiology. 2016; 124(4): 826–36. PubMed Abstract | Publisher Full Text\n\nMazer CD, Whitlock RP, Fergusson DA, et al.: Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery. N Engl J Med. 2017; 377(22): 2133–44. PubMed Abstract | Publisher Full Text\n\nMashour GA, Shanks A, Tremper KK, et al.: Prevention of intraoperative awareness with explicit recall in an unselected surgical population: a randomized comparative effectiveness trial. Anesthesiology. 2012; 117(4): 717–25. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrice DD, Hetherington RR, Utting JE: A simple study of awareness and dreaming during anaesthesia. Br J Anaesth. 1970; 42(6): 535–42. PubMed Abstract | Publisher Full Text\n\nTharmanathan P, Calvert M, Hampton J, et al.: The use of interim data and Data Monitoring Committee recommendations in randomized controlled trial reports: frequency, implications and potential sources of bias. BMC Med Res Methodol. 2008; 8: 12. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFleming TR, DeMets DL: Monitoring of clinical trials: issues and recommendations. Control Clin Trials. 1993; 14(3): 183–97. PubMed Abstract | Publisher Full Text\n\nSmith MA, Ungerleider RS, Korn EL, et al.: Role of independent data-monitoring committees in randomized clinical trials sponsored by the National Cancer Institute. J Clin Oncol. 1997; 15(7): 2736–43. PubMed Abstract | Publisher Full Text\n\nMontori VM, Devereaux PJ, Adhikari NK, et al.: Randomized trials stopped early for benefit: a systematic review. JAMA. 2005; 294(17): 2203–9. PubMed Abstract | Publisher Full Text\n\nBassler D, Briel M, Montori VM, et al.: Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA. 2010; 303(12): 1180–7. PubMed Abstract | Publisher Full Text\n\nMyles PS, Leslie K, McNeil J, et al.: Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet. 2004; 363(9423): 1757–63. PubMed Abstract | Publisher Full Text\n\nChan MT, Cheng BC, Lee TM, et al.: BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol. 2013; 25(1): 33–42. PubMed Abstract | Publisher Full Text\n\nMashour GA, Esaki RK, Tremper KK, et al.: A novel classification instrument for intraoperative awareness events. Anesth Analg. 2010; 110(3): 813–5. PubMed Abstract | Publisher Full Text\n\nSieber FE, Zakriya KJ, Gottschalk A, et al.: Sedation depth during spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture repair. Mayo Clin Proc. 2010; 85(1): 18–26. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRadtke FM, Franck M, Lendner J, et al.: Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction. Br J Anaesth. 2013; 110 Suppl 1: i98–105. PubMed Abstract | Publisher Full Text\n\nChanques G, Payen JF, Mercier G, et al.: Assessing pain in non-intubated critically ill patients unable to self report: an adaptation of the Behavioral Pain Scale. Intensive Care Med. 2009; 35(12): 2060–7. PubMed Abstract | Publisher Full Text\n\nShort TG, Leslie K, Campbell D, et al.: A pilot study for a prospective, randomized, double-blind trial of the influence of anesthetic depth on long-term outcome. Anesth Analg. 2014; 118(5): 981–6. PubMed Abstract | Publisher Full Text\n\nWhitlock EL, Rodebaugh TL, Hassett AL, et al.: Psychological sequelae of surgery in a prospective cohort of patients from three intraoperative awareness prevention trials. Anesth Analg. 2015; 120(1): 87–95. PubMed Abstract | Publisher Full Text | Free Full Text\n\nColak Z, Borojevic M, Bogovic A, et al.: Influence of intraoperative cerebral oximetry monitoring on neurocognitive function after coronary artery bypass surgery: a randomized, prospective study. Eur J Cardiothorac Surg. 2015; 47(3) 447–54. PubMed Abstract | Publisher Full Text\n\nCasati A, Fanelli G, Pietropaoli P, et al.: Monitoring cerebral oxygen saturation in elderly patients undergoing general abdominal surgery: a prospective cohort study. Eur J Anaesthesiol. 2007; 24(1): 59–65. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "52096",
"date": "30 Aug 2019",
"name": "Oluwaseun Johnson-Akeju",
"expertise": [
"Reviewer Expertise Anesthesiology"
],
"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 protocol for the ENGAGES-Canada is well written and presented according to established guidelines. In brief, the protocol is constructed around the hypothesis that eliminating or reducing the incidence of burst suppression would decrease incident delirium.\n\nIt may be beneficial to explicitly address whether the effects of cardiopulmonary bypass time, cardiopulmonary bypass temperature and total circulatory arrest would be addressed (in the context of burst suppression) in exploratory analyses.\n\nIt is reasonable to make clear how anesthetic management during cardiopulmonary bypass is managed. Do all centers use inhaled anesthetic-drugs and will the EEG be used to manage drug cardiopulmonary bypass drug dosing versus performed empirically by the perfusionist.\n\nI missed whether/what anesthetic drugs are being collected intraoperatively for exploratory analyses (there is mention of anesthetic depth in the prespecified analysis - EEG?). Burst suppression may be a \"non-modifiable readout\" of deliriogenic brains. Nuanced exploratory analyses of anesthetic-drug/index values etc. may be helpful.\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": "51528",
"date": "24 Sep 2019",
"name": "Lian Kah Ti",
"expertise": [
"Reviewer Expertise Important clinical outcomes after major surgery"
],
"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 trial is a pragmatic trial modeled after the ENGAGES trial published in JAMA in 2019. The findings are of importance because it may validate the findings of the ENGAGES trial, which were opposite of what was expected based on several meta-analysis of previous data.\n\nThis trial also gives the authors an opportunity to address some of the criticisms of the ENGAGES trial. These include:\nBy concentrating on cardiac surgery, this removes the heterogeneity of surgeries of the original trial.\n\nAchieve a better separation of the time spent in burst suppression of the groups. This is likely to happen simply due to the passage of time, as anesthesiologists are more aware of the problem of delirium today, and are more comfortable using lower MACs of volatile agents.\n\nExcluding the outliers in each group.\n\nHowever, there are several concerns, as below.\nThe use of different \"black box\" indices to guide MAC is based on the assumption that they are equal. However, being a pragmatic trial, it is perhaps a reflection of true practice.\n\nThe management of anesthesia during bypass is not clear, including the type of anesthesia (volatile vs. propofol), the involvement of the perfusionists, and the perfusion targets.\n\nAssessment of delirium is still once a day. Because of the fluctuating course of delirium, the protocol is heavily reliant on chart reviews, which may underestimate the incidence.\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? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/8-1165
|
https://f1000research.com/articles/12-53/v1
|
13 Jan 23
|
{
"type": "Research Article",
"title": "Using literature-based discovery to develop hypotheses for the moderating effect of massively multiplayer online games",
"authors": [
"Ananya Sinha Choudhury",
"Wendy Hui",
"John Lau",
"Wendy Hui",
"John Lau"
],
"abstract": "Background: Empirical studies have shown that the relationship between psychological flow state and game addiction tends to be weaker in massively multiplayer online (MMO) games compared with non-MMO games. However, a theoretical explanation for the moderating effect of MMO games is lacking in the literature. This paper uses interview data and a method for generating hypotheses, literature-based discovery (LBD), to identify potential moderating factors and develop theories about this relationship. Methods: The proposed method involved text mining 2,829 abstracts to generate a keyword list of potential underlying moderating factors. Interview data from three domain experts confirmed the usefulness of LBD. Instead of arriving at game addiction primarily through flow, the interview data revealed that different cognitive pathways may lead to game addiction in MMO games. Results: Specifically, the identified keywords led to three explanations for the observed moderating effect: (1) social interaction in MMOGs may prevent the progression from flow to game addiction or induce positive peer influence; (2) game performance typically measured using a score- or point-based system in non-MMO games offers an extrinsic motivation that is more in line with flow theory; and (3) intrinsic motivation and escapism may be more important drivers of MMO game addiction. This paper summarizes the domain experts’ views on the usefulness of LBD in theory development. Conclusions: This paper uses literature-based discovery (LBD) to demonstrate how the pathways to game addiction in MMO games differ from non-MMO games. LBD is a method for generating hypotheses seldom used in the social science literature.",
"keywords": [
"Literature-based discovery",
"massively multiplayer online games",
"flow",
"addiction"
],
"content": "Introduction\n\nAlthough there is still an ongoing discussion on whether game addiction exists (Griffiths 2000, Pontes 2018), the World Health Organization’s (WHO 2018) recent recognition of game addiction as a mental disorder signifies the increased prevalence of problematic game play in modern societies and the importance of continuing research efforts to understand the cognitive mechanisms that lead to game addiction. Systematic reviews have summarized the factors that contribute to game addiction (Kuss and Griffiths 2012, Karmakar 2020, Juthamanee and Gunawan 2021), but the relationships between these factors represent a knowledge gap that must be closed in the future (Juthamanee and Gunawan 2021).\n\nA key factor often overlooked in game addiction research is the role of game genres. Na et al. (2017) showed that the factors that contribute to addiction differ in different game genres, which implies that the underlying cognitive mechanisms leading to game addiction may also differ between genres. For example, flow theory is a popular explanation for game addiction because it suggests that psychological flow states cause game addiction. A recent meta-analysis (Li et al. 2021) showed that this relationship was significantly weaker in massively multiplayer online (MMO) games. However, a theoretical explanation for the moderating effect of MMO games is lacking in the literature.\n\nTo contribute to theory development along this line of research, this paper proposes the use of a method for generating hypotheses, literature-based discovery (LBD), which was pioneered by Swanson (1986) in the field of medical science. In this work, Swanson noted that Raynaud’s disease (Concept A) was linked to its effect on blood viscosity (Concept B), which in turn was related to a possible treatment in the form of fish oil (Concept C) (see Figure 1). Therefore, concepts A and C are likely to be related in the same way (Swanson 1986). This work represented a potential breakthrough because no previous study had investigated the relationship between Raynaud’s disease and fish oil.\n\nIn particular, LBD is useful in addressing the problem of knowledge overspecialization typically seen in multidisciplinary research topics. Knowledge overspecialization occurs when the growing body of literature in different domains makes it difficult for researchers in one domain to keep up with the related research in other domains, resulting in ineffective knowledge sharing. LBD has been broadly applied in the biomedical and physical sciences in addition to some engineering sciences. For example, Gordon et al. (2002) showed how LBD can be used to identify new genetic engineering applications by searching the Internet. Weber (2003) used LBD to discover a new drug application for thalidomide by searching the academic literature. Agosti et al. (2011) applied LBD to information acquisition, inspection, and interpretation of user interactions in information management system logs.\n\nThe remainder of this paper is organized as follows. The Literature Review section critically considers the relevant literature and identifies a knowledge gap that this paper helps to close. The Methodology section describes our search process, the extraction of relevant keywords, and the collection of interview data from three domain experts. The Discussion section interprets the interview data and provides a theoretical explanation for the moderating effect of MMO games on the relationship between flow and game addiction. Finally, the Conclusion section summarizes our findings and identifies a few future research directions.\n\n\nLiterature review\n\nOne of the popular theories to explain addiction is flow theory. Csikszentmihályi (1975) coined the term “flow” to describe the mental condition of full immersion in an activity. Central to this theory is the balance between the challenge presented by a task and the skill level of the person completing the task. In the context of video games, players experience anxiety when their skills do not match the difficulty of the task. However, players’ skill levels increase when they spend more time playing a game. Players achieve the flow state when the game challenges are balanced by their skill levels, and they feel a deep sense of enjoyment. As their skill levels continue to increase, however, players may find the game too easy and become bored. They then look for greater challenges to restore and maintain their flow state. They shift between “anxiety,” “flow,” and “boredom” states as the game progresses. In this way, players exchange playing time for satisfaction, which could lead to game addiction (Rau et al. 2006). Consistent with flow theory, many game addiction studies have shown a positive correlation between flow states and game addiction (e.g., Chou and Ting 2003, Hull et al. 2013, Ballabio et al. 2017).\n\nOther contributing factors to game addiction include players’ sociodemographic characteristics (e.g., Chen et al. 2015, Bianchini et al. 2017), personality traits (e.g., Andreassen et al. 2013, Dong et al. 2013), perceived enjoyment (Hull et al. 2013, Moslehpour and Batjargal 2013), and perceived benefits (e.g., Adiele and Olatokun 2014, Lee et al. 2017). However, uncoordinated multidisciplinary investigations make it difficult to incorporate these different factors into a comprehensive model for game addiction. In addition, contextual factors may exist. For example, Na et al. (2017) highlighted game genres as an under-researched factor in game addiction and showed that different factors have varying degrees of statistical significance in explaining addiction across different game genres. In the same vein, a recent exploratory meta-analysis conducted by Li et al. (2021) showed that the relationship between flow states and game addiction was significantly lower in MMO games than in non-MMO games (see Figure 2).\n\nBillieux et al. (2015) explained that MMOGs differ from other games in three ways. First, the virtual world of MMOGs exists independently of players. Second, players can level up by completing missions or quests to obtain new powers, skills, and game items. Finally, in-game social interactions are facilitated by allowing players to communicate easily with each other and form virtual social networks, known as guilds or clans. Some of these unique characteristics may make MMO games more addictive than non-MMO games. However, it remains unclear how the cognitive mechanisms leading to game addiction differ in MMO games. Laconi et al. (2017) explored the relationships between Internet gaming disorder, time spent on the Internet, player motives, game genres, and psychopathology. Kircaburun et al. (2018) showed how dark personality traits have a mediating role in problematic online gaming behavior alongside the moderating effects of game types. However, this is still an under-researched area in the game addiction literature. This paper contributes to the understanding of the role of game genres in game addiction by providing a theoretical explanation for the moderating effect reported in Li et al. (2021). Specifically, we supplement the LBD method with domain expert interviews to answer the following two research questions (RQs):\n\nRQ1: What are the underlying reasons for the moderating effect of MMO games on the relationship between flow and game addiction?\n\nRQ2: What are the alternate pathways or factors (other than flow) that lead to MMO game addiction?\n\n\nMethods\n\nFollowing Gordon et al. (2002), our LBD implementation included three main steps: (1) we conducted a comprehensive literature search, (2) we generated a list of useful B terms (or concepts) as keywords that might help to identify the underlying factors for the moderating effect of MMO games, and (3) we invited domain experts to evaluate these B terms and develop explanations for their moderating effect.\n\nIn this study, our objective was to identify factors (B terms) that may influence the specific relationships between our A (i.e., “flow”) and C (i.e., “game addiction”) concepts. We identified the possible pathways between A and C concepts in two sets of studies: (1) studies focusing on MMO games, and (2) studies not focusing on MMO games. Domain experts then evaluated the path differences between the two sets of studies to identify possible explanations for the moderating effect of MMO games on flow and game addiction.\n\nWe conducted six searches from October 2 to October 26, 2020, three for MMOG studies and three for non-MMOG studies. We searched the following databases: (1) Association for Computing Machinery Digital Library, (2) Academic Search Premier, (3) Web of Science, (4) ScienceDirect, (5) Scopus, (6) Wiley Online Library, (7) Business Source Complete, (8) Springer’s Behavioral Science journals, and (9) Business Source Premier. We limited the search to research article abstracts. We used the advanced search option for each database, which enabled us to use Boolean operators. For example, we performed the following search in each database for articles related to the concept of flow:\n\n1. Flow (A) in MMO studies: “flow” AND “experience” AND “games” AND “massively multiplayer.”\n\n2. Flow (A) in non-MMO studies: “flow” AND “experience” AND “games” AND NOT “massively multiplayer.”\n\nWe added the search term “experience” to the keywords to ensure that our search results were relevant to the psychological flow state. After the search for papers that studied flow and MMO games yielded few results, we used “immersion” in the search criteria because it has been used as an alternative term to “flow” in many relevant articles.\n\n3. Immersion (A) in MMO studies: “immersion” AND “experience” AND “games” AND “massively multiplayer.”\n\n4. Immersion (A) in non-MMO studies: “immersion” AND “experience” AND “games” AND NOT “massively multiplayer.”\n\nWe combined the search results from (1) and (3) above and removed duplicates using an R script to obtain a final set of flow-related MMO studies. Similarly, the search results from (2) and (4) above were combined and duplicates were removed to generate a final set of flow-related non-MMO studies.\n\nWe used the following keywords for addiction-related studies:\n\n5. Addiction (C) in MMO studies: “addiction” AND “games” AND “massively multiplayer.”\n\n6. Addiction (C) in non-MMO studies: “addiction” AND “games” AND NOT “massively multiplayer.”\n\nWe combined the search results from all nine databases again and removed all duplicates to generate the final sets of addiction related MMO and non-MMO studies. We added the search term “games” to ensure that the search results were relevant to video games.\n\nAccordingly, these searches generated four sets of documents. Table I shows the total number of non-duplicate abstracts in each set after the combined search of all databases.\n\nWe analyzed the text data using the tm and SnowballC packages in R. We first changed all texts to lowercase. We then removed all numbers, white spaces, and English stop words from the tm package. Finally, we stemmed the words. For each document set, we created a term–document matrix for the unigrams and bigrams. We identified the common unigrams and bigrams between the “flow” and “addiction” sets for both MMO and non-MMO studies. We considered the terms in these sets as the B terms that may suggest how MMO games weaken the relationship between flow and addiction.\n\nWe obtained four lists of B terms, as follows: (1) common unigrams for MMO studies, (2) common bigrams for MMO studies, (3) common unigrams for non-MMO studies, and (4) common bigrams for non-MMO studies. The lengths of these lists were 988, 1,346, 4,868, and 10,986, respectively. As our data set included more non-MMO studies, the corresponding lists of B terms were longer than those for MMO studies.\n\nWe used lexical statistics to rank the generated B terms. Specifically, for each B term in a keyword list, we computed the average term frequency-inverse document frequency (tf-idf) for both the flow and addiction sets. We ranked the B terms in each list by the sum of the average tf-idf of the “flow” set and the average tf-idf of the “addiction” set. Two of the authors then independently eliminated words they considered too general (e.g., games, Internet, systems, match) or irrelevant (e.g., experiment, questionnaire, evaluate, study), to obtain approximately 30 to 40 B terms in each list. The generation of this intermediate shortlist relied on the individual authors’ subjective judgment. The two authors then came together to discuss the findings and further reduced the length of each list to the 20 most promising B terms based on their consensus. Disagreements were resolved by consulting the third author. Table II presents the final lists of the top 20 common B terms (both unigrams and bigrams) for MMO and non-MMO studies, while Figure 3 illustrates the flowchart for our implementation of LBD.\n\nOur research included interviews with domain experts. Our study application was approved by the Sub-Committee on Research Ethics and Safety of the Research Committee of Lingnan University, Hong Kong (ref. EC059/2021). Each domain expert signed a written consent for prior to the interview. After finalizing the lists of B terms, we interviewed three domain experts, all of whom were active game addiction researchers, for one hour using a Web conferencing software tool. The appendix (Figshare:Appendices, https://doi.org/10.6084/m9.figshare.21719993.v1) presents the interview questions. To make the lists more manageable, we divided the B terms into (1) unigrams and bigrams that were common to MMO and non-MMO studies, (2) unigrams and bigrams that appeared only in MMO studies, and (3) unigrams and bigrams that appeared only in non-MMO studies. Each list included 15 to 20 keywords. We presented these keywords to the domain experts and asked them to select the terms that they felt may help explain the moderating effect of MMO games on the relationship between flow and game addiction. We identified three explanations.\n\nExplanation #1: Social interaction in MMO games may “break the flow” or induce positive peer influence\n\nThe critical role of social interactions in the game experience is a key difference between MMO games and non-MMO games. Using B terms such as “social environment,” “teamwork,” and “social setting,” the domain experts commented that social interactions in MMO games (both in-game and in real-life) may distract users’ attention during gameplay and prevent their progression from flow to game addiction. Considering the multiplayer nature of MMOGs, Expert 1 said:\n\nUnless you can find skilled teammates [to] play with you, … you might find [it] very difficult to complete the tasks or quests in an MMOG …. Therefore, the social setting and teamwork are quite important … in affecting the relationship between flow and game addiction in this study.\n\nIf the social environment is not that decent, for example, you have people coming in and out [of the MMO game] from time to time, the guild cannot retain players. Then, you will gradually lose interest in the MMO game.\n\nExpert 2 made a similar comment.\n\n[O] ne reason MMO games tend to weaken the correlation between flow and game addiction [could] be that people always play in a team. If one of the players must leave the game or, for some reason, must stop playing or is interrupted, the whole team must be reorganized.\n\nConsidering real-life social interactions, Expert 3 noted that some players prefer to play with their real-life friends. This peer influence may prevent their progression to game addiction:\n\nSome of my gaming friends … tell me that they prefer MMO games, but they have a regular set [of] … game mates. They prefer not to play with strangers in the game. Let’s say … your teammates … [are] nonaddictive gamers, which somehow has a positive peer influence on you too. Your friends can motivate you to play more healthily in the game.\n\nExplanation #2: Non-MMOGs offer extrinsic motivation in line with flow theory\n\nBased on the B term “extrinsic motivation,” the interview data suggested that MMO games and non-MMO games offer their players different types of extrinsic motivation. On the one hand, non-MMO games with a score- or point-based system provide a greater sense of achievement, which can strengthen the relationship between flow and game addiction. On the other hand, this sense of achievement may be missing in MMO games because they are often open-ended and game performance depends more on rankings relative to others. According to Expert 2,\n\n[In] arcade games like Angry Birds or Candy Crush, … you have a target …. The players tend to want to achieve a goal and want to achieve something like three stars …. I [don’t] see that much of this element in MMO games.\n\nOne more thing about extrinsic motivation. I think that [it applies to] both MMO and non-MMO games, but it [is] more influential [in] MMOGs because you feel like there are other … players in the game. Everyone can see your ranking and … your performance.\n\nAs discussed in the Literature Review section, the balance between challenging gameplay and player skills is central to the experience of flow. In non-MMO games, players often begin with simple tasks and are challenged by increasingly complex tasks as their skills improve. This type of game progression is more in line with flow theory than the game progression in open-ended MMOGs.\n\nExplanation #3: Intrinsic motivation and escapism may be more important drivers of MMO game addiction\n\nUsing the B terms “intrinsic motivation” and “escapism,” Expert 1 highlighted the relationship between escapism and intrinsic motivation and the importance of intrinsic motivation in MMOGs:\n\nIntrinsic motivation, I would say, … [is] something quite correlated with achievement or escapism. But intrinsic motivation is more [about] how you motivate yourself to spend time [in] the MMO game. Sometimes it is even more important than extrinsic motivation, such as the reward you might receive. You don’t know why but sometimes you just lose interest [in] the game, so you quit. If people do not feel a sense of worth in playing the game, they will quit. Sometimes they will not stay even if you provide them with an extrinsic reward.\n\nIn accordance with this comment, it should be noted that the virtual worlds in MMO games can provide players with an experience that is unavailable in the real world, which can divert their minds from real-life unpleasantness. The players’ avatars may also allow them to identify with their MMO game characters and motivate them to continue playing the game even in the absence of flow. Therefore, “escapism” may represent an important alternative pathway to MMO game addiction because players may use gameplay as a maladaptive coping strategy (Billieux et al. 2015).\n\nSummary\n\nWe focused on the interview data that explained the weakened relationship between flow and game addiction observed in MMO games. Three explanations were identified. First, even if a game player really enjoys playing an MMO game, they cannot continue to play if their team members leave in the middle of the game. Social interactions can break their flow experience and prevent addiction. Positive peer influence may also help prevent addiction among players who prefer to play MMO games with their real-life friends. Second, compared with the open-ended nature of MMO games, the reward systems of non-MMO games are typically more in line with flow theory. Third, intrinsic motivation and escapism may provide important alternative pathways to game addiction in MMO games.\n\nDuring their interviews, the domain experts were asked to comment on the advantages and disadvantages of using computer-generated keywords to identify potential moderating factors. They were also asked about their overall experience with LBD. Overall, they found that LBD was a useful research tool. Expert 3 observed the following:\n\nI’ve recently started some research on holistic education because of my new job. This field is totally brand new to me. Of course, there are some review papers, but if I use [LBD], it’ll become clearer to me.\n\nExpert 2 made a similar comment:\n\nPersonally, I really like it. I think it’s very efficient and effective because it’s neutral.\n\nHowever, not all of the generated terms may be useful; therefore, domain expertise is needed for LBD to be useful. In addition, the semantic meaning of a word in the social sciences may sometimes be ambiguous or depend on the context of use. LBD removes the contexts of use of keywords; therefore, the literature may need to be revisited. Expert 1 commented accordingly:\n\n[The] medical field … is [where LBD] comes from originally. However, I … have reservations regarding how it could be applied to the social sciences because people use different terminology for the same phenomenon. Also, when they use the … same terms, they sometimes do not refer to the same phenomenon. This is something that the LBD tool must consider.\n\nExpert 2 raised another limitation of the LBD method. When we search for keywords in the literature and use term frequency to identify promising terms, we may miss some relatively new concepts related to MMO games:\n\n[Y] ou will rank those keywords by frequency to retain meaningful keywords that also appeared more frequently. This is the indicator of the most promising moderating [factors]. If you wish to find some novel moderators that you feel … make sense theoretically but have been less studied in the literature, you might wish to carefully go through less frequent keywords in your list.\n\nIn terms of the presentation of potential moderators among the keywords, the domain experts found that it was appropriate to divide the keywords into (1) those that are common to both MMO and non-MMO studies and (2) those that are not common to both sets of studies. The domain experts also agreed on 20 keywords as being roughly the optimal length because a longer list would become too difficult to evaluate:\n\nExpert 1: “I think 20 is a good number for a researcher. But if you talk to gamers then you should reduce it to 10.”\n\nExpert 2: “I think it’s a good length.”\n\nExpert 3: “Actually, I think that’s reasonable.”\n\nFinally, all of the domain experts would consider using LBD if a free software tool were available; however, one domain expert pointed out that useful guidelines should also be provided.\n\n<Note: The quotes of the experts have been edited to correct grammatical errors because English is not their first language.>\n\n\nDiscussion\n\nNowadays, the academic community produces publications at an accelerated rate, which makes it difficult to connect and integrate the necessary knowledge from the disjointed literature. This problem of knowledge overspecialization is common in multidisciplinary research topics, such as game addiction. In this study, we used domain expert interview data with the LBD method to explain the moderating effect of MMO games on the relationship between flow and game addiction.\n\nThe domain expert interview data suggested that the relationship between flow and game addiction may be weakened in MMO games for three reasons. First, the need to play as a team may sometimes prevent players’ progression from flow to game addiction. Positive peer influence may also help prevent game addiction. Second, achieving flow depends not only on the game being challenging but also on the players’ skills (Csikszentmihályi 1990). Unlike most non-MMO games that use a point-based system to track players achievements, the open-ended progression in MMO games may not be appealing to more goal-oriented players. Third, intrinsic motivation and escapism may provide important alternative pathways to MMO game addiction.\n\nThe underlying cognitive mechanisms behind the formation of game addiction differ according to different game genres; therefore, our findings suggest that different game genres require dedicated research attention (e.g., You et al. 2017, Blasi et al. 2019, Lee et al. 2021).\n\nOur results suggest that the underlying motivational factors for game addiction differ for different game genres. Specifically, compared with non-MMO games, the achievement motive for MMO game players may be smaller, but they may be more likely to use their gameplay as a maladaptive strategy to cope with negative real-life experiences. This perspective is consistent with PsychGuides.com (n.d.), which divides game addiction into two categories: (1) standard video games that typically have a clear goal, such as saving a princess, and (2) MMO games that typically have no ending. Game addiction in the first category is suggested to be mostly driven by completing missions or beating high scores or preset standards. In contrast, addicted players in the second category form virtual social networks with other players and use their gameplay to escape from reality and gain in-game social acceptance. Therefore, game genres must be considered in effective treatments for game addiction.\n\nAlthough we received generally positive feedback from the domain experts, we found three issues that must be addressed to improve our implementation of LBD.\n\nFirst, we relied on subjective judgment to remove irrelevant items from the B terms. Although we reached consensus on the final lists only after two researchers independently produced an intermediate shortlist, we believe there is room to improve the objectivity of generating B terms with LBD. In future, we will explore the possibility of automatic ontology generation (Bedini and Nguyen 2007) to replace the use of lexical statistics in the generation of keywords.\n\nSecond, some keywords have similar meanings. The term vectors should be clustered to enable an accurate reflection of the importance of keywords in the lexical statistics. The final lists after keyword consolidation will be a more comprehensive representation of the related concepts. Therefore, they will become more useful for domain experts.\n\nThird, we asked the domain experts to freely discuss any moderating factors that they found from the presented keyword lists, which allowed us to extract rich and in-depth knowledge. However, it is quite time-consuming to conduct interviews. An alternative approach to collect feedback from domain experts asynchronously or in response to a long list of B terms would be to ask them to evaluate the usefulness of each keyword using a Likert scale individually and independently. The keywords could then be ranked using the average usefulness scores. In this way, rating each keyword individually will be less cognitively demanding than devising a flow theory based on a complete keyword list.\n\n\nConclusion\n\nWe comprehensively searched the literature and found more than 2,000 abstracts for flow (Concept A) and game addiction (Concept C). We identified both flow- and game addiction-related B terms, which three domain experts evaluated to generate possible explanations for the observed weakened relationship between flow and game addiction in MMO games. The interview data suggested that in-game social interactions and the open-ended nature of MMO games may prevent players’ progression from flow to game addiction in MMO games. Offline social interactions with friends may also induce positive peer influence to prevent game addiction. The unique features of MMO games may also create other pathways to game addiction. Specifically, addicted MMO game players may tend to use their gameplay as a maladaptive strategy to cope with negative real-life experiences. Our results also suggest that effective game addiction treatments may need to consider the related game genres.\n\nAlthough the domain experts had generally positive feedback on the use of LBD, our discussions identified some limitations of the implemented LBD method. To address these issues in the future, we will attempt to build an ontology and group similar keywords together before generating lists of B terms. In this way, we will ensure that the useful keywords in the literature are accurately and comprehensively represented in the search results. We will also consider reducing the level of cognitive complexity involved in the tasks of domain expert. Finally, we will apply the LBD method to identify effective but overlooked game addition treatments in the future.",
"appendix": "Data availability\n\nFigshare: Interviews of experts, https://doi.org/10.6084/m9.figshare.21601716.v1 (Sinha Choudhury and Hui 2022).\n\nThis project contains the following underlying data:\n\n- Interview 1.docx\n\n- Interview 2.docx\n\n- Interview 3.docx\n\nFigshare: R script_code to extract keywords, https://doi.org/10.6084/m9.figshare.21601626.v1 (Sinha Choudhury and Hui 2022).\n\nFigshare: Input files, https://doi.org/10.6084/m9.figshare.21719951.v1 (Sinha Choudhury and Hui 2022).\n\nFigshare: Appendices (Interview questions), https://doi.org/10.6084/m9.figshare.21719993.v1 (Sinha Choudhury 2022).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAdiele I, Olatokun W: Prevalence and determinants of Internet addiction among adolescents. Comput. Hum. Behav. 2014; 31: 100–110. Publisher Full Text\n\nAgosti M, Crivellari F, Di Nunzio GM: Web log analysis: A review of a decade of studies about information acquisition, inspection and interpretation of user interaction. Data Min. Knowl. Disc. 2011; 24: 663–696. Publisher Full Text\n\nAndreassen CS, Griffiths MD, Gjertsen SR, et al.: The relationships between behavioral addictions and the five-factor model of personality. J. Behav. Addict. 2013; 2(2): 90–99. PubMed Abstract | Publisher Full Text\n\nBallabio M, Griffiths MD, Urbán R, et al.: Do gaming motives mediate between psychiatric symptoms and problematic gaming? An empirical survey study. Addict. Res. Theory 2017; 25(5): 397–408. Publisher Full Text\n\nBedini I, Nguyen B: Automatic Ontology Generation: State of the Art. Technical report. University of Versailles;2007 December 2007.\n\nBianchini V, Cecilia MR, Roncone R, et al.: Prevalence and factors associated with problematic Internet use: An Italian survey among L’Aquila students. Riv. Psichiatr. 2017; 52(2): 90–93. PubMed Abstract | Publisher Full Text\n\nBillieux J, Deleuze J, Griffiths MD, et al.:Internet gaming addiction: The case of massively multiplayer online roleplaying games.In el-Guebaly N, Carrà G, Galanter M, editors. Textbook of Addiction Treatment: International Perspectives Milano:Springer;2015; 1515–1525. Publisher Full Text\n\nBlasi MD, Giardina A, Giordano C, et al.: Problematic video game use as an emotional coping strategy: Evidence from a sample of MMORPG gamers. J. Behav. Addict. 2019; 8(1): 25–34. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen Y-L, Chen S-H, Gau SS-F: ADHD and autistic traits, family function, parenting style, and social adjustment for Internet addiction among children and adolescents in Taiwan: A longitudinal study. Res. Dev. Disabil. 2015; 39: 20–31. PubMed Abstract | Publisher Full Text\n\nChou TJ, Ting CC: The role of flow experience in cyber-game addiction. Cyberpsychol. Behav. 2003; 6(6): 663–675. PubMed Abstract | Publisher Full Text\n\nCsikszentmihályi M: Beyond Boredom and Anxiety San Francisco, CA:Jossey-Bass Publishers;1975.\n\nCsikszentmihalyi M: The Psychology of Optimal Experience. Harper and Row:1990.\n\nDong G, Wang J, Yang X, et al.: Risk personality traits of Internet addiction: A longitudinal study of Internet-addicted Chinese university students. Asia Pac. Psychiatry 2013; 5(4): 316–321. Publisher Full Text\n\nGordon M, Lindsay RK, Fan., W.: Literature-based discovery on the World Wide Web. ACM Trans. Internet Technol. 2002; 2(4): 261–275. Publisher Full Text\n\nGriffiths M: Does internet and computer “addiction” exist? Some case study evidence. Cyberpsychol. Behav. 2000; 3(2): 211–218. Publisher Full Text\n\nHull DC, Williams GA, Griffiths MD: Video game characteristics, happiness and flow as predictors of addiction among video game players: A pilot study. J. Behav. Addict. 2013; 2(3): 145–152. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJuthamanee S, Gunawan J: Factors related to Internet and game addiction among adolescents: A scoping review. Belitung Nursing Journal 2021; 7(2): 62–71. Publisher Full Text\n\nKarmakar I: A review of IT addiction in IS research. AMCIS 2020 Proceedings, 19. 2020.Reference Source\n\nKircaburun K, Jonason PK, Griffiths MD: The Dark Tetrad traits and problematic online gaming: The mediating role of online gaming motives and moderating role of game types. Personal. Individ. Differ. 2018; 135: 298–303. Publisher Full Text\n\nKuss DJ, Griffiths MD: Internet gaming addiction: A systematic review of empirical research. Int. J. Ment. Heal. Addict. 2012; 10: 278–296. Publisher Full Text\n\nLaconi S, Pirès S, Chabrolbet H: Internet gaming disorder, motives, game genres and psychopathology: Computers in Human. Behaviour 2017; 75: 652–659. Publisher Full Text\n\nLee H, Kim JW, Choi TY: Risk factors for smartphone addiction in Korean adolescents: Smartphone use patterns. J. Korean Med. Sci. 2017; 32(10): 1674–1679. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee ZWY, Cheung CMK, Chan TKH: Understanding massively multiplayer online roleplaying game addiction: A hedonic management perspective. Inf. Syst. J. 2021; 31(1): 33–61. Publisher Full Text\n\nLi M, Reiners T, Hui W: Break the flow: A meta-analysis of the relationship between flow and game addiction in massively multiplayer online games. Working paper. Curtin University.2021. Publisher Full Text\n\nMoslehpour M, Batjargal U: Factors influencing Internet addiction among adolescents of Malaysia and Mongolia. Jurnal Administrasi Bisnis. 2013; 9(2): 101–116. 0216–1249.\n\nNa E, Choi I, Lee TH, et al.: The influence of game genre on Internet gaming disorder. J. Behav. Addict. 2017; 6(2): 1–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPontes HM:Making the case for video game addiction: Does it exist or not?Ferguson C, editor. Video Game Influences on Aggression, Cognition, and Attention Cham:Springer;2018. 978-3-319-95494-3. Publisher Full Text\n\nPsychGuides.com: Video game addiction symptoms, causes and effects.n.d. Accessed October 14, 2021. Reference Source\n\nRau P-LP, Peng S-Y, Yang C-C: Time distortion for expert and novice online game players. Cyberpsychol. Behav. 2006; 9(4): 396–403. PubMed Abstract | Publisher Full Text\n\nSinha Choudhury A, Hui WWY:Interviews of experts. figshare. Journal contribution.2022. Publisher Full Text\n\nSinha Choudhury A, Hui WWY:R script_code to extract keywords. figshare. Journal contribution.2022. Publisher Full Text\n\nSinha Choudhury A, Hui WWY:Input Files. figshare. Dataset.2022. Publisher Full Text\n\nSinha Choudhury A:Appendices. figshare. Dataset.2022. Publisher Full Text\n\nSwanson DR: Fish oil, Raynaud’s syndrome, and undiscovered public knowledge. Perspect. Biol. Med. 1986; 30(1): 7–18. PubMed Abstract | Publisher Full Text\n\nWeber D: Thalidomide and its derivatives: New promise for multiple myeloma. Cancer Control.2003; 10(5): 375–383. Publisher Full Text\n\nWorld Health Organization (WHO): Gaming disorder.2018.Reference Source\n\nYou S, Kim E, Lee D: Virtually real: Exploring avatar identification in game addiction among massively multiplayer online role-playing games (MMORPG) players. Games and Culture. 2017; 12(1): 56–71. Publisher Full Text"
}
|
[
{
"id": "209925",
"date": "23 Oct 2023",
"name": "Piotr Siuda",
"expertise": [
"Reviewer Expertise game studies",
"cultural studies",
"media studies",
"online research 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 the opportunity to read this article. Overall, I find the topic fascinating and under-explored. However, I have some serious doubts about whether the paper should be indexed in its current form. Here are my remarks to all sections of the paper:\nIntroduction\nI would expect a clearly defined aim here and a specific indication of what has been done for this study. When it comes to the aim, you should rephrase the final part of the second paragraph. As for the methods, it is a bit unclear whether this is some literature search (LBD) or interviewing people (“interview data from three domain experts”). The methods section does not clarify this, especially since you introduce another NLP stage there (see the comments below).\nSome parts of this section must be elaborated instead of just indicating relevant literature. I suggest explaining what factors contributing to game addiction are pinpointed in the literature more clearly. The same goes for describing how addiction differs for different genres. Explaining all this in the paper rather than just giving references would be more informative.\n“For example, flow theory is a popular explanation for game addiction because it suggests that psychological flow states cause game addiction”–this statement lacks references. Additionally, it is currently unclear how flow causes addiction.\nOverall, this section needs to be expanded, and some concepts must be explained more clearly.\nLiterature review\nParagraph 1. I cannot see the connection between flow and addiction well explained here. This connection must be indicated precisely as this is the paper’s core.\nI have some similar remarks as for the Introduction. Please explain and elaborate on the papers by Na et al. (2017) and Li et al. (2021). This is especially so for the Li et al. paper, as it seems that the authors of the present article want to enrich and continue this line of research (they want to explain the moderate effects of addiction to MMO games theoretically).\nFigure 2 should be placed in Methods, and please make it similar to Figure 1.\nPlease explain why and how “Some of these unique characteristics may make MMO games more addictive than non-MMO games.” Was this researched previously? Additionally, you stress that MMO games are less addictive, so introducing this part is unclear. Please provide a rationale for it (is this connected to RQ2?). Overall, I am a bit lost here, and I am not sure whether you see the MMO games as more or less addictive.\nExplain Laconi et al. (2017) and Kircaburun et al. (2018) in more detail.\nConsider moving RQs to the Introduction (see the previously mentioned remark on the lack of precise aim).\nMethods\nThis section needs to be revised thoroughly.\nUsually, I would say that mixing a literature review with some other methods in a single paper is dubious, to say the least, and that the paper should be either a review or a research paper. However, from what I understand, this was purposeful. Nevertheless, it is unclear whether LBD is about searching the literature and using the interviews together or whether the interviews are an extra part here. In other words, please be as specific as possible about the procedures for LBD.\nAdditionally, the literature search is unclear.\nI am not sure why the two searches were needed. Why not search for flow in games and then analyze the abstracts to select papers on MMO and non-MMO games?\n\nIt is unclear why only abstracts were studied. This seems to be a significant overlook.\n\nUsing Boolean operators is a bit strange. You forget many other keywords, e.g., OR “MMO”, OR “videogames.”\n\nIf “immersion” is used instead of “flow,” why not include it in the first search (OR “immersion”)?\n\nIt is unclear why the present process was so complicated. Why not look for addiction papers in the first place? I mean, introducing “addiction” immediately, in the first search?\n\n“We combined the search results from all nine databases again and removed all duplicates to generate the final sets of addiction-related MMO and non-MMO studies. We added the search term “games” to ensure that the search results were relevant to video games”. It is super confusing. The term “games” was added? Where exactly?\n\nTable 2 should be before Step 2. I would rather see a proper (not the one presented) Flowchart to explain the search process better. How many papers were reached in the first place? How many duplicates were eliminated, etc.?\n\nTaken as a whole and looking at a Discussion, I am not even sure whether the search for papers on non-MMO games (and using NLP for these) was needed. Please explain the reasons behind it more clearly.\nStep 2\nSo, this is another part that complicates your methodology. Does LBD include using NLP, or is this your innovation? If so, this needs to be adequately explained. How NLP here allows you to extract relevant data, and why is this data relevant?\nBy text data you mean abstracts or whole articles? If these are abstracts, this should be clear from the start. And if these are abstracts, I believe this is a significant overlook and does not make your research reliable.\n\nAlso, I would need a more robust rationale for why unigrams and bigrams are a proper way to consider moderating factors. For me, they seem a bit coincidental, especially since the authors stress that the choice of these was a subjective one (I know you mention this in the Discussion, but it needs improving). I would suggest some strong rationale, as stated above. Otherwise, other methods may seem more appropriate, e.g., topic modeling based on some discursive analysis.\nThe paper lacks a Results section, and this is because of how the study was designed. I suggest using the subtitle “Methods and Results” instead of “Methods.”\nIt is unclear how the experts were chosen, why they are considered experts, how the recruitment process went, how many non-responses were there, what is the exact experience of experts, etc. This is important for the validity and reliability of the study.\n“Summary” repeats what was already stated. I would instead see more nuances for the results. For a one-hour interview, I am sure the experts had much more expertise to share.\nDiscussion\nTheoretical contributions\nThe second paragraph repeats the results, and I do not see the theoretical contribution that was promised.\n“The underlying cognitive mechanisms behind the formation of game addiction differ according to different game genres.” This was already obvious initially, but what is the theoretical contribution here?\nPractical implications\nAgain–you repeat what was already stated. No practical implications here. “Therefore, game genres must be considered in effective treatments for game addiction.”–this should be expanded exponentially, along with some other practical implications (e.g., education, industry, etc.),\nConclusion\nAgain, this is all repeating what was there before.\nInstead of all this repetition, the Discussion (skip the Conclusion) should present clearly how the theory was enriched and the practical implications in different areas, e.g., treatment, education, and industry (backed by references). When it comes to the theoretical implications, it should be made clear what part of the theory is being expanded (on addiction, on gamers, on flow, on MMO). Currently, claiming that there are some theoretical implications is only a fancy way of marketizing the paper without any relevant content.\nAll this should be taken seriously, as this paper is not acceptable in this form. Also, the concept of flow is barely mentioned in the Discussion, and it was supposed to be crucial for the whole study.\nOnce again, thank you for the opportunity to review this article.\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? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-53
|
https://f1000research.com/articles/12-52/v1
|
13 Jan 23
|
{
"type": "Opinion Article",
"title": "Genetic evolution and cellular interactions within the tumour microenvironment determine glioblastoma progression",
"authors": [
"Chloe Shard",
"Kimberley L. Alexander",
"Hui K. Gan",
"Guillermo A. Gomez",
"Kimberley L. Alexander",
"Hui K. Gan"
],
"abstract": "Glioblastoma (GBM) is the most aggressive form of primary brain cancer, with 5-year survival rates of less than 5%. Clinical management of GBM has not changed in the last 15 years, and current treatment approaches combine surgical resection, followed by radiotherapy and chemotherapy. Tragically, tumour recurrence is inevitable. Still, very little is known about how tumours evolve in response to therapy and become treatment resistant. In 2019, The Glioma Longitudinal AnalySiS (GLASS) consortium curated extensive, publicly accessible genomic profiling data captured from matched primary and recurrent tumours across 222 patients, along with comprehensive clinical annotations. Recently, this longitudinal genomic data resource was expanded by integrating matching transcriptomic and genomic data from 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma captured at two or more time points (Varn et al., 2022). This has enabled new insights into the dynamic changes in transcriptional programs, cellular compositions and microenvironment interactions within these brain tumours. In this commentary, we will focus on recurrent high-grade IDHwt and the implications of these findings for targeting tumour-microenvironment interactions that may pave new pathways for developing therapies for this type of brain tumour.",
"keywords": [
"Brain tumours",
"gliblastoma",
"recurrence",
"heterogeneity",
"tumour microenviroment",
"IDH",
"temozolomide"
],
"content": "Background\n\nGlioblastoma (GBM) is the most common and aggressive form of primary brain cancer (Ostrom et al., 2019; Wen et al., 2020). Current treatment approaches combine surgical resection, followed by radiotherapy and chemotherapy (Stupp et al., 2005; Stupp et al., 2009). Tragically, tumour recurrence is inevitable. GBM tumours are highly infiltrative, and complete surgical resection is not possible. Subpopulations of tumour cells escape resection, develop resistance to current treatments, and ultimately divide and repopulate the brain. There is no standard of care once tumour recurrence has occurred. Prognosis is poor, with a median survival rate of 15 months post-initial diagnosis, which has not improved in the past 15 years (van Linde et al., 2017; Ostrom et al., 2019; Wen et al., 2020). New therapies that effectively target renegade GBM cells are desperately needed. However, this requires greater insight into the genetic, transcriptional and microenvironmental changes that occur under therapeutic conditions that allow GBM cells to evade treatment and foster the persistence and expansion of therapy-resistant tumour cell populations.\n\nGBM tumours exhibit a high level of heterogeneity both between patients and within an individual’s tumour. Somatic alterations contribute to this heterogeneity, as clonal populations inheriting mutations that favour tumour progression arise over time (Brennan et al., 2013; Sottoriva et al., 2013; Wang et al., 2016; Muscat et al., 2017). This is proposed to promote the collective resistance of the tumour to therapy as selection pressures enrich for treatment-resistant tumour cell clones. Additionally, tumour heterogeneity impedes the development of effective treatment options, as not all patients respond favourably to the same treatment. Historically, mutations observed in the isocitrate dehydrogenase (IDH1 and IDH2) genes denoted two molecularly and clinically distinct forms of GBM, IDH wildtype (IDHwt; primary GBM) and IDH mutant (IDHmut; secondary GBM) (Parsons et al., 2008; Han et al., 2020). IDHwt tumours accounted for 95% of GBM cases and correlated with poorer prognoses. In 2021, the updated WHO Classification of Tumours of the Central Nervous System restricted the diagnosis of GBM to IDHwt tumours, with IDH-mutant tumours now classified as astrocytomas or oligodendrogliomas depending on the respective absence or presence of 1p19q co-deletions (Louis et al., 2021). As such, IDHwt tumours will be the focus of this commentary. Other common genetic alterations in GBM include amplifications of EGFR and PDGFR, activating mutations in the TERT promoter, loss of PTEN and NF1, the simultaneous gain of chromosome 7 and loss of heterozygosity of chromosome 10, and aberrations in RTK/Ras/PI3K signalling pathways, most of which negatively correlate with patient survival (Cancer Genome Atlas Research Network, 2008; Brennan et al., 2013; Barthel et al., 2019). Longitudinal mutational analysis has identified changes in molecular alterations from primary to recurrent GBM, although the reports have been conflicting (Kim et al., 2015; Wang et al., 2016; Muscat et al., 2017; Barthel et al., 2019; Draaisma et al., 2020). For example, several studies have identified reduced expression or loss of EGFR mutations in recurrent GBM, suggesting clonal replacement that favours reduced EGFR (Wang et al., 2016; van den Bent et al., 2015; Cioca et al., 2016). However, the opposite has also been observed (Neilsen et al., 2019). Conversely, the Glioma Longitudinal Analysis (GLASS) Consortium reported little evidence of recurrence-specific gene alterations, with the clonal representation of driver mutations remaining similar in primary and matched recurrence tumours (Barthel et al., 2019). Thus, rather than identifying a stereotyped trajectory in genetic evolution during therapy, they observed that most glioma tumours stochastically evolved along patient-specific paths (Barthel et al., 2019). Multiple studies have, however, identified a treatment-associated hypermutant genotype induced by the administration of alkylating agents, such as temozolomide which is part of the standard of care for GBM patients (Johnson et al., 2014; Wang et al., 2016; Barthel et al., 2019; Choi et al., 2018). Contrary to previous publications (Johnson et al., 2014), Barthel et al. (2019) did not identify a detrimental effect of the hypermutator phenotype on patient survival, so the impact of this genotype remains unclear. While genetic perturbations underlie GBM pathogenesis, it is clear that additional factors beyond somatic alterations influence therapy resistance and GBM recurrence.\n\nIn recent years, bulk RNA sequencing studies of gliomas have defined three reproducible transcriptional TCGA subtypes: classical, mesenchymal, and proneural (Verhaak et al., 2010, Wang et al., 2017). These subtypes partially correlate with genetic alterations; for example, alterations in EGFR are enriched in classical subtype tumours, while PDGFRA alterations are more common in proneural tumours (Verhaak et al., 2010). Subtype-associated differences in disease outcomes have also been observed, with mesenchymal tumours generally exhibiting a poorer prognosis, highlighting this molecular characterisation as a potentially useful clinical tool (Colman et al., 2010; Wang et al., 2017). Longitudinal analyses have demonstrated that subtype switching can occur over the time of tumour progression (Phillips et al., 2006; Halliday et al., 2014; Wang et al., 2016; Wang et al., 2017). Proneural to mesenchymal subtype switching upon disease recurrence is associated with increased resistance to therapy (Bhat et al., 2013, Ozawa et al., 2014, Phillips et al., 2006). However, the evolutionary temporal dynamics of the subtypes and the resultant recurrence-specific features are less known. Importantly, multiple subtypes can co-exist within the same tumour, as shown by multi-region bulk and single-cell RNA sequencing (Sottoriva et al., 2013, Patel et al., 2014), which contributes to intratumoral heterogeneity. Single-cell transcriptional analysis has allowed the interrogation of malignant cell subpopulations that give rise to GBM with diverse cellular compositions. Neftel et al. (2019) identified that GBM neoplastic cells exist in a limited set of transcriptional cellular states, including more stem cell-like states (neural-progenitor-like and oligodendrocyte-progenitor-like) and more differentiated states (astrocyte-like and mesenchymal-like). These states are plastic, and specific genetic alterations influence the relative frequency of each state in a tumour. For example, EGFR modifications are associated with a higher frequency of astrocyte-like cells. Beyond somatic alterations, the neoplastic transcriptional state also appears to be influenced by additional factors, such as the local microenvironment. For example, the Mesenchymal neoplastic cell state is associated with high expressions of hypoxia genes and the TCGA-MES subtype is enriched in macrophages and microglia (Neftel et al., 2019). Thus, multiple factors likely influence the dynamic evolution underpinning glioma recurrence.\n\nResistance to therapy is also influenced by interactions of tumour cells with the microenvironment of the brain (Perrin et al., 2019). The brain tumour microenvironment includes stromal cells of the native brain parenchyma, such as neurons, astrocytes, oligodendrocytes, pericytes and microvascular endothelial cells, as well as infiltrating and resident immune cells, such as myeloid cells (e.g., macrophages and microglia). Interactions between tumour cells and stromal cells in the microenvironment can elicit both pro- and anti-tumorigenic effects. For example, subpopulations of microglia can mediate either pro-inflammatory functions, facilitating the infiltration of cytotoxic T cells and decreased tumour growth, or anti-inflammatory functions, creating an immunosuppressive tumour environment that promotes tumour progression (Geribaldi-Doldán et al., 2021). GBM tumour cells can modify these interactions to fit specific survival needs allowing adaptation under environmental and therapeutic-induced stress. This selection pressure facilitates the formation of distinct regions across the tumour landscape, containing different populations of both malignant and stromal cells, distinguishable by anatomical features from histology analysis (Puchalski et al., 2018; Yu et al., 2020; Zadeh Shirazi et al., 2021; Ravi et al., 2022). Recent studies have highlighted that tumour recurrence is associated with transitions in the stromal landscape of tumours, including the immune microenvironment, that can favour tumour progression (Wang et al., 2017; Gangoso et al., 2021). Thus, understanding how GBM tumours hijack their microenvironments to promote progression will allow the identification of novel therapeutic targets beyond the driver mutation profile of tumours.\n\n\nGlioma Longitudinal Analysis Consortium (GLASS)\n\nMost studies using clinical GBM specimens have focused on primary tumour tissues captured at first surgical resection. Second and third surgical resections in GBM patients are infrequent; thus, limited tissue resources are available to study recurrent tumour interactions (Ringel et al., 2016; GLASS Consortium 2018). GBM tumours display high levels of inter-patient heterogeneity, which emphasises the need for large data sets to identify unifying trends in disease evolution. The Glioma Longitudinal AnalySiS (GLASS) consortium was initiated in 2015 to bring together leading experts across dispensary fields to accelerate understanding of glioma tumour evolution and expose therapeutic vulnerabilities (GLASS Consortium 2018). To achieve this, GLASS has curated an extensive, publicly accessible molecular and clinical longitudinal data resource from patients with multi-sampled glioma tumours. The GLASS consortium previously employed a wide-scope approach and performed genomic profiling of matched primary and recurrent tumours from 222 patients to track clonal dynamics (Barthel et al., 2019). For Varn et al. (2022), this data was expanded by integrating longitudinal genomic data with matched transcriptomic data, comprising a total of 128 IDHwt glioma patients with RNA sequencing performed for two or more time points. Moving towards a more complex, systems biological appraisal of glioma evolution, the authors provide a more comprehensive insight into the dynamic transcriptional and cellular composition changes glioma tumours undergo in response to current therapy.\n\n\nLongitudinal changes in histological features are associated with changes in cell state abundances\n\nPrevious studies have identified an association between changes in the tumour tissue microenvironment and tumour cell transcriptional state (Neftel et al., 2019). As such, the authors sought to identify longitudinal trends in transcriptional programs in recurrent tumours and their association with the physical structure and cell composition of the tumour microenvironment.\n\nThe authors observed that TCGA transcriptional subtype switching occurred in almost half of patients (49%) (Varn et al., 2022). Classical to mesenchymal was the most common transition, contributing to a slight decrease in classical tumours in favour of an overall increase in mesenchymal tumours across the cohort. To interrogate specific changes in the microenvironment and the tumour cell transcriptional state that may underlie this transition, the authors deconvoluted the GLASS gene expression dataset using CIBERSORTx (Newman et al., 2019). They identified 12 cell states representing both neoplastic and non-malignant cell compartments of the brain microenvironment. As observed in previous single-cell studies (Neftel et al., 2019), the neoplastic population could be further subdivided into distinct transcriptional states, including a differentiated-like state and two stem-like states (segregated by cell cycle activity). The relative abundance of the 12 cell states also varied across the TCGA transcriptional subtypes, supporting findings in previous publications (Neftel et al., 2019; Wang et al., 2017). By comparing matched primary and recurrent tumour transcriptomes, Varn et al. (2022) also observed an increase in oligodendrocyte populations at recurrence, independent of the extent of surgical resection. The role of oligodendrocytes within the tumour microenvironment has yet to be extensively studied. However, recent single cell (sc) RNA sequencing and in vitro studies have suggested bi-directional communication between tumour cells, non-malignant oligodendrocytes and oligodendrocyte precursor cells in the microenvironment, which may contribute to tumour progression (Hide et al., 2018; Caruso et al., 2020). The authors also observed a significant decrease in differentiated-like neoplastic cells at recurrence and little difference in the abundances of stem-like and proliferating stem-like cell populations (Varn et al., 2022), supporting the concept that relative cell compositions of the microenvironment shift as a GBM tumour evolves.\n\nUsing Ivy GBM atlas project (Ivy GAP) data (Puchalski et al., 2018), which comprises bulk RNA sequencing from five micro-dissected histological features along with multiplex immunofluorescence, the authors identified that cell state composition was more closely associated with histological features than with the patient from which they were derived (Varn et al., 2022). For example, ‘leading-edge’ features were enriched in oligodendrocytes and stem-like neoplastic cells, while differentiated-like neoplastic cells were enriched in ‘pseudopalisading cells around necrosis’ and ‘cellular tumour’ features (Varn et al., 2022). This suggests that changes in histological features may influence cell composition at tumour recurrence. After using Ivy GAP histological feature gene signatures to deconvolute the GLASS dataset, a correlation between longitudinally changing neoplastic cell state abundances and histological features was detected (Varn et al., 2022). A recent spatial transcriptomics study by Ravi et al. (2022) has since supported an association between cell state composition and physical tumour structure. The neoplastic cell states identified by Neftel et al. (2019) were also spatially segregated across distinct tumour tissue regions and hypothesised as an indication of reactive adaptation to environmental stress. While Varn et al. (2022) concluded that in most cases, the subtype switch observed at recurrence was attributable to changes in histological feature composition over time, they noted that some changes appear to be independent of this phenomenon. For example, tumours undergoing proneural-to-mesenchymal transition appeared to lose stem-like cells independently of the histological feature composition, indicating that other factors may influence cell state abundances at recurrence (Varn et al., 2022). Moreover, regardless of transcriptional subtype transition, IDHwt tumours showed significantly higher ‘leading-edge’ content at recurrence (Varn et al., 2022), which suggests that this may be a general feature of recurrent tumours.\n\n\nRecurrence specific phenotypes\n\nWhile the TCGA molecular subtypes have been a critical asset in interrogating the clinically significant molecular differences across GBM patients at diagnosis, their application to recurrent tumours may be more limited. Stratifying recurrent GBM tumours into reoccurring molecular subtypes may help determine patient-specific treatment plans for secondary tumours and identify trajectories of therapy-driven evolution as cells adapt to resist treatment. Three distinctive recurrence-associated phenotypes, i.e., neuronal, mesenchymal and proliferative, are driven by somatic mutations, interactions with microenvironment cells and changes to histological feature composition (Varn et al., 2022). Additionally, some tumours exhibited multiple phenotypes highlighting that recurrent tumours are still highly heterogeneous.\n\nThe neuronal recurrence-associated phenotype was the most common subtype observed in 66% of tumours in the GLASS IDHwt cohort (Varn et al., 2022). This phenotype was not associated with any significant impacts on patient survival. The neuronal recurrence phenotype was characterised by increased neuronal signalling gene signatures in stem-like neoplastic cell populations and an increase in leading-edge histological features. Varn et al., hypothesised that these characteristics result from enhanced tumour-neuron interactions as recurrent tumours invade the native brain parenchyma (Varn et al., 2022). To support this, they utilised scRNA-seq from spatially defined GBM regions previously produced by Yu et al. (2020) to confirm that neoplastic cells collected from the invasive rim had significantly higher expression of the stem-like neoplastic cell recurrence signature versus those collected from the tumour core. To further validate this observation, the authors performed multiplex immunofluorescence in recurrent glioma using the neuronal marker SNAP25 (Varn et al., 2022). They identified a high number of neurons and SNAP25 + neoplastic cells (SOX2+) in the infiltrating tumour region compared to the cellular tumour region, lending support to increased signalling between neoplastic cells and neighbouring neural cells at recurrence. Studies exploring neuron-to-glioma synapses have recently attracted significant research interest due to the potential influences on tumour proliferation and invasion (Venkataramani et al., 2019; Venkatesh et al., 2019). More recently, Venkataramani et al. (2022) employed patient derived xenograft (PDX) models to show that the leading edge of GBM is enriched in neoplastic cells expressing neuronal and neural-progenitor-like cell states, supporting Varn et al. (2022) observations. They also observed that leading-edge GBM cells utilise neuronal migration pathways to invade the native parenchyma where they receive synaptic input from neurons to enhance migration (Venkataramani et al., 2022). Thus, the neuronal recurrence subtype may be particularly vulnerable to therapeutic interventions that disrupt synaptic communication between tumour cells and neurons.\n\nThe mesenchymal recurrence phenotype was observed in 45% of IDHwt tumours in the GLASS cohort and was significantly associated with poorer patient outcomes than the non-mesenchymal recurrence phenotypes (Varn et al., 2022). This supports previous observations using TCGA data where mesenchymal subtype tumours were associated with treatment resistance and reduced survival (Carro et al., 2010; Bhat et al., 2013; Wang et al., 2017). The mesenchymal recurrence phenotype was characterised by an abundance of differentiated-like neoplastic cells expressing a mesenchymal-like signature and showed an enrichment of myeloid cells (Varn et al., 2022). The authors deconvoluted TCGA data to compare myeloid-specific gene expression profiles between mesenchymal and non-mesenchymal transcriptional subtypes to determine whether neoplastic and tumour-infiltrating myeloid cell interactions may be responsible for driving the transition of recurrent tumours towards this subtype (Varn et al., 2022). Intriguingly, mesenchymal tumours displayed a distinct myeloid-specific gene expression profile, exhibited an immunosuppressive phenotype and were enriched in chemokine signalling and lymphocyte chemotaxis functions. Following transcriptional subtype transitions over time, a significant induction of this signature was identified in recurrent tumours undergoing a mesenchymal transition (Varn et al., 2022). Using the IVY gap data (Puchalski et al., 2018), Varn et al., identified that this specific mesenchymal-myeloid signature was most associated with the ‘pseudopalisading cells around necrosis and microvascular proliferation’ histological features, which are features that are enriched with blood-derived macrophages. Thus, the authors hypothesised that some blood-derived macrophages directly interact with mesenchymal neoplastic cells at these specific regions (Varn et al., 2022). To test this, Varn et al., screened for candidate ligand-receptor pairs expressed in mesenchymal neoplastic cells and myeloid cells that specifically associate with mesenchymal transitions over time. This identified oncostatin M (OSM), expressed by myeloid cells, and oncostatin M receptor (OSMR), expressed by differentiated-like neoplastic cells, as the top candidate genes. Using multiplex immunofluorescence, the co-localisation of OSM+ myeloid cells and OSMR+ neoplastic cells around blood vessels was confirmed in mesenchymal IDHwt glioma samples (Varn et al., 2022). No co-localisation patterns were observed in the classical subtype tumours. Association between microglia/macrophage OSM expression and induction of mesenchymal-like expression programs in glioma has been reported by previous studies and proposed to be induced via the upregulation of STAT3 signalling in neoplastic cells (Natesh et al., 2015; Junk et al., 2017; Hara et al., 2021; Chen et al., 2021). OSM is a cytokine belonging to the IL-6 family, which is secreted by macrophages and microglia in the brain to regulate inflammatory responses (Modur et al., 1997). There is contradictory evidence for the role of OSM in glioma progression with some studies suggesting it exhibits anti-tumorigenic effects (Friedrich et al., 2001), while others have reported pro-invasive properties and an overall negative association between OSM expression and glioma patient survival (Natesh et al., 2015, Chen et al., 2021). Beyond the influence of stromal cells in the microenvironment, Varn et al. (2022) also observed that specific somatic alterations, such as NF1, EGFR or PDGFRA, are associated with mesenchymal transitions. These somatic alterations also affected non-neoplastic cell abundance; for example, NF1 mutants exhibited increases in granulocytes and myeloid cells, supporting previous observations (Wang et al., 2017). Thus Varn et al. (2022) have identified a complex interplay of microenvironmental and genetic factors that drive tumour transition towards the more aggressive mesenchymal subtype. Exploring potential vulnerabilities in tumour-myeloid interactions may be one avenue that can be exploited to improve patient survival.\n\nThe proliferative recurrence phenotype, characterised by increased proliferating stem-like neoplastic cells, was identified in 37% of IDHwt tumours (Varn et al., 2022). By analysing orthogonal DNA and RNA sequencing data of primary and matched recurrent tumour pairs, Varn et al. (2022) identified an increase in proliferating stem-like neoplastic cells associated with a hypermutation genotype at recurrence. As previously established, alkylating agents, such as Temozolomide, can induce hypermutation (Wang et al., 2016; Johnson et al., 2014). Using multiplex immunofluorescence, Varn et al. (2022) confirmed an increase in proliferating stem-like cells (SOX2+/Ki67+ cells) in recurrent IDHwt tumours relative to matched initial tumour tissue. Although the authors identified a positive association between proliferating stem-like cells and microvascular proliferation across the GLASS cohort, no corresponding increase in this histological feature was observed in hypermutant recurrence tumours (Varn et al., 2022). This suggests that factors other than the physical structure of the tumour, such as genetic alterations, influence the relative abundance of proliferating stem-like cells. Hypermutant recurrent tumours have been associated with an increased frequency of CD8+ T cells when compared to their primary tumours, contributing to a potentially more immunologically reactive microenvironment (Wang et al., 2017). However, Varn et al. (2022) did not observe any significant changes in the relative abundances of stromal cells, including T-cells, between hypermutated recurrences and their matched initial tumours. Treatment-associated hypermutation is more frequently observed among IDHmut tumours than IDHwt tumours suggesting sensitivity to mutation upon loss of IDH function (Barthel et al., 2019). Indeed, the authors detected the proliferative recurrence phenotype in 53% IDHmut tumours, which is negatively associated with patient survival (Varn et al., 2022). No such survival association was seen in IDHwt tumours. The clinical relevance of the hypermutation phenotype is still elusive for IDHwt tumours and highlights the need for future studies into the impact of hypermutation on disease progression.\n\n\nConclusions\n\nOne major obstacle to effective treatment for IDHwt GBM tumours is the high cellular heterogeneity that is a feature of both primary and recurrent tumours. Molecular characterisation of primary tumours, such as the gene expression-based TCGA subtypes, has dramatically advanced our understanding of clinically relevant molecular differences across patient groups associated with therapy responses. However, the translation of these findings to improve patient outcomes is still limited. In this study, the GLASS consortium has more comprehensibly mapped the molecular characteristics of tumours over patients’ disease trajectories (Varn et al., 2022). They identified that genetic and environmental factors shape the composition of cell states in IDHwt tumours. This has provided a framework for recurrent GBM molecular stratification, identifying three recurrence-specific phenotypes which may display distinct therapeutic vulnerabilities (Figure 1).\n\nA) The Glioma Longitudinal AnalySiS (GLASS) consortium cohort comprises a comprehensive molecular data resource of glioma tumour tissues, including clinical annotations, imaging and genomic data sampled at multiple time points along the course of glioma progression. For Varn et al. (2022), this data was expanded by integrating matched longitudinal bulk transcriptomic data. B) Recurrent IDHwt gliomas can be stratified into three recurrence-specific phenotypes: neuronal, mesenchymal, and proliferative. Each phenotype is associated with specific histological features, molecular alterations, and clinical outcomes. Phenotype presentation across the GLASS cohort varies in frequency, and notably, some recurrent tumours can exhibit multiple phenotypes at once, indicating intra-tumour heterogeneity. Figure created with BioRender.com.\n\nFuture studies should further elucidate how the interplay between tumour cell states, driver mutations and the microenvironment can be exploited to skew tumours towards a sensitised molecular subtype that can be effectively treated with radiotherapy and/or chemotherapy. Achieving this aim will require experimental GBM models that better recapitulate the parental tumour, assess therapeutics along the clinical time course, and build predictive treatment models (Schäfer et al., 2019; Gomez et al., 2019; Lenin et al., 2021). Incorporating such methods into standard-of-care practice will help to facilitate personalised therapies for GBM patients that lead to better patient outcomes.",
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PubMed Abstract | Publisher Full Text | Free Full Text\n\nZadeh Shirazi A, McDonnell MD, Fornaciari E, et al.: A deep convolutional neural network for segmentation of whole-slide pathology images identifies novel tumour cell-perivascular niche interactions that are associated with poor survival in glioblastoma. Br J Cancer. 2021 Aug; 125(3): 337–350. Epub 2021 Apr 29. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "310825",
"date": "28 Sep 2024",
"name": "Dinorah Friedmann-Morvinski",
"expertise": [
"Reviewer Expertise glioblastoma",
"tumor plasticity",
"immunotherapy",
"tumor microenvironment",
"pre-clinical models of cancer"
],
"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 commentary delves into the complex landscape of glioblastoma (GBM) progression, specifically focusing on IDH-wildtype (IDHwt) tumors. It explores how genetic evolution and intricate interactions within the tumor microenvironment contribute to treatment resistance and recurrence. The authors highlight the significance of longitudinal analyses, such as those facilitated by the Glioma Longitudinal Analysis Consortium (GLASS), in unraveling the dynamic changes that occur in these tumors over time. The manuscript offers a well-structured and insightful exploration of the dynamic evolution of IDHwt gliomas, emphasizing the challenges posed by their substantial cellular heterogeneity.\nStrengths:\nLeverages longitudinal data to provide a crucial temporal perspective on glioma evolution and identify potential therapeutic targets at different stages. Integrates histological and molecular data for a comprehensive understanding of tumor progression, revealing key correlations between cell states, mutations, and microenvironment. Identifies distinct recurrence-specific phenotypes and their potential vulnerabilities, offering valuable insights for developing targeted therapies for recurrent gliomas. Cites up-to-date literature and relevant research in the field.\n\nAreas for Further Exploration:\nIn the tumor microenvironment section, further expand on the role of ECM dynamics, including remodeling, mechanical properties and stiffness, in shaping tumor evolution and therapeutic resistance. Provide a more refined analysis of the diverse roles of myeloid cells within the TME, considering the contributions of distinct macrophage and microglia subtypes. Further explore the concept of phenotypic plasticity and its implications for therapy, particularly in light of its inclusion as an emerging hallmark of cancer in D. Hanahan's recent review.\nOverall, this commentary offers valuable insights into the complex landscape of GBM progression, emphasizing the need for considering both genetic and environmental factors in developing effective therapies. The identification of recurrence-specific phenotypes opens new avenues for personalized treatment approaches, although further validation and exploration of therapeutic implications are needed. A deeper discussion into specific aspects of the microenvironment, and a focused on phenotypic plasticity would enhance its significance.\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? Yes\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? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-52
|
https://f1000research.com/articles/11-1279/v1
|
09 Nov 22
|
{
"type": "Research Article",
"title": "The conditional effect of family resilience on family quality of life during the Covid-19 pandemic",
"authors": [
"Tery Setiawan",
"Ria Wardani",
"Ellen Theresia",
"Ria Wardani",
"Ellen Theresia"
],
"abstract": "Introduction This study examines how the Covid-19 economic impact and parental stress are moderated by family resilience to relate to the family quality of life (FQOL). Methods We modify the measure of FQOL, developed by Beach Center on Disability, by including only four domains (i.e., family interaction, parenting, emotional well-being, and material well-being) to adjust to our research context. Results Based on 169 participants, our CFA displays that all employed measures in the study are valid and reliable. Our regression analysis shows that there are significant direct relations of parental stress & family resilience with family quality of life. However, we find that family resilience only positively moderates the relation between the Covid-19 economic impact and family quality of life. Discussion This study presents a view on how the Covid-19 pandemic affects the way families live and hence, their quality of life.",
"keywords": [
"family quality of life (FQOL)",
"family resilience",
"Covid-19",
"parental stress",
"Indonesia"
],
"content": "Introduction\n\nThe emergence of coronavirus disease (Covid)-19 in Indonesia, as in the rest of the world, has changed almost all aspects of human life rapidly. Due to the Covid-19 pandemic, the government implemented a large-scale social restriction policy that involved the closing of offices, factories, and schools as well as putting in place social distance in individuals’ interaction (Meiliana, 2020). As a result, the policy has forced family members to spend as much time as possible at home, making it more as home confinement (Wang et al., 2020). Children are no longer able to carry out learning activities at school, as well as leisure activities with their peers. In the meantime, parents are also the subject to home confinement. They need to work from home while, at the same time, are expected to oversee their children study at home (Griffith, 2020).\n\nAlthough the experience of working from home is likely to be unpleasant for most families, this appears to be a better option than being unemployed or forced to close a business due to the pandemic. Data from the Ministry of Manpower on 27 May 2020 shows that there are at least 1.79 million workers who must be laid off due to the Covid-19 pandemic (Idhom, 2020). This number is predicted to continue to grow up to four to five million people (Gusman, 2020). To further complicate, Covid-19 places the elders as individuals with the highest risk of getting infected (Aronson, 2020). Therefore, the tradition of asking grandparents for help in supervising the children is no longer an option. With health protocols in force, this also means limited opportunity in receiving social support from family, neighbours, and friends. The lack of social support places a greater stress among parents. Based on all this, we argue that the combination of economic hardship and parental stress is likely to have negative impact on family processes, which can be observed in their quality of life (Hall & Clare, 2003; Hsiao, 2018).\n\nInvestigating family quality of life, rather than individual, during the pandemic is important, yet remains little studied; let alone studies in the Asian context, such as Indonesia. In a mundane life, children and parents are an integral part of a society which generally reflect a society’s quality of life (for further explanation, see the ecological system of a family by Bronfenbrenner, 1986). Children’s living condition is heavily contingent on their parents’ living condition, similar to how parents’ satisfaction with their life is largely dependent on their working condition as well as how their children feel and perceive towards their life (Prime et al., 2020; Thomas et al., 2017). During the Covid-19 pandemic, this claim has become even more evident. A significant change, e.g., unemployment, that occurs within a family is likely to be experienced by the whole system. Therefore, investigating family quality of life (from here onwards is abbreviated FQOL) is of great importance to unfold the potential effects brought by the pandemic.\n\nIn relation to the Covid-19 pandemic, parents are deemed to have a certain level of stress in their parental role (Griffith, 2020). The stress is assumed to be more increased when there are additional demands arise from the pandemic, e.g., uncertainty in employment, medical conditions caused by Covid-19 infection, etc. In addition, the response policy to the Covid-19 pandemic may significantly pose external demands to parents, e.g., inability to have quality time outside home. Consequently, parents have a higher chance to run out of psychological resources to be able to regulate their emotions which can affect their effectiveness in their parental role (Östberg, 1998). As such, the pandemic not only decreases both material and psychological resources among parents, it also heightens their daily stress level. As a result, the heightened stress level may impair their family quality of life (Hall & Clare, 2003; Hsiao, 2018; Melberg, 2012).\n\nNevertheless, previous studies have shown that despite economic and psychological obstacles there are some who demonstrate competent family functioning (Patterson, 2002). According to Walsh (2003), the family’s ability to fulfil their functions of providing basic needs, nurturing children, and other family functions amid ongoing economic and psychological strains is known as family resilience. There are three key family processes that have been shown to protect and even increase family quality of life, namely family belief systems, family organizational patterns, and communication/problem solving processes. All three key processes are argued to reduce stress among family members during the pandemic, (Prime et al., 2020). Therefore, despite economic hardships during the pandemic families with high level of family resilience are expected to be able to deal with the adversity positively and hence, maintain their quality of life.\n\nTaken together, it is of great importance to scrutinize family quality of life using relevant predictors during the Covid-19 pandemic. Yet, as previously mentioned, there is still very little research on the economic impact of Covid-19 on families in Indonesia. When such study exists, either it relies on secondary data (cf Radhitya et al., 2020) or it mainly focuses on the economic indicators of the family. Thus, our study has two-fold relevance. First, for a theoretical purpose, we empirically test a theoretical model of risk and protective factors to family quality of life. As such, we are able to delineate and predict to what extent family quality of life is affected by economic aspect of the Covid-19 pandemic. Second, for a methodological purpose, we extend the applicability of FQOL measure in the general family context (see Zuna et al., 2009a for a validation of FQOL measure in families without disabilities). In summary, we aim to investigate to what extent family resilience moderates the relation between Covid-19 economic impact & parental stress during Covid-19 and family quality of life in several cities of Indonesia. We will do so by employing general population of adults aged 18 above who are married and have, at least, one child.\n\n\nTheoretical framework and hypotheses\n\nIn this section, we provide brief theoretical explanations related to psychological constructs employed in the study. We carefully selected these constructs based on the literature available. We will start the explanation from the outcome variable and continue to relevant predictors.\n\nHistorically, quality of life is an interest of scholars in the field of health science, especially patients with disabilities (Hoffman et al., 2006; Hu et al., 2011). Its importance has inspired many studies not to focus merely on individuals, but also on family (e.g., FQOL measure). In 1998, WHO initiated a research attempted to devise a universal instrument of quality of life, which can cover both ‘ill’ and ‘well’ samples (Division of Mental Health and Prevention of Substance Abuse, 1998). Its exploratory study consisted of patients with ill disease, ‘healthy’ patients, and health care providers. The final study involved 13 countries and 8,294 participants. The validity analyses suggested the measure to include six domains and 24 specific facets, including negative and positive feelings that usually refer to well-being measure. The measure has a two-fold indication. One, quality of life measure is a concern of every individual, regardless of their physical background. Two, the notion greatly overlaps with the concept of well-being; measuring one inevitably includes the other and vice versa. In times of the pandemic, people and their families are likely to be affected by ever-changing and pervasive health policies. Therefore, it is vital to investigate FQOL to predict the impact the pandemic has on a family and protect them against the risk factors resulted from the pandemic.\n\nThe conceptualization of FQOL relies on the following theoretical frameworks, (1) systemic concepts, (2) performance concepts, (3) individual-member concepts, and (4) family-unit concepts (Zuna et al., 2009b). In a nutshell, the organizing frameworks suggest that the macro-level systems outside the family, e.g., healthcare, education, along with their policies and programs are associated with individuals’ demographic and characteristics, which directly impact individuals (Hoffman et al., 2006). As each family member is associated to each other and to their habitat, any change experienced by a family member directly (and indirectly) impacts the whole family system (Samuel et al., 2012). Therefore, a substantial change to normality brought by the Covid-19 pandemic is considered to highly impact family quality of life.\n\nBesides health effects, the most direct impact of the Covid-19 pandemic comes from the economic aspect. Due to Covid-19, a lot of business are forced due to a wide-spread lockdown measure. Especially Indonesia, this has led to millions of job loss (Idhom, 2020). Although the government has provided subsidies for those who lost jobs during the pandemic, the support is not sufficient to cover monthly bills and necessities for the whole family (Saptoyo, 2021). Based on the family systems theory, the significant economic change will likely to disrupt the family balance (Samuel et al., 2012). The relationship between parents’ adversity and child’s well-being work in a mutually reinforcing system; stress and disruption experienced by one party will affect the other. This significant economic change is expected to impact all dimensions of FQOL (Hall & Clare, 2003).\n\nIn detail, FQOL is generally thought to include dimensions such as closeness, family interaction, family’s financial situation and a room for personal growth (Hu et al., 2011). Based on its conceptualization, most of the FQOL scales emerge as an alternative and practical measure to the use of multiple measures. In this study, we specifically use the Beach Center FQOL scale (Beach Center on Disability, 2012). The measure consists of five domains, namely family interaction, parenting, emotional well-being, material well-being, and disability-related support. For the purpose of the study that focuses on general population, we retain four dimensions and leave out the last dimension. This use can be equally compared to FQOL scale proposed by Zuna et al. (2009a).\n\nStudies show that through aerosol droplets, a single-stranded ribonucleic acid (RNA) of the Covid-19 can infect up to 2.5 noninfected individuals (Kaye et al., 2021). This infection has been shown to cost a human’s life or, at a less severe level, hospitalization. Due to the severity of the disease, the Covid-19 called for a special set of social and health protocols. As a result, the protocols inevitably started to disrupt supply chain of many trades, caused sudden unemployment, and forced closure of a great number of business (Akbulaev et al., 2020; International Labour Organization, 2020). Not only does it pose economic cost on individuals, it has also precipitated many psychosocial impacts such as depression, substance abuse, etc (Bu et al., 2020; Maital & Barzani, 2020). The latter impact, of course, can also be caused by the former due to a sudden change.\n\nSpecifically in Indonesia, the arrival of the Covid-19 has brought many unprecedented challenges to the families. According to a joint survey conducted by UNDP, UNICEF, Prospera and the SMERU Research Instittute (2021), 74.3% of all the households they interviewed during October to November, 2020 admit that their family was earning less than they were in January of the same year. This, in turn, heightened the proportion of low-income households across the country. In specific, this economic impact was felt greater among families in urban areas. The drop in income was also reported in all variety of income groups. On the other hand, the economic impact was exacerbated by increased cost of daily life, such as groceries. Covid-related expenditures, e.g., face mask, mobile communication also played a part in increasing living cost. Therefore, it is safe to say that the Covid-19 pandemic has brought economic hardships in most families across Indonesia.\n\nIn relation to FQOL, the economic impact seems to have a direct relation with the way families have to adapt. Hsiao (2018) shows that parental income plays a significant role on the FQOL. Many people are less satisfied with their financial circumstances during the pandemic (SMERU et al., 2021). For others, the situation is even worse due to sudden unemployment or the closing of a business, and hence, forcing them to temporarily rely on government subsidy and aid (Gusman, 2020; Idhom, 2020). Based on this, we expect that the Covid-19 economic impact, marked by less income and increased expenditure, is negatively related to FQOL (H1).\n\nIn general, parental stress is inherent in the parental role on a daily basis (Cronin et al., 2015). The parental role includes providing care and developing intimate relationships, both of which can be exhausting and rewarding in itself. As such, it is common for parents to report some degree of parental stress in performing the role. Specifically, parental stress is defined as a set of physiological and psychological negative reactions towards the process of adaptation and demands in carrying out parental roles (Pontoppidan et al., 2018). Without any specific family hardship, to some degree the stress is assumed to have no significant implication on the family. On the contrary, in times of difficulty, parental stress is likely to increase and will negatively affect parent–child relationship (Respler-Herman et al., 2012). In addition, the degree of parental stress is strongly dependent on the stage of child development and the demands faced by parents (Louie et al., 2017; Pontoppidan et al., 2018).\n\nIn looking further at parental stress, one should also consider it from the perspective of how parents respond to their stressful situations (Cronin et al., 2015). This becomes a key for parents in managing the stress they experience and finding effective coping strategies. Specifically, when parents perceive the role of parents as rewarding, for example through happiness, enjoyment, optimism, intimacy and satisfaction with the child, then they are likely to reap satisfaction from performing the parental roles (Berry & Jones, 1995). Those with high parental satisfaction are expected to enjoy performing their role as parents, enjoy being close to children and can show positive emotions when they are with the children. On the other hand, parents who perceive parenting as burdensome and demanding are expected to have a high degree of stress to the extent that they have difficulty in recognizing their children’s basic needs (Respler-Herman et al., 2012).\n\nIn line with this, parental stress scale (PSS) was developed as a way to determine the extent of parental stress in carrying out parenting role (Berry & Jones, 1995; Pontoppidan et al., 2018). This is measured through the dichotomy of the parental stress subscale and the parental satisfaction subscale. PSS has been adapted in various countries such as China, Spain, Portugal, Denmark, Malaysia, and many others (Pontoppidan et al., 2018). Given the fact that the Covid-19 pandemic has brought many difficulties to a large number of families in Indonesia, it is likely that the level of parental stress is increased while the parental satisfaction is decreased. Events, such as supervising child (ren) while working at home, being restricted to indoor activity, are likely to cause disturbances among parents (Griffith, 2020). Therefore, in times of the Covid-19 pandemic, we expect that parental stress is negatively related to FQOL (H2).\n\nResilience has been widely studied both at the individual as well as at the family levels (Masten, 2019). While the former level refers to individual’s capacity to ‘bounce back’ from difficulty (Smith et al., 2008), the latter refers to the capacity of a family system to survive and emerge from unfavourable circumstances, and to get stronger and more empowered (Walsh, 2003). This definition is in line with the conception of family as an adaptive system and a context for human development.\n\nFamily resilience has extended the development of theory in the field of family stress, coping, and adaptation (Patterson, 2002). During difficult times, family resilience will manifest itself in the extent to which a family is able to fulfil family functions, i.e., family membership, economic support, nurturance, and protection (Li et al., 2019). We can claim that family resilience is a buffering factor in which families can rely on in times of hardship. However, it is important to note that there are times when families are able to swiftly bounce back from one adversity but take longer to recover from another type of adversity. This suggests that family resilience is also a process of continual growth and change across the life-span (Walsh, 2003).\n\nFurthermore, Walsh (2003, 2016) identify three key processes within domains of family functioning to define family resilience. The dimensions are (1) family belief system which consists of sub-components of making meaning of adversity, positive outlook, transcendence and spirituality; (2) organizational processes that consists of flexibility, connectedness, and mobilizing sources and economic resources sub-components; and (3) communication/problem-solving processes consisting of clarity, open emotional sharing, collaborative problem-solving. The three key processes enable families to work together in times of great stress in order to fulfil family functions mentioned earlier (Prime et al., 2020).\n\nSpecifically, it is argued that family belief systems reflect by and large how families view happiness as well as adversity (Walsh, 2003). The latter, indeed, shapes family members in their search for a meaning in times of crisis. During the Covid-19 pandemic, those with well-functioning belief system tend to look for positive motivation and encourage each other to get past the adversity. As Walsh (2016) argues, this type of family is likely to see adversity as a challenge which they can overcome with their available resources. At the same time, this way of thinking drives family members for a closer connection among each other. Through the times of the pandemic, well-functioning families show flexibility in adapting to new challenges. They are likely to adapt to a new situation by turning to each other for emotional and material resources and thus, strengthening their connectedness (Prime et al., 2020). Furthermore, families with well-functioning belief system and positive organizational pattern are able to show positive collaboration in times of crisis. Through connectedness, they are able to share their opinions and feelings openly (Walsh, 2003). This open communication allows family members to create effective decision-making process and hence, they are likely to operate effectively in their efforts to solve problems. On the whole, the combination of three key process of family resilience is a buffer to protect family functioning in times of crisis. Therefore, we hypothesize that family resilience positively moderates the relation between Covid-19 economic impact and FQOL (H3). Similarly, parental stress is likely to be heightened due to unprecedented social policies implemented during the Covid-19 pandemic. However, taking into account the potential buffering effect of family resilience, we expect that it positively moderates the relation between parental stress and FQOL (H4).\n\nWe employ demographic information to further explore the FQOL. Typical information such as gender, age, educational level, and number of child are included as individual’s characteristics. We also take demographic information as control variables to help ensure that there are no spurious relationships when considering the relevant predictors.\n\n\nMethods\n\nPrior to the study, we have carefully reviewed our steps of data collection to ensure that we conform to the ethical principles of psychology and social science fields. The ethical committee of the Faculty of Psychology where the authors are affiliated have approved the ethical clearance for the questionnaire and the survey (3/Psy/2021 on 1 June 2021). In addition, we have published the protocol for this study and it is publicly available (dx.doi.org/10.17504/protocols.io.3byl4jbz2lo5/v1). In this section, we start by explaining participants involved and continue to measures employed in the study. Finally, we conclude by delineating our strategy for analysis to answer the proposed hypotheses.\n\nThis study was conducted online from August 2021 until October 2021 using Qualtrics involving participants from all around the archipelago. This was done by involving local enumerators from several big cities, i.e., Bandung, Jakarta & its vicinities, Makassar, and Ambon, and instructed them to purposively distribute the Qualtrics link to local universities. Although we did not aim for a nationwide generalizability, we believe that the selection of these cities represent a relevant case of Covid-19 impact on mostly urban areas (see Gusman, 2020; Idhom, 2020; Radhitya et al., 2020). Our selection criteria of participants were (1) a parent who lives together with their child (ren) and with or without their spouse or partner, and (2) has lived in their city of residence for at least two years. We acknowledge that there are limitations to our purposive sampling strategy, such as sampling representativeness. However, due to the Covid-19 measures, this was the best option to pursue in gathering participants from various locations. We also acknowledge that our participants would be biased towards middle income family due to the requirement of internet connection, accessible device and an intermediate skill of operating it. For this, sociodemographic information will be treated as control variables in the main analysis to ensure that there are no spurious relationships.\n\nIn a span of 3-month period, we distributed the survey link and successfully recruited 212 participants. The survey took about fifteen to twenty minutes to complete. The participants did not receive reward in any form. From 212 participants, we were only able to involve 169 participants due to either a substantial number of missing values or incomplete survey after 2 months. One from Takengon, two from Medan, 66 from Bandung and its vicinities (e.g., Cimahi, Garut, Sumedang, Tasikmalaya), 41 from Jakarta and its vicinities (i.e., Bekasi, Bogor, Serang, and Tangerang), 18 from Semarang and its vicinities (Cilacap, Yogyakarta, and Kebumen), four from Palangkaraya and its vicinities (i.e., Tarakan and Pontianak), seven from Surabaya and its vicinities (i.e., Nganjuk, Rembang, and Sampit), three from Denpasar and its vicinity (i.e., Labuan Bajo), nine from Makassar and its vicinities (i.e., Sengkang and Manado), 17 from Ambon, and finally one from Timika Papua. Table 1 provides the overview of our participants.\n\nPrior to filling in the questionnaire, the participants were given brief information of the study. Next to that, they were required to give an informed consent that they have been given sufficient time to carefully read the study information and there was no undue influence on their decision to participate. If agreed, participants were allowed to move on to the questionnaire. Otherwise, they would be directed to the end of the survey. No ‘consent for publication’ was necessary as the survey did not require personal information, such as name, initial, and other traceable information. We also disabled the recording of the internet protocol (IP) address on the Qualtrics survey to ensure that no unnecessary personal information was recorded. In terms of data management, only the research team had access to the dataset excluding the local enumerators.\n\nWe employed measures that have been tested in previous studies. To ensure their applicability in our research context, we conducted confirmatory factor analysis (CFA) using lavaan package in R version 4.2.1 (RRID:SCR_001905; https://lavaan.ugent.be/). In addition, we calculated Alpha Cronbach to assess the internal consistency of all the measures and average variance extracted (AVE) and composite reliability (CR) to measure the amount of variance that is accounted for by the latent constructs (Fornell & Larcker, 1981). The conventional benchmark for reliability level is larger than 0.70 or 0.80 (Brunner & Süß, 2005). As for AVE, the value should be larger than any correlation found between any pair of latent constructs or minimum at 0.50 (Fornell & Larcker, 1981). However, when AVE is found to be lower than 0.50 but CR is higher than 0.60, Fornell and Larcker (1981) argue that due to a more conservative estimate of convergent validity a construct with AVE lower than 0.50 can still be considered valid. Table 2 provides a bivariate correlation of the variables along with the value of AVE.\n\n* Bold indicates significance at 0.05.\n\nAs mentioned earlier, we employed a measure of FQOL by Beach Center on Disability (Hoffman et al., 2006). The scale assesses family member’s perception towards the different aspects of family life. The original scale consists of five domains, namely family interaction, parenting, emotional well-being, physical/material well-being, and disability-related support. There are 25 items in the original scale, but with the exclusion of disability-related dimension we employed 19 items spread across four dimensions. Family interaction is assessed through items such as, “My family enjoys spending time together”. Parenting is measured by items such as, “Family members help the children learn to be independent”. Emotional well-being is assessed through items such as, “My family has the support we need to relieve stress”. Finally, material well-being poses items such as, “My family has a way to take care of our expenses”. All items are rated on a five-point Likert scale, with 1 being very dissatisfied and 5 being very satisfied.\n\nBased on the CFA results, we observe that the measurement model is indeed composed of four dimensions. However, the first model did not show a good fit with the data. We noticed that one item from each dimension of material well-being, family interaction, and parenting shared a substantial variance with other dimensions. After the removal the CFA shows a better fit model, Chi-squared = 191.94, p < 0.001, confirmatory fit index (CFI) = 0.94, root mean square error of approximation (RMSEA) = 0.08, and the standardized root mean squared error (SRMR) = 0.04 (see Appendix 1 in the extended data for a final list of items). According to Hooper et al. (2008), such fit measures are considered as a good fit model. The factor loadings of the remaining items range from 0.47 to 0.72, indicating a good level of accounted variance (Peterson, 2000). In addition, the dimensions of the scale have a high level of reliability, with α = 0.89 for family interaction, α = 0.87 for parenting, α = 0.81 for emotional well-being and finally α = 0.74 for material well-being.\n\nAccording to a report by SMERU et al. (2021), Covid-19 has brought economic challenges to many families across Indonesia. They based their conclusion on two main economic indicators, namely reduced income and increased expense. Therefore, to assess the economic impact brought by the Covid-19 pandemic, we asked two items regarding respondents’ change of income and expense. Respondents were asked to rate the items on a three-point Likert scale. The option categories range from 1 being income/expense is reduced to 3 income/expense is increased. Later in the analysis, we reversed the answer on a change of income item and calculated the total score for both items. Due to a two-item scale, we calculated its reliability by running a Pearson correlation and the result shows a significant correlation (r = 0.17, p = 0.02).\n\nParental stress scale (PSS) was employed to determine the extent of parental stress in carrying out parenting role during the Covid-19 pandemic (Berry & Jones, 1995; Pontoppidan et al., 2018). The scale is composed of two subscales, that is the level of parental stress and the parental satisfaction. Parental stress subscale asks respondents to rate their perception towards their parental role through items, such as “Having children has been a financial burden”. While parental satisfaction asks respondents to rate their satisfaction towards their parental role through items, such “I feel close to my child (ren)”. All items combined make up a total of 18 items and are rated on a five-point Likert scale, with 1 being strongly disagree and 5 being strongly agree. To compute the scale, we reversed the answer on all items in parental satisfaction subscale and then calculated the total score based on all items.\n\nThrough CFA, the first model shows a poor fit model. We observed that four items of parental stress subscale and one item of parental satisfaction subscale had a substantial shared variance with another subscale. After the removal of those items, the CFA shows a good fit model, Chi-squared = 116.89, p < 0.001, CFI = 0.95, RMSEA = 0.07, and the SRMR = 0.05. The factor loadings range from 0.51 to 0.71, indicating an acceptable level. The two subscales show a high level of reliability, α = 0.88 for parental stress and α = 0.90 for lack of parental satisfaction.\n\nWe assessed family resilience by employing family resilience framework by Walsh (2003). The framework proposes a multidimensional scale of family resilience, consisting of belief systems, organizational pattern and communication/problem solving (Walsh, 2016). Belief systems asks respondents to rate themselves on statements, such as “We try to understand the stress situation and focus on our choice”. Organizational pattern consists of statements on family’s flexibility and the way they organize themselves in times of crisis, such as “We are flexible in adapting to a new challenge”. Finally, communication/problem solving assesses respondents’ way of communication in a family through statements, such as “We can express our opinion and be honest to one another”. Similar to previous scales, all items are rated on a five-point Likert scale, with 1 being strongly disagree and 5 being strongly agree. In total, the original scale consists of 32 items.\n\nThe first model in our CFA shows a poor fit model. Four items from belief systems dimension, and one item each from organizational pattern and communication/problem solving dimensions should be reconsidered due to cross loadings and low factor loading. After the removal of those items, the CFA demonstrates a good fit model, Chi-squared = 443.34, p < 0.001, CFI = 0.94, RMSEA = 0.06, and the SRMR = 0.05. The factor loadings of the remaining items range from 0.46 to 0.73, showing an acceptable level. Finally, all the dimensions of the scale show a high level of reliability, α = 0.91 for belief system, α = 0.93 for problem solving and α = 0.82 for organizational pattern.\n\nWe employed straightforward demographic questions concerning age, gender, educational level, and the number of child (ren). These items help us in the main analysis to ensure that there are no spurious relationships of interest when individual characteristics are factored in the statistical models.\n\nPrior to running the main analyses, we conducted preliminary tests to ensure that our data fit the statistical assumptions, i.e., linearity, normal distribution, and multicollinearity. The ANOVA tests show that most of our predictors have a linear relationship with the FQOL. Moreover, the values of skewness and kurtosis of all our variables are in the range of −0.40 to 0.58 to −0.71 to 1.46, respectively, which suggest an acceptable range of normal distribution (Kim, 2013). Finally, the multicollinearity tests show that the values of variance inflation factor (VIF) and tolerance statistics are within acceptable range, that is from 1.01 to 1.08 and 0.93 to 0.99, respectively (Field, 2009; O’Brien, 2007). Based on all this, we can safely continue to our moderation analysis. In doing so, we mean-centred the predictors to enable easier interpretation on the results, i.e., high level of family resilience refers to above the mean and low level refers to below the mean.\n\n\nResults\n\nWe ran a moderation analysis in a step-wise fashion. Table 3 provides the full results of the analysis. In Model 1, we included only the main predictors of Covid-19 economic impact and parental stress. Here, although the relation of Covid-19 economic impact with FQOL is negative, it is not significant enough to affect FQOL (b = −0.12, p = 0.22). Furthermore, Model 1 shows that there is indeed a significant negative relation between parental stress and FQOL (b = −0.46, p < 0.00). Based on Model 1, we can conclude that the results disconfirm a hypothesis on the negative relation between Covid-19 economic impact and FQOL (H1) but fully supports a hypothesis on the relation between parental stress and FQOL (H2).\n\n* Bold indicates significance at 0.05.\n\nSubsequently, Model 2 adds family resilience into the model. Here, it shows that there is a substantial positive relation between family resilience and FQOL (b = 0.69, p < 0.00). This result indicates a plausible conditional effect of family resilience on the relation between the predictors and FQOL. However, the interaction effect should be tested further. Hence, we continue to Model 3 and Model 4.\n\nIn Model 3, with the inclusion of interactions between Covid-19 economic impact & parental stress and family resilience, we demonstrate that the significance of main effects remain similar (b = −0.27, p < 0.00 for parental stress; b = 0.78, p < 0.00 for family resilience). Further, we notice that there is a positive interaction between Covid-19 economic impact and family resilience on FQOL (b = 0.32, p = 0.02). On the contrary, there is no significant interaction between parental stress and family resilience on FQOL (b = 0.22, p = 0.08). Therefore, the results partially confirm the moderation hypotheses. We confirm that family resilience positively moderates the relation between Covid-19 economic impact and FQOL (H3), however, we reject the notion that family resilience positively moderates the relation between parental stress and FQOL (H4).\n\nFigure 1 shows that although the medium and high family resilience groups seem to show a decrease in FQOL, here, we clearly see that those with medium to high family resilience level are better positioned in their quality of life in relation to their perception towards Covid-19 economic impact. Interestingly, those with low family resilience level are likely to show an increase in their FQOL when they perceive higher Covid-19 economic impact. On the other hand, Figure 2 shows that the main effect of parental stress is large enough to hinder the positive effect of family resilience on FQOL. Regardless of family resilience levels, those who perceive high parental stress are likely to show a substantial decrease in their FQOL.\n\nFinally, in Model 4, we made sure that our previous relations do not substantially change by including demographic characteristics. Here, we show that demographic characteristics appear to have no significant relation with FQOL and at the same time, the previously found significant relations do not substantially change. Therefore, we can safely assume that the significant relations between parental stress & family resilience, on one hand, and FQOL, on the other, are not affected by individual characteristics.\n\n\nDiscussion and conclusion\n\nThe Covid-19 pandemic unquestionably has become an unparalleled challenge for families across the world, especially in Indonesia. Taken into account the most notably effect of the pandemic, namely economical and psychological impacts, we aim to answer to what extent the Covid-19 economic impact & parental stress during the pandemic are related to FQOL while moderated by family resilience in several cities of Indonesia. The results show mixed findings, with most of the proposed hypotheses are supported.\n\nFirst, although many reports show that the economic impact brought by the Covid-19 pandemic hit hard many families across the income level (SMERU et al., 2021), we do not find that this impact is negatively related to FQOL among our respondents. This conflicts with other previous studies that show when family’s material well-being is affected, such as due to unemployment change, their family interaction and parenting are more likely to be reduced (Tsai & Chen, 2017). Hence, the low FQOL is assumed. We offer two reasons regarding this finding. One, according to many reports, local governments were claimed to be cooperative efficiently with the central government of Indonesia in delivering aid to those who have lost employment and substantially reduced income due to the pandemic (Hanaf et al., 2020). In addition, several social assistance programs, such as the Family Hope Program (Program Keluarga Harapan; PKH) and food staples program through grocery card (Kartu Sembako) were quickly modified not only aimed for the lowest-income families but also for new beneficiaries who were affected by the pandemic (SMERU et al., 2021). In several areas, there were even cash transfer programs directly to the households. Therefore, although the economic impact was heavily felt families were still able to cope with economic assistances from the government. Second, closely related to the delivery time of the assistances, this study was conducted in the middle of 2021 where many government aids have started to be delivered (Saptoyo, 2021). Thus, the Covid-19 economic impact may have worn down and families have adapted to their new financial circumstances.\n\nOn the contrary, the assessed parental stress level during the pandemic is shown to be significantly related to FQOL. This is in line with the claim that impact of parental stress can spill-over to their relationship with the children and their children’s well-being (Berry & Jones, 1995). In this situation, the Covid-19 pandemic is considered to be a major stressor for the parents and hence, affecting their behaviours towards their children. Studies have shown that parents have a higher chance to experience burnout and perform ‘bad’ parenting, such as children maltreatment (Chung et al., 2020; Griffith, 2020; Lawson et al., 2020). As a consequence, the relationship between parents and child (ren) are impaired and most importantly, negatively affect their FQOL (Summers et al., 2005).\n\nNext, we have shown that family resilience is positively, directly, related to FQOL. As Prime et al. (2020) argue, family resilience should foster positive outcomes in times of Covid-19 among family members. Although the quality of relationships are most likely to be affected during the pandemic, those with high level of family resilience should be able to improve and maintain quality family relationships. Apart from that, Walsh (2016) suggests that in times of crisis such families will develop new ways of viewing challenges and thus, encouraging positive outlook out of the crisis.\n\nFurthermore, we have also confirmed the moderating effect of family resilience on the relation between the family stressor and FQOL. Specifically, on average, we find that our respondents are economically impacted by the Covid-19 pandemic (see Table 1). Although the impact is not related to FQOL, with family resilience we can claim that their FQOL is relatively maintained and even increased, even for families with a low level of family resilience. This finding corroborates previous studies that show family resilience help families in developing new ways of dealing with challenges relying on resources at their disposal (Li et al., 2019). Through well-functioning ways of seeing a crisis or challenge, flexibility among family members, and open communication, they can rely on each other and create a better decision-making in attempting to ameliorate their momentarily-deprived economy (Walsh, 2003). As a consequence, family resilience may foster positive psychological outcomes in times of crisis. However, this claim should be further studied since our study does not test any causality.\n\nIn spite of the direct relation between family resilience and FQOL, the buffering effect of family resilience is shown to be less effective in moderating the negative relation between parental stress and FQOL. This finding opens alternative explanations to the literature of family resilience as well as parental stress. First, parental stress during crisis times is highly likely to be heightened and thus, largely affect the way families navigate themselves in solving the crisis. Therefore, even when protective factors are present within the family, such as positive family relationships, parental stress will most likely still reduce many aspects of the quality of family life, such as parenting and family well-being (Tsai & Chen, 2017; Zuna et al., 2009b). Second, it shows a persisting effect of parental stress during crisis times. Unlike economic impact of Covid-19, parental stress seems to persist even when the pandemic has turned to one year. Keeping the Covid-19 pandemic situation in mind, this is logical because psychological help, extended family members’ help, and even neighbours’ help is still very limited due to health protocols during the pandemic. Therefore, parental stress is likely to persist in affecting FQOL. Finally, the finding opens a possible discussion that family resilience should be considered as a process and may work differently in different stages of crisis. Similar to the notion of resilience in general, family resilience should be viewed in its temporal context during the times of crisis (Masten, 2019).\n\nWe acknowledge a couple of limitations in this study. One, we realize that our small sample may not reflect the whole picture of the family situation across Indonesia. Conducting online survey in times of the pandemic apparently remains a challenge to many Indonesians, ranging from ‘too exhausted viewing screen’, less enthusiastic, low internet coverage, to a lack of skills in operating the application (Wisanti et al., 2021). Therefore, we were not able to acquire a desired sample size. Two, the study was a one-shot study. We do not have data on the variables of interests prior to the pandemic. Therefore, we cannot compare the disparity between the two conditions. Most importantly, we cannot draw any causal conclusion regarding the relations under study. We know that there is a different dynamic in the relationships between parental stress and family resilience and FQOL during the pandemic, but we cannot be sure to what extent the pandemic has brought changes to these relationships.\n\nIn conclusion, the findings of the study shed a light into family circumstances in Indonesia during the Covid-19 pandemic, which has not received adequate academic attention. We show that after a one-year experience of Covid-19, on average, respondents do not feel that the economic impact is negatively related to their FQOL. However, unlike the economic impact, parental stress is negatively related to the FQOL. This might be due to the many changes they had to undergo during the pandemic which has exacerbated their parental stress level. On a positive note, we find that family resilience can help families buffer the economic impact of the Covid-19 pandemic on their FQOL, although not so much with parental stress. Based on this, government agencies and other related parties should put more attention to offering psychological help to families through available mediums, e.g., social media and hotline numbers, that are Covid-19 proof.\n\n\nAuthor’s note\n\nThis research adheres to research ethics provided the Committee on Publication Ethics (COPE).",
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}
|
[
{
"id": "155874",
"date": "17 Nov 2022",
"name": "Tita Alissa Bach",
"expertise": [
"Reviewer Expertise healthcare",
"psychology",
"human factors",
"sociology",
"behavioural and social 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\nAbstract:\nThis is maybe due to the word limit, but the abstract is not very clear.\n\nGeneral feedback:\n\nAre Covid 19 measures still valid in Indonesia? This study seems to be focusing on as if the measures were still ongoing. please adjust more timely to what is happening now and put your study in this context. I understand this study happened in the past when the measures were still valid, and this is fine, but the way reads now, it feels as if it was still like that, which is not true. Otherwise, your study does not really feel so relevant now when most countries have moved on from Covid 19 measures. Maybe put in the context as \"lessons learned\", and then generalise/extrapolate your findings and study into how people can learn from your findings now when the measures have been lifted. I believe that family resilience is crucial to cope with challenges, not necessarily only during covid measures. So maybe approach your study as a case study during covid measures.\n\nIn the discussion, I feel the unique characteristics of Indonesia are not really put into account. Families being resilient can be different in different countries due to local/cultural aspects. How is this for your findings in Indonesia?\n\nWhy were participants only recruited from local universities? To my knowledge, married couples are more limited there.\n\nIt seems to be very ambitious to recruit the whole country. What was the reason not to target a specific study population? This is a survey study that can be done in collaboration with for example a maternity clinic, or wherever families/married couples hang around. In addition, targeting a study population will enable calculation of a response rate, which is lacking in your study. Once a response rate is available, non-response bias can be evaluated as this is a big factor for survey studies.\n\nYou mention that you involved \"participants from all around the archipelago\" - yet only included several big cities. It is probably best to adjust these sentences? Also because in the same paragraph, you said \"although we did not aim for a nationwide generalizability...\" then why mention in the first place that you recruited the whole nation?\n\nIn which language was the survey for participants? Was the original survey (presumably in English) translated to Indonesian? How was the process? How was the Indonesian version validated?\n\nAlthough it is negative findings based on Table 3, please discuss why demographic information does not influence.\n\nHave you considered cultural differences as a factor here? Bandung and Jakarta may be rather similar, but when you start to involve Makassar and Ambon that can have different cultural attributes, this can explain some of your findings. Indonesia is too big to assume coherent and similar cultural factors and beliefs.\n\nWhy only include typical demo info? What can make up resilience apart from included demo info? Could it be how long the couples have been married, whether both parents work, whether parents live together or live with other family members, access to support important for family resilience?\n\nIs the survey available for free for replication of your study?\n\nIf the survey is online, do you have data for the average time someone took to finish the survey? You wrote that it takes about 15-20 minutes, is this the case though for your participants?\n\nIndividual characteristics:\n\"number of children\" not child.\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?\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? Yes",
"responses": [
{
"c_id": "9109",
"date": "05 Jan 2023",
"name": "Tery Setiawan",
"role": "Author Response",
"response": "We would like to truly thank the reviewer for very insightful remarks and suggestions for the manuscript. We believe that your feedback has helped the manuscript greatly improve. The followings are responses to your remark/suggestion: Response to Reviewer 1 Comments Abstract: This is maybe due to the word limit, but the abstract is not very clear. Response: Thank you for your feedback on our abstract. We have added more information to revise the abstract accordingly. General feedback: Are Covid 19 measures still valid in Indonesia? This study seems to be focusing on as if the measures were still ongoing. please adjust more timely to what is happening now and put your study in this context. I understand this study happened in the past when the measures were still valid, and this is fine, but the way reads now, it feels as if it was still like that, which is not true. Otherwise, your study does not really feel so relevant now when most countries have moved on from Covid 19 measures. Maybe put in the context as \"lessons learned\", and then generalise/extrapolate your findings and study into how people can learn from your findings now when the measures have been lifted. I believe that family resilience is crucial to cope with challenges, not necessarily only during covid measures. So maybe approach your study as a case study during covid measures. Response: Thank you for your suggestion on extrappolating the current findings. We agree that, indeed, the findings can be generalized to different circumstances. For that, we have revised it accordingly. The revision is incorporated in the following part (of the last paragraph of the text) : “Finally, the current findings suggest that unexpected challenge or a sudden change is inevitably part of every family life. One way to overcome this is by adapting family resilience as a system, in which the adaptation is largely dependent on the way family members utilize their relationship and exchange of social support (Masten, 2019).” In the discussion, I feel the unique characteristics of Indonesia are not really put into account. Families being resilient can be different in different countries due to local/cultural aspects. How is this for your findings in Indonesia? Response: Thank you for your comment on the unique characteristics of Indonesian families. We agree with this and we have responded to the comment accordingly in the text. The revision is incorporated in the following part: “In addition, we should also take into account by which family systems work in Indonesia. Reciprocation between parents and children are still regarded highly in the Asian context, including Indonesia (Tsai & Chen, 2017).” Why were participants only recruited from local universities? To my knowledge, married couples are more limited there. Response: Thank you for your comment on this. We agree that we should have been more clear on the reason of recruiting from local universities. We have revised it accordingly in the text. The revision is incorporated in the following part: “Employing networks of local universities enable us to reach alumni and their extended networks.” It seems to be very ambitious to recruit the whole country. What was the reason not to target a specific study population? This is a survey study that can be done in collaboration with for example a maternity clinic, or wherever families/married couples hang around. In addition, targeting a study population will enable calculation of a response rate, which is lacking in your study. Once a response rate is available, non-response bias can be evaluated as this is a big factor for survey studies. Response: Thank you for your comment on the data collection procedure. We agree that having a cooperation with certain institutions would enable us gather a specific set of sample and thus, enabling us to calculate a sampling representativeness. However, the aim of the study itself was to capture FQOL from various areas where we were able to access in such a short time. Therefore, this was the best solution available at the time. You mention that you involved \"participants from all around the archipelago\" - yet only included several big cities. It is probably best to adjust these sentences? Also because in the same paragraph, you said \"although we did not aim for a nationwide generalizability...\" then why mention in the first place that you recruited the whole nation? Response: Thank you for your correction. We completely agree to revise such statements. The revision is incorporated in the following part: “This study was conducted online from August 2021 until October 2021 using Qualtrics covering a wide coverage of Indonesia”. In which language was the survey for participants? Was the original survey (presumably in English) translated to Indonesian? How was the process? How was the Indonesian version validated? Response: Thank you for your comment on the process of the translation. We agree that we should have made it more explicit in the text. Therefore, we have revised the part accordingly. The revision is incorporated in the following part: “To serve the purpose of this study, we translated the measures into Indonesian language. Specifically for parental stress and family resilience measures, we checked our translation with the Indonesian studies that have involved the measures previously...” Although it is negative findings based on Table 3, please discuss why demographic information does not influence. Response: We have added a plausible explanation in response to this. The revision is incorporated in the following part: “It is also worth discussing why demographic characteristics are not related to the FQOL. First, by the time the survey was underway, most family members, irrespective of their gender, education and a number of children, were experiencing a similar change in their quality of life. After all, the Covid-19 pandemic has been shown to affect most, if not all, families in Indonesia (SMERU et al., 2021)…” Have you considered cultural differences as a factor here? Bandung and Jakarta may be rather similar, but when you start to involve Makassar and Ambon that can have different cultural attributes, this can explain some of your findings. Indonesia is too big to assume coherent and similar cultural factors and beliefs. Response: Thank you for your remark on the cultural differences. We acknowledge that local cultural differences might have played a role in determining our findings. However, we do not have sufficient information to infer such arguments. Although we have incorporated your remark on this in our study limitation in a discussion section. The revision is incorporated in the following part: “One, we realize that our small sample may not reflect the whole picture of the family situation across Indonesia and therefore, we cannot infer anything about local cultural differences across the regions These differences, of course, might have played a role in determining the level of FQOL.” Why only include typical demo info? What can make up resilience apart from included demo info? Could it be how long the couples have been married, whether both parents work, whether parents live together or live with other family members, access to support important for family resilience? Response: Thank you for your comment and we completely agree with this. In conducting this study, we were warned of the ‘online exhaustion’ among people during the Covid-19 pandemic. Therefore, we had to sacrifice some of the important questions, such as the ones you mentioned, to ensure that the completion rate is quite enough for us to compute the main analyses. Nevertheless, we have also incorporated this information in our study limitation to encourage others scholars to include them in future studies. The revision is incorporated in the following part: “The anticipation of ‘online exhaustion’ also encouraged us to reduce a number of questions, such as years of marriage and co-residing with parent(s), so that we would still have a high completion rate.” Is the survey available for free for replication of your study? Response: Thank you for your question. Yes, the survey, along with its protocol, is available online so that other scholars are able to replicate the study. The statement is incorporated in the following part: “The protocol, along with the measures employed in this study, can be used for replication and future studies.” If the survey is online, do you have data for the average time someone took to finish the survey? You wrote that it takes about 15-20 minutes, is this the case though for your participants? Response: Thank you for your valuable question on the completion time. We have responded to the question accordingly in the text. The revision is incorporated in the following part: “In the end, we did not compute the time average taken by participants, because we set the online survey to allow participants to take a break during their participation thus, allowing multiple sessions or even days to finish the full questionnaire.” Individual characteristics: \"number of children\" not child. Response: Thank you for your correction. We have revised it accordingly."
}
]
},
{
"id": "155877",
"date": "01 Dec 2022",
"name": "Christiany Suwartono",
"expertise": [
"Reviewer Expertise social psychology",
"psychometrics",
"forgiveness",
"and positive psychology."
],
"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 was conducted when there was a sharp increase of Covid-19 positive cases in July - August 2021, and it declined during September 2021. The authors conducted an interesting study and the article makes an early contribution to the knowledge of family dynamics and economic conditions during Covid-19 in Indonesia - although the coverage of the geographic area in this research needs to be noted.\n\nThe abstract needs to be improved especially in the method section and results.\n\nKeywords can also be improved - as a suggestion: covid-19 economic impact.\nMethods:\nIt was a good initiative and practice to publish the study protocol before the authors conduct the research. It allows other researchers to replicate this research.\n\nDemographic data:\nThe results found that Covid-19 economic impact was not significant; the authors should inform the reader more about demographic data from this sample: like the number of children in frequency (or %). A family consisting of a small number of children will have different economic burdens. Also with other categories variables: gender, and educational background. Did the authors ask about the participant's employment status?\n\nHow about the distribution of responses regarding respondents’ change of income and expense? How many of the participants responded that their income/expense is reduced or income/expense is increased? (The authors wrote three options about this one).\n\nMaybe this descriptive analysis can contribute to the result explanation of this research. The authors could add one more table to describe.\n\nThe covid-19 economic, family resilience, parental stress, and family quality of life findings were interesting. Based on the demographic data of the majority of the participants; did the authors consider that the children's age range, cultural role, and geography might influence the variables of interest?\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?\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": "9110",
"date": "05 Jan 2023",
"name": "Tery Setiawan",
"role": "Author Response",
"response": "We truly thank the reviewer for very insightful remarks and suggestions for the manuscript. We believe that your feedback has helped the manuscript greatly improve. The following are responses to your remarks/suggestions. Response to Reviewer 2 Comments: The research was conducted when there was a sharp increase of Covid-19 positive cases in July - August 2021, and it declined during September 2021. The authors conducted an interesting study and the article makes an early contribution to the knowledge of family dynamics and economic conditions during Covid-19 in Indonesia - although the coverage of the geographic area in this research needs to be noted. The abstract needs to be improved especially in the method section and results. Response: Thank you for your suggestion on the abstract. We agree and therefore, have revised it accordingly. Keywords can also be improved - as a suggestion: covid-19 economic impact. Response: Thank you for your suggestion on the keyword. We have added your suggested keyword to the list of keywords. Methods: It was a good initiative and practice to publish the study protocol before the authors conduct the research. It allows other researchers to replicate this research. Response: Thank you for your encouragement. We also believe that providing protocol and materials are necessary for replication as well as further future investigations. Demographic data: The results found that Covid-19 economic impact was not significant; the authors should inform the reader more about demographic data from this sample: like the number of children in frequency (or %). A family consisting of a small number of children will have different economic burdens. Also with other categories variables: gender, and educational background. Did the authors ask about the participant's employment status? Response: Thank you for your input on demographic information. We agree with this suggestion and we have provided such information in the text. We have also provided a new table as you suggested. In response to your question on the employment status, yes, we asked participants such information. This information is now available in the new table (Table 2) How about the distribution of responses regarding respondents’ change of income and expense? How many of the participants responded that their income/expense is reduced or income/expense is increased? (The authors wrote three options about this one). Response: Thank you for your feedback on providing more information of respondents’ change of income and expense. This information is now available in the new table (Table 2). Maybe this descriptive analysis can contribute to the result explanation of this research. The authors could add one more table to describe. Response: Thank you for your suggestion on adding more information of the descriptive analysis. We have now provided a new table (Table 2) containing frequency of several demographic information to be used later in discussing the findings. Next to this, we have provided an additional explanation as to why we find no evidence on the relation between economic impact of the Covid-19 pandemic and FQOL. The revision is incorporated in the following part (of discussion): “Three, we notice that most of our participants did not report a substantial decrease in income due to the pandemic. This is also in line with a large number of employees and housewife/husband (and a considerable number of entrepreneur) who reported no change…” The covid-19 economic, family resilience, parental stress, and family quality of life findings were interesting. Based on the demographic data of the majority of the participants; did the authors consider that the children's age range, cultural role, and geography might influence the variables of interest? Response: Thank you for your remark on the cultural differences. We acknowledge that local cultural differences might have played a role in determining our findings. Even though we do not have sufficient information to infer such arguments, we have provided this as an alternative explanation which, of coure, should be further investigated. The revision is incorporated in the following part: “In addition, we should also take into account by which family systems work in Indonesia. Reciprocation between parents and children are still regarded highly in the Asian context, including Indonesia (Tsai & Chen, 2017).”"
}
]
}
] | 1
|
https://f1000research.com/articles/11-1279
|
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